Q2 2021 Revolution Medicines Inc Earnings Call

August 11, 2021

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Operator: Good day, ladies and gentlemen, and welcome to the Revolution Medicine second quarter fiscal year 2021 financial results conference call and webcast. At this time, all participants are in a listen-only mode. Following Mary's prepared remarks, we will have a question and answer session. To ask a question at that time, please press star followed by the number on your touchtone telephone. Please be advised that today's conference call is being recorded. If anyone has difficulty hearing the conference, please press star zero for the operator. I would now like to hand the conference over to Peg Horn, Revolution's Chief Operating Officer, for opening remarks. Peg, you may begin.

Operator 1: Good day, ladies and gentlemen, and welcome to the Revolution Medicines Q2 fiscal 2021 financial results conference call and webcast. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will have a question and answer session. To ask a question at that time, please press star followed by 1 on your touchtone telephone. Please be advised that today's conference call is being recorded. If anyone has difficulty hearing the conference, please press star zero for operator assistance. I would now like to hand the conference over to Peg Horn, Revolution's Chief Operating Officer, for opening remarks. Peg, you may begin.

Operator: Good day, ladies and gentlemen, and welcome to the Revolution Medicines Q2 fiscal 2021 financial results conference call and webcast. At this time, all participants are on a listen-only mode. Following management's prepared remarks, we will have a question and answer session. To ask a question at that time, please press star followed by the one on your touchtone telephone. Please be advised that today's conference call is being recorded.

Good day, ladies and gentlemen, and welcome to the Revolution Medicine second quarter fiscal 2021 financial results conference call and webcast. At this time all participants are in a listen only mode.

Following managements prepared remarks, we will have a question and answer session.

Ask a question at that time, Please press star followed by the one on your Touchtone telephone.

Leaves me about to today's conference call is being recorded.

Operator: If anyone has difficulty hearing the conference, please press star zero for operator assistance. I would now like to hand the conference over to Peg Horn, Revolution's Chief Operating Officer, for opening remarks. Peg, you may begin.

Anyone has difficulty hearing the conference. Please press star zero for operator, I would now like to hand, the conflict over to Peg Horn revolutions, Chief operating officer for opening remarks, Craig you may begin.

Peg Horn: Good afternoon, everyone, and thank you all for joining us today. Joining me on today's call are Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer, Dr. Steve Kelsey, the Company's President of Research and Development, and Jack Anders, our Senior Vice President of Finance and Principal Accounting Officer. As we begin, I'd like to caution you that our presentation today will contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act regarding the current beliefs of the company with respect to our business. These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statements.

Margaret Horn: Good afternoon, everyone, and thank you all for joining us today. Joining me on today's call are Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer, Dr. Steve Kelsey, the Company's President of Research and Development, and Jack Anders, our Senior Vice President of Finance and Principal Accounting Officer. As we begin, I'd like to caution you that our presentation today will contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act regarding the current beliefs of the company with respect to our business.

Margaret A. Horn: Good afternoon, everyone, and thank you all.

Good afternoon, everyone and thank you all for joining US today joining me on today's call are Dr. Mark Goldsmith Revolutions, Chairman and Chief Executive Officer, Dr. Steve <unk>, The company's President research and development and Jack Anders Our senior Vice President of Finance and principal accounting officer.

Margaret A. Horn: Thank you all for joining us today.

Margaret A. Horn: Hall, Dr. Mark Goldsmith, Revolutions Chairman and Chief Executive Officer, Dr. Stephen Kelsey

Margaret A. Horn: Dr. Steve Kelsey, the company's President of Research and Development, and Jack Anders, our Senior Vice President of Finance and Principal Accounting.

Margaret A. Horn: As we begin, I'd like to caution you that our presentation today will contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act regarding the current beliefs of the company with respect to our

As we begin I'd like to caution you that our presentation today will contain forward looking statements within the meaning of the private Securities Litigation Reform Act regarding the current beliefs of the company with respect to our business. These statements are subject to a number of assumptions risks and uncertainties actual results may.

Margaret Horn: These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statements.

Margaret A. Horn: These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statement. I encourage you to review the legal disclaimer slide we are presenting today.

Differ materially from these statements and except as required by law. The company undertakes no obligation to revise or update any forward looking statements I encourage you to review the legal disclaimer slide Europe, presenting today as well as all of the Companys filings with the SEC concerning these and other matters.

Peg Horn: I encourage you to review the legal disclaimer slide we are presenting today, as well as all of the company's filings with the SEC concerning these other matters. During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call. With that, I will turn the call over to Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer. Mark?

Margaret Horn: I encourage you to review the legal disclaimer slide we are presenting today, as well as all of the company's filings with the SEC concerning these other matters. During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call. With that, I will turn the call over to Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer. Mark?

Margaret A. Horn: Presenting today, as well as all of the company's filings with the SEC concerning these other matters. During this presentation, we will be referring to a few

During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call.

Mark A. Goldsmith: Your presentation will be posted to our website immediately prior to this call. With that, I will turn the call over to Dr. Mark Goldsmith.

With that I will turn the call over to Dr. Mark Goldsmith Revolutions, Chairman and Chief Executive Officer Mark.

Mark A. Goldsmith: Thank you and good afternoon. This is Revolution Medicine's first earnings call, and we look forward to having this opportunity to connect with our investors on a regular basis. After our prepared remarks today, we will host a Q&A session.

Mark Goldsmith: Thank you and good afternoon. Welcome to our Q2 earnings call. This is Revolution Medicines' first earnings call, and we look forward to having this opportunity to connect with our investors on a regular basis. After our prepared remarks today, we will host a Q&A session. Treatment for RAS-addicted cancers reached an important milestone in Q2 with the first FDA approval of a targeted medicine for lung cancer carrying the KRAS G12C mutation, Amgen's Lumakras or sotorasib. Likewise, R&D at Revolution Medicines continued making excellent progress, reinforcing our belief that the company's innovative and cohesive asset portfolio can drive rational, mechanism-based, and beneficial combination treatments for patients with RAS-addicted cancers. Our ambition is to serve remaining and significant unmet needs for patients with KRAS G12C positive tumors and even larger opportunities to benefit those with cancers driven by other non-G12C RAS variants, as shown on slide four.

Thank you and good afternoon welcome to our Q2 earnings call. This is revolution medicines first earnings call and we look forward to having this opportunity to connect with our investors on a regular basis. After our prepared remarks today, we will host a Q&A session.

Mark A. Goldsmith: Treatment for RAS-addicted cancers reached an important milestone in Q2, with the first FDA approval of a targeted medicine for lung cancer carrying the KRAS-G12C mutation, Amgen's Lumicras or Sotiracib. Likewise, R&D at Revolution Medicines continued making excellent progress, reinforcing our belief that the company's innovative and cohesive asset portfolio can drive rational, mechanism-based, and beneficial combination Our ambition is to serve remaining and significant unmet needs for patients with K-RAS G12C positive tumors, and even larger opportunities to benefit those with cancers driven by other non-G12C RAS variants, as shown on slide 4.

Treatment for rapid they could cancers reached an important milestone in Q2 with the first FDA approval of a targeted medicine for lung cancer carrying the <unk> mutation Amgen Luna crafts or soda rapid.

Mark Goldsmith: Likewise, R&D at Revolution Medicines continued making excellent progress, reinforcing our belief that the company's innovative and cohesive asset portfolio can drive rational, mechanism-based, and beneficial combination treatments for patients with RAS-addicted cancers. Our ambition is to serve remaining and significant unmet needs for patients with KRAS G12C positive tumors and even larger opportunities to benefit those with cancers driven by other non-G12C RAS variants, as shown on slide four.

Likewise R&D at Revolution medicines continued making excellent progress reinforcing our belief that the company's innovative and cohesive asset portfolio can drive rational mechanism based and beneficial combination treatments for patients with Ras addicted cancers.

Our ambition is to serve remaining and significant unmet needs for patients with <unk> positive tumors, and even larger opportunities to benefit those with cancers driven by other non <unk> variance as shown on slide four.

Mark A. Goldsmith: Today we will highlight important progress we've made on our exciting tricomplex RAS-ON inhibitors that extends the momentum we've described previously. We will also provide an update on several aspects of RMC4630, an advanced and important asset in our RAS companion inhibitor portfolio. We will report on two combination drug strategies that have been under evaluation in the RMC-4630-02 study. The so-called clamping approach, with our SHIP2 inhibitor RMC4630 in combination with the MEK inhibitor CoB-Metnib directed against advanced RAS-addicted cancers lacking a targeted RAS inhibitor. And a second approach with RMC4630 combined with the EGF receptor inhibitor osimertinib aiming to enhance clinical benefit in EGF receptor mutant lung cancer.

Mark Goldsmith: Today, we will highlight important progress we've made on our exciting tri-complex RAS(ON) inhibitors that extends the momentum we've described previously. We will also provide an update on several aspects of RMC-4630, an advanced and important asset in our RAS Companion Inhibitors portfolio. We will report on two combination drug strategies that have been under evaluation in the RMC-4630-02 study. The so-called clamping approach with our SHP2 inhibitor RMC-4630 in combination with the MEK inhibitor cobimetinib, directed against advanced RAS-addicted cancers lacking a targeted RAS inhibitor. A second approach with RMC-4630, combined with the EGFR inhibitor osimertinib, aiming to enhance clinical benefit in EGFR mutant lung cancer.

Today, we will highlight important progress we've made on our exciting try complex Ras on inhibitors that extends the momentum. We've described previously we.

We will also provide an update on several aspects of RMC 4630, and advanced an important asset in our Ras companion inhibitor portfolio.

We will report on to combination drug strategies that have been under evaluation in the RMC 463002 study.

Mark Goldsmith: The so-called clamping approach with our SHP2 inhibitor RMC-4630 in combination with the MEK inhibitor cobimetinib, directed against advanced RAS-addicted cancers lacking a targeted RAS inhibitor. A second approach with RMC-4630, combined with the EGFR inhibitor osimertinib, aiming to enhance clinical benefit in EGFR mutant lung cancer.

The so-called clamping approach with our ship two inhibitor <unk> in combination with the NEC inhibitor Kobe met nib directed against advanced Ras addicted cancers, lacking a targeted Ras inhibitor.

And a second approach with RMC for six <unk> combined with the EGF receptor inhibitor off the merit to nib aiming to enhance clinical benefit and EGF receptor mutant lung cancer.

Mark A. Goldsmith: We will also explain our continued commitment to treatment strategies combining a direct RAS inhibitor with RMC4630, and we'll announce an exciting high-priority combination study sponsored by Revolution Medicines evaluating RMC4630 in combination with sodoracib in KRAS G12C positive lung cancer under a new clinical trial collaboration and supply agreement with Amgen that builds on and is a complement to the Code Break 101 trial exploring this combination across multiple cancer The ARMC 4630-03 study is designed to allow us to better define patients who may most benefit from the combination of our SHIP-2 inhibitor with the KRAS G12C inhibitor through analysis of cohorts with and without certain mutations. Steve Kelsey, Revolution's President of R&D, will provide more information on the new O3 study and our other clinical programs after I provide an update on our RAS-ON inhibitors.

Mark Goldsmith: We will also explain our continued commitment to treatment strategies combining a direct RAS inhibitor with RMC-4630, and we'll announce an exciting high priority combination study sponsored by Revolution Medicines evaluating RMC-4630 in combination with sotorasib in KRAS G12C-positive lung cancer under a new clinical trial collaboration and supply agreement with Amgen that builds on and is a complement to the CodeBreaK 101 trial exploring this combination across multiple cancer types. The RMC-4630-03 study is designed to allow us to better define patients who may most benefit from the combination of our SHP2 inhibitor with the KRAS G12C inhibitor through analysis of cohorts with and without certain co-mutations.

We will also explain our continued commitment to treatment strategies, combining a direct ras inhibitor with RMC for six REO.

And we will announce an exciting high priority combination study sponsored by Revolution medicines evaluating RMC for six trio in combination with <unk> in <unk> positive lung cancer under a new clinical trial collaboration and supply agreement with Amgen that builds on and is a complement to the COVID-19 break.

101 trial exploring this combination across multiple cancer types.

Mark Goldsmith: The RMC-4630-03 study is designed to allow us to better define patients who may most benefit from the combination of our SHP2 inhibitor with the KRAS G12C inhibitor through analysis of cohorts with and without certain co-mutations.

The RMC for <unk> III study is designed to allow us to better define patients who made most benefit from the combination of our ship two inhibitor with a <unk> inhibitor through analysis of cohorts with and without certain co mutations.

Mark Goldsmith: Steve Kelsey, Revolution's President of R&D, will provide more information on the new 03 study and our other clinical programs after I provide an update on our RAS(ON) inhibitors. For KRAS G12C positive lung cancer and colorectal cancer in particular, we continue to believe there's an opportunity to increase clinical response rates and/or durability. As suggested by this table on slide 5, summarizing some key outcomes reported with first generation KRAS G12C off inhibitors so far, that show both the clinical benefit of targeted drugs and areas of ongoing opportunities. With these unmet needs in mind, we are pursuing development of several new RAS(ON) inhibitors. A key element of the strategy for our KRAS G12C ON inhibitor is consistent with the successful generational paradigm established previously with advanced generation targeted inhibitors for tumors with EGF receptor mutations.

Mark Goldsmith: Steve Kelsey, Revolution's President of R&D, will provide more information on the new O3 study and our other clinical programs after I provide an update on our RAS(ON) inhibitors. For KRAS G12C positive lung cancer and colorectal cancer in particular, we continue to believe there's an opportunity to increase clinical response rates and/or durability. As suggested by this table on slide five, summarizing some key outcomes reported with first generation KRAS G12C RAS(OFF) inhibitors so far, that show both the clinical benefit of targeted drug and areas of ongoing opportunities.

Steve Kelsey revolutions, President of R&D, who will provide more information on the new <unk> III study and our other clinical programs. After I provide an update on our RASK on inhibitors.

Mark A. Goldsmith: For KRAS G12C positive lung cancer and colorectal cancer in particular, we continue to believe there's an opportunity to increase clinical response rates and or durability, as suggested by this table on slide five, summarizing some key outcomes reported with first generation KRAS G12C off inhibitors so far that show both the clinical benefit of targeted drugs and areas of ongoing opportunity. With these unmet needs in mind, we are pursuing the development of several new RAS-ON inhibitors.

For <unk> <unk> positive lung cancer and colorectal cancer in particular, we continue to believe there is an opportunity to increase clinical response rates <unk> durability as suggested by this table on slide five summarizing some key outcomes reported with first generation <unk>.

<unk> inhibitor, so far that show, both the clinical benefit of targeted drug and areas of ongoing opportunities.

Mark Goldsmith: With these unmet needs in mind, we are pursuing development of several new RAS(ON) inhibitors. A key element of the strategy for our KRAS G12C (ON) inhibitor is consistent with the successful generational paradigm established previously with advanced generation targeted inhibitors for tumors with EGF receptor mutations.

With these unmet needs in mind, we are pursuing development of several new Ras on inhibitors.

Mark A. Goldsmith: A key element of the strategy for our KRAS G12C ON inhibitor is consistent with the successful generational paradigm established previously with advanced generation targeted inhibitors for tumors, with EGF Receptor Mutation. In Q1 of 2021, we introduced the compelling profile of the development candidate RMC6291, our first-in-class potent oral and selective tricomplex inhibitor for KRAS G12C, as summarized on slide 10. Expanding from earlier examples shown previously, in Q2, we reported additional examples of deeper, more uniform, and or more sustained anti-tumor effects in xenograft KRAS-G12C cancer models compared to a first-generation RAS-off inhibitor.

A key element of the strategy for our <unk> inhibitor is consistent with the successful generational paradigm established previously with advanced generation targeted inhibitors for tumors.

With EGF receptor mutations.

Mark Goldsmith: In Q1 of 2021, we had introduced the compelling profile of a development candidate, RMC-6291, our first-in-class potent oral and selective tri-complex inhibitor for KRAS G12C, as summarized on slide 10. Expanding from earlier examples shown previously, in Q2, we reported additional examples of deeper, more uniform, and/or more sustained antitumor effects in xenograft KRAS G12C cancer models compared to a first-generation RAS-OFF inhibitor. These experiments are part of a growing body of evidence that RMC-6291 has best-in-class potential among KRAS G12C inhibitors. Also in Q2, various newly emergent RAS or RAS pathway mutations were reported in 39% of patients exhibiting resistance to treatment with adagrasib. The described mutations provide a critical roadmap for treatment approaches to combat these mechanisms of clinical failure.

In Q1 of 2021, we had introduced introduced the compelling profile of a development candidate RMC six to 91, our first in class potent oral and selective try complex inhibitor for <unk> as summarized on slide 10.

Expanding from earlier examples shown previously in Q2, we reported additional examples of deeper more uniform Andrew a more sustained anti tumor effects in xenograft here atrophy 12 feet cancer models compared to a first generation Ras off inhibitor.

Mark Goldsmith: These experiments are part of a growing body of evidence that RMC-6291 has best-in-class potential among KRAS G12C inhibitors. Also in Q2, various newly emergent RAS or RAS pathway mutations were reported in 39% of patients exhibiting resistance to treatment with adagrasib. The described mutations provide a critical roadmap for treatment approaches to combat these mechanisms of clinical failure.

These experiments are part of a growing body of evidence that RMC 69, one has best in class potential among <unk> <unk> inhibitors.

Also in Q2, various newly emergent Ras or Ras pathway mutations were reported and 39% of patients exhibiting resistance to treatment with that are granted and the described mutations provide a critical roadmap for treatment approaches to combat these mechanisms of clinical failure.

Mark Goldsmith: As shown in this table on slide 14, the company has expanded on initial results published in Cancer Discovery by Dr. Ryan Corcoran's team at the Massachusetts General Hospital and Harvard Medical School, by demonstrating that RMC-6291 is active against all second site resistance mutations reported thus far from patients treated with adagrasib. As many of these mutations also confer resistance to sotorasib and other KRAS G12C off inhibitors, the activity of RMC-6291 in this setting illustrates a distinguishing property of the molecule that may be useful for preventing or treating emergence of these resistance mutations. RMC-6291 continues on track in its IND-enabling development program toward its expected IND filing in H1 2022.

As shown in this table on slide 14. The company has expanded on initial results published in cancer discovery by Dr. Brian <unk> team at the Massachusetts General Hospital, and Harvard Medical School.

By demonstrating that RMC 60, 91 is active against all second sight resistance mutations reported thus far from patients treated with <unk>.

Mark Goldsmith: As many of these mutations also confer resistance to sotorasib, and other KRAS G12C OFF inhibitors, the activity of RMC-6291 in this setting illustrates a distinguishing property of the molecule that may be useful for preventing or treating emergence of these resistance mutations. RMC-6291 continues on track in its IND-enabling development program toward its expected IND filing in H1 2022.

As many of these mutations also confer resistance to <unk> and other K restaurant towards the off inhibitors. The activity of <unk> 91 in this setting illustrates the distinguishing property of the molecule that may be useful for preventing or treating emergence of these resistance mutations RMC 69, one continues on.

Mark A. Goldsmith: As shown in this table on slide 14, the company has expanded on initial results published in Cancer Discovery by Dr. Ryan Corcoran's team at the Massachusetts General Hospital and Harvard Medical School by demonstrating that RMC6291 is active against all second site resistance mutations reported thus far from patients treated with Adagracib. As many of these mutations also confer resistance to sodoracib and other KRAS G12C-off inhibitors, the activity of OMC6291 in this setting illustrates a distinguishing property of the molecule that may be useful for preventing or treating the emergence of these resistance mutations. RMC 1691 continues on track in its IND Enabling Development Program toward its expected IND filing in the first half of 2020-2022.

Tracking its IND, enabling development program toward its expected IND filing in the first half of 2000.2022.

Mark Goldsmith: We also showed additional progress in addressing non-G12C oncogenic RAS variants, which account for approximately 85% of all incident RAS-addicted cancers and for which no targeted treatments are available. Earlier in 2021, we had described the compelling profile of our second development candidate, RMC-6236, a first-in-class potent oral RAS-selective tri-complex inhibitor for multiple variants of RAS, as summarized on slide 17. Expanding from earlier examples of KRAS G12V and KRAS G12D cancer models shown previously, in Q2, we described additional preclinical data in a growing body of evidence that RMC-6236 has first-in-class and best-in-class potential for treating KRAS G12V and/or KRAS G12D tumors across multiple histotypes.

We also showed additional progress in addressing non G. <unk> oncogenic, Ras variance, which account for approximately 85% of all incident, Ras addicted cancers and for which no targeted treatments are available.

Earlier in 2021, we have described the compelling profile of our second development candidate RMC 63, six a first in class potent oral and Ras selective try complex inhibitor for multiple variants of Ras as summarized on slide 17.

Mark Goldsmith: Expanding from earlier examples of KRAS G12V and KRAS G12D cancer models shown previously, in Q2, we described additional preclinical data in a growing body of evidence that RMC-6236 has first-in-class and best-in-class potential for treating KRAS G12V and/or KRAS G12D tumors across multiple histotypes.

Expanding from earlier examples of K, Ras <unk> V and <unk> 12 D cancer model shown previously in Q2, we described additional preclinical data and a growing body of evidence that RMB 63, six is first in class and best in class potential for treating <unk> and or <unk>.

Mark A. Goldsmith: We also showed additional progress in addressing non-G12C oncogenic RAS variants, which account for approximately 85% of all incident RAS-addicted cancers and for which no targeted treatments are available. Earlier in 2021, we had described the compelling profile of our second development candidate, RMC6236, a first-in-class, potent, oral, and RAS-selective tricomplex inhibitor for multiple variants Expanding from earlier examples of KRAS G12V and KRAS G12D cancer models shown previously, in Q2, we described additional preclinical data in a growing body of evidence that RMC6236 has first-in-class and best-in-class potential for treating KRAS G12V and KRAS G12D tumors across multiple histotypes.

<unk> 12, the tumors across multiple hits the types.

Mark Goldsmith: Among the multiple resistance mechanisms, resistance mutations in adagrasib-treated patients that were reported in Q2, a notable group of emergent RAS variants was described that are expected to be insensitive to KRAS G12C off inhibitors and to RMC-6291. As shown on slide 22, these mutations include new substitutions at KRAS G12 in the upper panel, KRAS G13 in the lower panel, and NRAS Q61 also in the lower right panel. Importantly, we've now shown in preclinical experiments that RMC-6236 is active against all of these clinically observed variants, as well as a broader panel of KRAS G12 mutants that to date haven't been described in patients.

Mark Goldsmith: Among the multiple resistance mechanisms, multiple resistance mutations in adagrasib-treated patients that were reported in Q2, a notable group of emergent RAS variants was described that are expected to be insensitive to KRAS G12C off inhibitors and to RMC-6291. As shown on slide 22, these mutations include new substitutions at KRAS G12 in the upper panel, KRAS G13 in the lower panel, and NRAS Q61 also in the lower right panel.

Among the multiple resistance mechanisms of resistance mutations in the <unk> treated patients that were reported in Q2.

Notable group of emergent Ras variance was described that are expected to be insensitive to <unk> inhibitors, and two RMC six to 91.

As shown on slide 2022 Slide 22. These mutations include new substitution at <unk> 12 in the upper panel K Ras <unk> 13 in the lower panel and <unk> 61 also in the lower right panel.

Mark Goldsmith: Importantly, we've now shown in preclinical experiments that RMC-6236 is active against all of these clinically observed variants, as well as a broader panel of KRAS G12 mutants that to date haven't been described in patients.

Importantly, we've now shown in preclinical experiments that RMC 63, six is active against all of these clinically observed variance as well as a broader panel of <unk> 12 mutants.

To date haven't been described in patients hence.

Mark Goldsmith: Hence, these findings indicate that RMC-6236 has important properties that may be useful for preventing or treating emergence of these RAS oncogene switch resistance mutations. In Q2, we also reported information about the potential for additive benefit in combinations of either RMC-6291 or RMC-6236 with a checkpoint inhibitor. For example, shown on the left of slide 26, in immunocompetent mice engrafted with the syngeneic RAS mutant tumor, RMC-6236 induced a favorable transformation of the tumor immune microenvironment, characterized by an increase in infiltrating CD8 T-cells and a decrease in immune suppressive M2 macrophages. As shown on the right, RMC-6236 alone was quite active against growth of these syngeneic tumor grafts, including inducing a number of complete responses.

Hence these findings indicate that RMC 63, six is important properties that may be useful for preventing or treating emergence of these ras oncogene switch resistance mutations.

In Q2, we also reported information about the potential for additive benefit and combinations of either RMC 69, one or RMC 63, six with a checkpoint inhibitor.

Mark A. Goldsmith: Among the multiple resistance mechanisms, resistance mutations in adagrassib-treated patients that were reported in Q2, a notable group of emergent RAS variants was described that are expected to be insensitive to KRAS G12C off-inhibitors and to RMC6291. As shown on slide 22, these mutations include new substitutions at KRAS G12 in the upper panel, KRAS G13 in the lower panel, and NRAS Q61 also in the lower right panel.

Mark Goldsmith: For example, shown on the left of slide 26, in immunocompetent mice engrafted with the syngeneic RAS mutant tumor, RMC-6236 induced a favorable transformation of the tumor immune microenvironment, characterized by an increase in infiltrating CD8 T-cells and a decrease in immune suppressive M2 macrophages. As shown on the right, RMC-6236 alone was quite active against growth of these syngeneic tumor grafts, including inducing a number of complete responses.

For example, as shown on the left of Slide 26.

Competent mice and grafted with <unk> Ras mutant tumor.

RMC 63, six induced a favorable transformation of the tumor immune microenvironment characterized by an increase in infiltrating CDA T cells and a decrease in immune suppressive <unk> macrophages as shown on the right RMC six to $3 six alone was quite active against growth of east and generic tumor graft.

Mark A. Goldsmith: Importantly, we've now shown in preclinical experiments that RMC6236 is active against all of these clinically observed variants, as well as a broader panel of KRAS G12 mutants that to date haven't been described in patients. Hence, these findings indicate that RMC6236 has important properties that may be useful for preventing or treating the emergence of these RAS oncogene switch resistance mutations. In Q2, we also reported information about the potential for additive benefit in combinations of either RMC6291 or RMC6236 with a checkpoint inhibitor.

Including inducing a number of complete responses.

Mark Goldsmith: An anti-PD-1 antibody alone was active as well, but the two together led to complete responses in all animals. These results are encouraging about the potential clinical benefit of combining our RAS(ON) inhibitors with PD-1 inhibitors in treating anti-PD-1 sensitive tumors. Like RMC-6291, RMC-6236 continues on track in IND-enabling development, and we continue making very good progress on advancing additional mutant-selective RAS(ON) inhibitors. Our corporate goal is to select a third development candidate this year to advance into IND-enabling development and others subsequently.

Anti PD, one antibody alone was active as well, but the two together led to complete responses in all animals.

These results are encouraging about the potential clinical benefit of combining our rason inhibitors with PD one inhibitors in treating anti PD one sensitive tumors.

Mike RMC 69, one RMC 63, six continues on track and our IND, enabling development and we continue making very good progress on advancing additional mutant selective <unk> inhibitors. Our corporate goal is to select a third development candidate this year to advance into IND, enabling development and other subsequently.

Mark Goldsmith: Today, we'd like to show you some new evidence of our drug discovery capabilities by focusing briefly on two programs we've disclosed in late lead optimization, KRAS G13C and KRAS G12D. Shown on the left of slide 29 is a graphical surface representation of a switch I-II region of the RAS(ON) protein, which shows that amino acids 12, highlighted in blue, and 13, highlighted in red, lie adjacent to each other in the protein, and both are very close to the RAS(ON) inhibitor binding site, highlighted in dark pink. Our previous work enabled RMC-6291 to selectively engage the oncogenic cysteine at position 12 in the mutant KRAS G12C (ON) protein, as indicated by the upward shift of the KRAS G12C protein band in the cross-linking experiment on the left.

<unk>.

Today, we'd like to show you some new evidence of our drug discovery capabilities by focusing briefly on two programs. We have disclosed in late lead optimization K Ras G 13, C and K Ras <unk>.

Mark A. Goldsmith: For example, shown on the left of slide 26, in immunocompetent mice engrafted with the syngeneic RAS mutant tumor, RMC6236 induced a favorable transformation of the tumor immune microenvironment characterized by an increase in infiltrating CD8 T cells and a decrease in immune suppressive M2 macrophages. As shown on the right, RMC6236 alone was quite active against the growth of these syngeneic tumors. An anti-PD-1 antibody alone was active as well, but the two together led to complete responses in all animals.

Shown on the left of Slide 29 is a graphical surface representation of the switch one two region of the Ras on protein.

Which shows that amino acids 12 highlighted in blue and 13 highlighted in red by adjacent to each other in the protein and both are very close to the rason inhibitor binding site highlighted in dark pink.

Mark Goldsmith: Our previous work enabled RMC-6291 to selectively engage the oncogenic cysteine at position 12 in the mutant KRAS G12C (ON) protein, as indicated by the upward shift of the KRAS G12C protein band in the cross-linking experiment on the left.

Our previous work enabled RMC $6.91 to selectively engage the oncogenic cysteine at position 12 in the mutant <unk> protein as indicated by the upward shift of the <unk> protein band and the cross linking experiment on the left.

Mark Goldsmith: We have now been able to engineer new RAS(ON) inhibitor compounds that covalently engage the specific oncogenic cysteine at position 13 in the mutant KRAS G13C ON protein, as indicated by the upward shift of the KRAS G13C ON protein in the middle panel. Further, the exquisite molecular control we bring to the design of these remarkable compounds enables selective covalent binding to the cysteine 13 variant by one compound without detectable binding to the cysteine 12 variant. Conversely, selective covalent binding to the cysteine 12 variant by another compound without covalent binding to the cysteine 13 variant, despite the similar positions of the cysteines at positions 12 and 13 in these RAS variants.

Mark A. Goldsmith: These results are encouraging about the potential clinical benefit of combining our RAS-on inhibitors with PD-1 inhibitors in treating anti-PD-1 sensitive tumors. Like RMC6291, RMC6236 continues on track in IND-enabling development, and we continue making very good progress on advancing additional mutant-selective RAS-on inhibitors. Our corporate goal is to select a third development candidate this year to advance into IND-enabling development, and others subsequently.

We've now been able to engineer new Ras on inhibitor compounds that covalently engaged the specific oncogenic cysteine at position 13 in the mutant <unk> protein.

As indicated by the upward shift of the <unk> protein in the middle panel.

Further the exquisite molecular control, we bring to the design of these remarkable compounds enables selective covalent binding to the sustained 13 variant by one compound without detectable binding to the sustained 12 variant.

Mark Goldsmith: Conversely, selective covalent binding to the cysteine 12 variant by another compound without covalent binding to the cysteine 13 variant, despite the similar positions of the cysteines at positions 12 and 13 in these RAS variants.

Mark A. Goldsmith: Today we'd like to show you some new evidence of our drug discovery capabilities by focusing briefly on two programs we disclosed in late lead optimization, KRAS G13C and KRAS G12D. Shown on the left of slide 29 is a graphical surface representation of the SW1-2 region of the RAS-ON protein, which shows that amino acids 12, highlighted in blue, and 13, highlighted in red, lie adjacent to each other in the protein. And both are very close to the Ras-on inhibitor binding site, highlighted in dark pink.

Or Conversely, selective covalent binding to the sustained 12 variant by another compound without covalent binding to the sustained 13 variant.

Despite the similar positions of the <unk> App positions 12, and 13 in these rats variance.

Mark Goldsmith: Thus, the covalent warheads in these compounds are tuned to work only when positioned precisely and optimally with the free thiol group of the particular cysteine residue for which they are designed, a degree of on-target selectivity that is very encouraging. We also report today that we have extended covalent chemistry beyond cysteines to the oncogenic aspartic acid in the KRAS G12D(ON) variant, an exciting innovation and major achievement. Shown on the right of slide 29 is a representative compound that binds and cross-links to the KRAS G12D(ON) variant, as indicated by the upward shift of the KRAS G12D(ON) protein. Important evidence of the selectivity of this engagement is the absence of significant cross-linking to its close cousin, the KRAS G13D variant, despite the close proximity of aspartate 12 and aspartate 13 to one another.

Thus the covalent warheads and these compounds are tuned to work only when positioned precisely and optimal optimally with the free file group of the particular cysteine residue for which they are designed a degree of on target activity that is very encouraging.

We also report today that we have extended covalent chemistry beyond <unk> to the oncogenic aspartic acid in the K Ras <unk> D on variant and exciting innovation and major achievement.

Shown on the right of Slide 29 is a representative compound that binds and cross links to the <unk> on variant as indicated by the upward shift of the <unk> protein.

Mark A. Goldsmith: Our previous work enabled RMC6291 to selectively engage the oncogenic cysteine at position 12 in the mutant KRAS-G12C on-protein, as indicated by the upward shift of the KRAS-G12C protein band in the cross-linking experiment on the left. We have now been able to engineer new RAS-on inhibitor compounds that covalently engage the specific oncogenic cysteine at position 13 in the mutant k-RAS G13C-on protein, as indicated by the upward shift of the KRAS G13C protein in the middle panel.

Important evidence of the selectivity of this engagement is the absence of significant cross linking to its close cousin the K Ras G 13D variant. Despite the close proximity of our sparked a 12 and aspartame <unk> to one another.

Mark Goldsmith: We're very proud of both of these quite differentiated chemical series that enable potent and highly mutant-selective inhibition of oncogenic RAS signaling. Indeed, as shown here, each of these compounds shows impressive tumor cell growth inhibition in the corresponding genetic context, as anticipated by the specific cross-linking pattern shown above. These laboratory-based feats offer further insight into the groundbreaking drug design and execution capabilities deployed as we continue expanding our portfolio of RAS(ON) inhibitor assets, and we look forward to providing further updates as these programs reach further milestones. We'd also like to provide an update on the good progress within our RAS companion inhibitor pipeline. Previously, we identified combinations with RAS inhibitors as a core strategic element of our SHP2 inhibitor program, and we remain optimistic about this strategy.

We're very proud of both of these quite differentiated chemical series that enable potent and highly mutant selective inhibition of oncogenic Ras signaling.

Indeed as shown here each of these compounds shows impressive tumor cell growth inhibition and the corresponding genetic context as anticipated by the specific cross linking pattern shown above.

Mark A. Goldsmith: Further, the exquisite molecular control we bring to the design of these remarkable compounds enables selective covalent binding to the cysteine-13 variant by one compound without detectable binding to the cysteine-12 variant. Or, conversely, selective covalent binding to the cysteine-12 variant by another compound without covalent binding to the cysteine-13 variant, despite the similar positions of the cysteines at positions 12 and 13 in these RAS variants. Thus, the covalent warheads in these compounds are tuned to work only when positioned precisely and optimally with the free-thial group of the particular cysteine residue for which they are designed, a degree of on-target selectivity that is very encouraging.

These laboratory based feeds offer further insight into the groundbreaking drug design and execution capabilities deployed as we continue expanding our portfolio of rasp inhibitor assets and we look forward to providing further updates as these programs reach further milestones.

Mark Goldsmith: We'd also like to provide an update on the good progress within our RAS companion inhibitor pipeline. Previously, we identified combinations with RAS inhibitors as a core strategic element of our SHP2 inhibitor program, and we remain optimistic about this strategy.

We'd also like to provide an update on the good progress within our Ras companion inhibitor pipeline previously we identified combinations with Ras inhibitors as a core strategic elements of our ship two inhibitor program and we remain optimistic about this strategy.

Mark Goldsmith: To illustrate this concept, we recently shared data on this example of a drug-resistant KRAS G12C colorectal tumor xenograft in slide 32. In contrast to another colorectal cancer model we showed previously that is highly sensitive to single-agent RMC-6291, this particular colorectal cancer model exhibits only a modest growth inhibition response to RMC-6291 monotherapy in the blue line, which we believe relates to the role of wild type or normal RAS proteins in supporting growth of these tumors. Notably, combining our SHP2 inhibitor RMC-4550, a tool compound we often use for preclinical research, with RMC-6291 induced deep and sustained regressions in the tumor xenografts as shown on slide 32.

To illustrate this concept we recently shared data on this example of a drug resistant K Ras <unk> colorectal tumors in the graph in slide 32.

In contrast to another colorectal cancer model. We showed previously that is highly sensitive to single agent RMC $6.91. This particular colorectal cancer model exhibits only a modest growth inhibition response to RMC 69, one mono therapy and the Blue line, which we believe relates to the role of wild type of norm.

Mark A. Goldsmith: We also report today that we have extended covalent chemistry beyond cysteine to the Oncogenic Aspartic Acid in the KRAS G12D On Variant, an exciting innovation and major achievement. Shown on the right of slide 29 is a representative compound that binds and cross-links to the KRAS G12D ON variant as indicated by the upward shift of the KRAS G12D protein. Important evidence of the selectivity of this engagement is the absence of significant cross-linking to its close cousin, the KRAS G13D variant, despite the close proximity of Aspartame 12 and Aspartame 13 to one another.

<unk> Ras proteins and supporting growth of these tumors.

Mark Goldsmith: Notably, combining our SHP2 inhibitor RMC-4550, a tool compound we often use for preclinical research, with RMC-6291 induced deep and sustained regressions in the tumor xenografts as shown on slide 32.

Notably combining our ship two inhibitor RMC 45, five O a tool compound we often used for preclinical research with RMC 69, one induced deep and sustained regressions in the tumor xenograft as shown on slide 32.

Mark Goldsmith: Hence, while RMC-6291 itself has a superior preclinical profile to first generation KRAS G12C inhibitors, as measured in a variety of models we've shown previously, additional antitumor impact can be obtained by the additive contribution of our SHP2 inhibitor. We believe that combining such agents in the clinic will prove to be a compelling therapeutic strategy. Now I'll turn things over to Dr. Steve Kelsey, our President of R&D, to bring you up to date on these efforts.

Hence while RMC 69, one itself has a superior preclinical profile to first generation <unk> inhibitors as measured in a variety of models. We have shown previously additional antitumor impact can be obtained by the additive contribution of our ship two inhibitor.

Stephen M. Kelsey: We're very proud of both of these quite differentiated chemical series that enable potent and highly mutant selective inhibition of oncogenic RAS signaling. Indeed, as shown here, each of these compounds shows impressive tumor cell growth inhibition in the corresponding genetic context as anticipated by the specific cross-linking pattern shown above. These laboratory-based feeds offer further insight into the groundbreaking drug design and execution capabilities deployed as we continue expanding our portfolio of asson inhibitor assets, and we look forward to providing further updates as these programs reach further milestones.

We believe that combining such agents in the clinic will prove to be a compelling therapeutic strategy and now I'll turn things over to Dr. Steve Kelsey.

Our president of R&D to bring you up to date on these efforts.

Steve Kelsey: Thank you, Mark. In monotherapy clinical studies to date, RMC-4630, our clinical stage SHP2 inhibitor, compares favorably with competitors and is well set up for continued evaluation of potential combination benefits with RAS inhibitors. Notable features of our RMC-4630 program include the use of an innovative intermittent dosing schedule to optimize for activity and tolerability, an absence of cardiac and liver dose-limiting toxicities in the dose escalation work, a focus on patients with RAS mutant tumors, observed clinical activity with best responses, including partial response, and a complete response, observed reduction in driver oncogene frequency detected in circulating tumor DNA samples, and evidence of favorable modulation of the tumor immune microenvironment in tumor samples from treated patients.

Thank you Mark.

In monotherapy clinical studies to date RMS in full six three are all clinical stage ships inhibitor compares favorably with competitors.

And as well setup for continued evaluation of potential combination benefits with <unk> inhibitors.

Steve Kelsey: Notable features of our RMC-4630 program include the use of an innovative intermittent dosing schedule to optimize for activity and tolerability, an absence of cardiac and liver dose-limiting toxicities in the dose escalation work, a focus on patients with RAS mutant tumors, observed clinical activity with best responses, including partial response and a complete response, observed reduction in driver oncogene frequency detected in circulating tumor DNA samples, and evidence of favorable modulation of the tumor immune microenvironment in tumor samples from treated patients.

Notable features of our RMC for <unk> III program include the use of an innovative intermittent dosing schedule to optimize for activity and tolerability.

Stephen M. Kelsey: We'd also like to provide an update on the good progress within our RAS companion inhibitor pipeline. Previously, we identified combinations with RAS inhibitors as a core strategic element of our SHIP-2 inhibitor program, and we remain optimistic about this strategy. To illustrate this concept, we recently shared data on this example of a drug-resistant KRAS G12C colorectal tumor xenograft in slide 32. In contrast to another colorectal cancer model we showed previously that is highly sensitive to single agent RMC6291, this particular colorectal cancer model exhibits only a modest growth inhibition response to RMC6291 monotherapy in the blue line, which we believe relates to the role of wild type or normal RAS proteins in supporting the growth of these tumors.

In absence of cardiac liver dose limiting toxicities in the dose escalation work.

Our focus on patients with Ras mutant tumors.

Observed clinical activity with best responses, including partial response and the complete response.

Observed reduction and drive oncogene frequencies detected in circulating tumor DNA samples.

And evidence of favorable modulation of the tumor immune microenvironment in tune of phone calls from treated patients.

Steve Kelsey: In Q2 at the annual ASCO meeting, another prominent SHP2 inhibitor program, TNO155 by Novartis, presented its first monotherapy clinical data that showed a different clinical strategy and dosing paradigm with less encouraging output so far. We continue to believe that RMC-4630 has the potential to be a class-leading SHP2 inhibitor and thereby a class-leading RAS companion inhibitor. The earliest combination studies we were able to begin before RAS inhibitors were available for clinical testing were combinations with inhibitors of two other targets in the RAS signaling pathway, MEK and EGFR. Today, we provide an update on both.

Steve Kelsey: In Q2 at the annual ASCO meeting. Another prominent SHP2 inhibitor program, TNO155 by Novartis, presented its first monotherapy clinical data that showed a different clinical strategy and dosing paradigm with less encouraging output so far. We continue to believe that RMC-4630 has the potential to be a class-leading SHP2 inhibitor and thereby a class-leading RAS companion inhibitor.

In Q2 of the annual Africa, New thing.

Another prominent ship two inhibitor program TNI 155 by Novartis presented its first monotherapy clinical data that showed a different clinical strategy and the dosing paradigm with less encouraging so far.

We continue to believe that RMC for trio has the potential to be a class leading ship two inhibitor.

Stephen M. Kelsey: Notably, combining our SHIP2 inhibitor RMC4550, a tool compound we often use for preclinical research, with RMC6291 induced deep and sustained regressions in the tumor xenografts, as shown on slide 32. Hence, while RMC6291 itself has a superior preclinical profile to first-generation KRAS G12C inhibitors, as measured in a variety of models we've shown previously We believe that combining such agents in the clinic will prove to be a compelling therapeutic strategy, and now I'll turn things over to Dr. Steve Kelsey, our President of R&D, to bring you up to date on these efforts.

And thereby a class leading Ross companion inhibitor.

Steve Kelsey: The earliest combination studies we were able to begin before RAS inhibitors were available for clinical testing were combinations with inhibitors of two other targets in the RAS signaling pathway, MEK and EGFR. Today, we provide an update on both.

The earliest combination studies, we were able to begin the full Ras inhibitors were available for clinical testing.

Combinations with inhibitors of two other targets in the Ras signaling pathway.

<unk> and Egfr.

And today, we provide an update on both.

Steve Kelsey: In the absence of direct inhibitors for most RAS mutants, our first approach was to try to clamp the RAS pathway by combining our inhibitor of SHP2, RMC-4630, which suppresses the top of the signaling cascade or upstream of RAS, with cobimetinib, a MEK inhibitor which suppresses the bottom of the signaling cascade or downstream of RAS. Preclinical work from several groups, including ourselves, had suggested modest but undoubtedly combinatorial antitumor potential for this approach, which we felt merited clinical evaluation in the context of serious unmet needs. In the RMC-4630-02 study, a group of patients with RAS mutant non-small cell lung cancer were treated with the RMC-4630 plus cobimetinib combination using the recommended phase 2 dosing schedule that we had described last fall. 11 subjects were evaluable for efficacy.

In the absence of direct inhibitors, but most Ras mutants I'll first approach was to try to plan the Ras pathway by combining our inhibitor of ship to RMB <unk> six three O, which suppresses the top of the signaling cascade or upstream of Ross.

With koby matching it.

<unk> inhibitor, which suppresses the bolstering of the segment on the Cascade or guidance stream, Nebraska.

Preclinical work from several groups, including ourselves.

Stephen M. Kelsey: In monotherapy clinical studies today,

Suggested modest, but undoubtedly combinatorial antitumor potential for this approach, which we felt merited clinical evaluation in the context of serious unmet needs.

Stephen M. Kelsey: Clinical Stage Ship-to-Inhibitor compares favorably with competitors and is well set up for continued evaluation of the potential combined benefits of your asset.

Steve Kelsey: In the RMC-4630-02 study, a group of patients with RAS mutant non-small cell lung cancer were treated with the RMC-4630 plus cobimetinib combination using the recommended phase 2 dosing schedule that we had described last fall. 11 subjects were evaluable for efficacy.

In the RMC 463002 study.

Stephen M. Kelsey: Notable features of our RNC4630 program include the use of an innovative intermittent dosing schedule to optimize for activity and tolerability.

A group of patients with Ras mutant non small cell lung counts so were treated with the RMC 463 hundred plus COVID-19 that new combination.

Using the recommended phase II dose and schedule that we have described last fall.

Stephen M. Kelsey: An Absence of Cardiac and Liver Dose-Limiting Toxicities in the Dose-Escalation World, a focus on patients with RAS mutant tumours, observed clinical activity with best responses including partial response and a complete response. Observed reduction in driver oncogene frequency detected in circulating tumor DNA samples, and evidence of

11 subjects were evaluable for efficacy.

Steve Kelsey: We observed acceptable tolerability and one patient with a KRAS G12V tumor mutation and gene amplification of that mutation exhibited a confirmed partial response with an almost 45% tumor volume reduction. In a group of patients with RAS mutant colorectal cancer, we had 25 efficacy evaluable subjects. Here, too, we observed acceptable tolerability, but the best clinical response was stable disease. Together, these results are encouraging in that they further support the antitumor activity of RMC-4630 in a way that can deliver clinical benefit in RAS-driven cancers and can be combined tolerably with other drugs. However, the combination also showed insufficient clinical benefit to justify advancing this approach. To us, it strongly points us back to the primary hypothesis for RAS-addicted cancers, which is to focus our efforts on using RMC-4630 as a companion for direct RAS inhibitors.

Observe acceptable tolerability and one patients with a K Ras June 12, the tumor mutation.

And gene amplification of that mutation exhibited a confirmed partial response with an almost 45% tumor volume reductions.

And a group of patients with Ras mutant colorectal cancer, we had 22 five efficacy evaluable subjects.

Stephen M. Kelsey: of the Tumor Immune Microenvironment in Tumor Samples from Treated Patients, at Q2 of the annual ASCO meeting. Another prominent ship-to-inhibitor program, TNO 155 by Nevartis, presented its first monotherapy clinical data that showed a different clinical strategy and dosing paradigm with less encouraging output so far. We continue to believe that RMC 4630 has the potential to be a class-leading SHP2 inhibitor and, thereby,

Here too, we observe acceptable tolerability, but the best clinical response or stable disease.

Steve Kelsey: Together, these results are encouraging in that they further support the antitumor activity of RMC-4630 in a way that can deliver clinical benefit in RAS-driven cancers and can be combined tolerably with other drugs. However, the combination also showed insufficient clinical benefit to justify advancing this approach. To us, it strongly points us back to the primary hypothesis for RAS-addicted cancers, which is to focus our efforts on using RMC-4630 as a companion for direct RAS inhibitors.

Together. These results are encouraging and that further support the antitumor activity of RMC for trio in a way that can deliver clinical benefits in Ras driven cancers.

And can be combined tolerably with other drugs. However, the combination of also showed in sufficient clinical benefit to justify advancing this approach.

So us strongly points response, the primary hypothesis for <unk> campuses.

Stephen M. Kelsey: and thereby a class-leading RAS companion inhibitor. The earliest combination studies we were able to begin, before RAS inhibitors were available for clinical testing, were combinations with inhibitors of two other targets in the RAS signaling pathway, MEK and EGFR, and today we provide an update on both.

Which is to focus our efforts on using <unk> as a companion for direct Ras inhibitors.

Steve Kelsey: Our second and quite different approach was to try to enhance the clinical benefit of a best-in-class receptor tyrosine kinase inhibitor, osimertinib, by including RMC-4630 to suppress adaptive resistance mechanisms that may eventually reduce the efficacy of the EGFR inhibitor upon long-term treatment. Pre-clinical work had supported the antitumor potential for this approach, which we felt merited clinical evaluation. We had previously communicated that we were not confident these two agents with well-recognized on-pathway side effects could be combined clinically, a precedent set by the combination of osimertinib with the MEK inhibitors. Indeed, last quarter, we reported intolerability at the early dose levels in the RMC-4630-02 study.

Our second I'm quite different approach was to try to enhance the clinical benefit of our best in class receptor tyrosine kinase inhibitor Aussie Merck.

Stephen M. Kelsey: In the absence of direct inhibitors for most RAS mutants, our first approach was to try

By including RMC 463 O to suppress adaptive resistance mechanisms that may eventually reduce the efficacy of the Egfr inhibitor upon long term treatment.

Stephen M. Kelsey: to Clamp the RAS Pathway by combining our inhibitor of SHP2, RMC4630.

Stephen M. Kelsey: which suppresses the top of the.

Preclinical work has supported the antitumor potential for this approach, which we felt merits of clinical evaluation.

Stephen M. Kelsey: with Covimetanib, a MEK inhibitor that suppresses the bottom of the signaling cascade or downstream of that, preclinical work from several groups, including ourselves.

Steve Kelsey: We had previously communicated that we were not confident these two agents with well-recognized on-pathway side effects could be combined clinically, a precedent set by the combination of osimertinib with the MEK inhibitors. Indeed, last quarter, we reported intolerability at the early dose levels in the RMC-4630-02 study.

We had previously communicated that we were not confident these two agents with well recognized on pathway side effects could be combined clinically a precedent set by the combination of all the Merck with the Mac inhibitors.

Stephen M. Kelsey: had suggested modest but undoubtedly combinatorial anti-tumour potential for this approach, which we felt merited clinical...

And indeed last quarter, we reported in Tolerability early dose levels in the RMB 2463 O O two study.

Stephen M. Kelsey: Narrative Clinical Evaluation in the Context of Serious Unmet Needs

Steve Kelsey: In fact, we did not identify a combination dosing schedule with acceptable tolerability, even employing our intermittent dosing paradigm for RMC-4630, indicating that the combined on-target toxicity caused by suppression of RAS signaling in normal tissues caused by these two agents together presents too big a hurdle to justify advancing this approach. Again, this outcome reiterates our prime combination hypothesis for treating RAS-addicted cancers, which is combining RMC-4630 or other RAS companion inhibitors with direct RAS inhibitors. That strategy will be our highest priority going forwards. In view of the response rates, emerging drug resistance profiles, and resistance mechanisms for the leading KRAS G12C ON inhibitors, we continue to have conviction about combining RMC-4630 with direct RAS inhibitors.

Stephen M. Kelsey: A group of patients with rasputin non-small cell lung cancer were treated with the IRM-C4630 plus COVID-19 combination, using the recommended phase two dosing schedule that we described last fall. 11 subjects were valuable for efficacy. We observed acceptable tolerability, and one patient with a KRAS G12V tumor mutation and gene amplification of that mutation exhibited a confirmed partial response with an almost 45% tumor volume reduction. In a group of patients with RAS mutant colorectal cancer, we had 25 efficacy-evaluable subjects. Here too, we observed acceptable tolerability, but the best clinical response was stable disease.

In fact, we did not identify a combination dosing schedule with acceptable tolerability, even employing our intermittent dosing paradigm for RMC full six three of them.

Indicating that the combined on target toxicity caused by suppression of Ras signaling in normal tissues caused by these two agents together presents too big a hurdle to justify advancing this approach.

Steve Kelsey: Again, this outcome reiterates our prime combination hypothesis for treating RAS-addicted cancers, which is combining RMC-4630 or other RAS companion inhibitors with direct RAS inhibitors. That strategy will be our highest priority going forwards. In view of the response rates, emerging drug resistance profiles, and resistance mechanisms for the leading KRAS G12C OFF inhibitors, we continue to have conviction about combining RMC-4630 with direct RAS inhibitors.

Okay.

Reiterate saw prime combination hypothesis for treating Rhapsody, two campuses, which is combining arms in full six three O or other Ras companion inhibitors with direct rasp inhibitors.

That strategy will be our highest priority going forwards.

In view of the response rates emerging drug resistance profiles and resistance mechanisms for the leading K Ras G told see often visitors.

Stephen M. Kelsey: Together, these results are encouraging in that they further support the anti-tumor activity of RMC4630 in a way that can deliver clinical benefits in RAS-driven cancer and can be combined tolerably with other treatments.

We continue to have conviction about combining RMC for cereal with direct rasp inhibitors.

Steve Kelsey: Since, to our understanding, all clinical toxicity driving our selection of the recommended phase 2 dose of RMC-4630 have been attributable to RAS pathway effects in normal tissues, we have no reason to believe that combining RMC-4630 with a RAS mutant selective inhibitor would be compromised by additive dose-limiting toxicities. Amgen continues to enroll the CodeBreaK 101 Subpart C study of sotorasib with RMC-4630 in advanced non-small cell lung cancer, colorectal cancer, and other solid tumors. As noted earlier in the quarter. The dose escalation work continues, evaluating RMC-4630 at the target dose of 200 milligrams daily on a day one, day two weekly schedule. The full dose used by us in monotherapy, in combination with sotorasib at 960 milligrams daily. A combination dose for expansion is expected to be achieved by Amgen in H2 of this year.

To our understanding.

Clinical toxicity driving a selection of the recommended phase two dose of bonds for <unk> have been attributable to Ras pathway effects in normal tissues.

Stephen M. Kelsey: However, the combination also showed insufficiency.

Stephen M. Kelsey: Efficient Clinical Benefit to Justify Advancing This Approach. To us, it's strongly poignant.

We have no reason to believe that combining <unk> with a ras mutant selective inhibitor would be compromised by ablative dose limiting toxicities.

unknown: [inaudible]

Stephen M. Kelsey: for Direct Ras Inhibitors. Our second and quite different approach was to try to enhance

Steve Kelsey: Amgen continues to enroll the CodeBreaK 101 Subpart C study of sotorasib with RMC-4630 in advanced non-small cell lung cancer, colorectal cancer, and other solid tumors. As noted earlier in the quarter. The dose escalation work continues, evaluating RMC-4630 at the target dose of 200mg daily on a day 1, day 2 weekly schedule. The full dose used by us in monotherapy in combination with sotorasib at 960mg daily. A combination dose for expansion is expected to be achieved by Amgen in the H2 of this year.

Amgen continues to enroll the Covid break one O. One sub part C study hopes of tourists with RMC for <unk> in advanced non small cell lung cancer.

Stephen M. Kelsey: Clinical Benefit of a Best-in-Class Receptorizing Kinase Inhibitor, Ozymir, by including RMC4630 to suppress adaptive resistance mechanisms that may eventually reduce the efficacy of the EGFR inhibitor upon long-term treatment

Colorectal cancer and other solid tumors.

As noted earlier in the quarter.

The dose escalation work continues evaluating RMC full six trio at the target dose of 200 milligrams daily on a day one day two week to schedule.

Stephen M. Kelsey: Preclinical work has supported the antitumor potential for this probe.

Stephen M. Kelsey: which we felt merited a clinical evaluation, although we had previously communicated that we were not.

The full dose used by us in monotherapy in combination with <unk> at 960 milligrams daily.

Stephen M. Kelsey: Incidentally, these two agents with well-reputed...

Stephen M. Kelsey: Incident set by the combination of ozomertinib with the MAG inhibitor. And indeed, last quarter, we reported...

A combination dose for expansion is expected to be achieved by Amgen in the second half of this year.

Stephen M. Kelsey: We reported intolerability at early dose levels in the RMC463002 study.

Steve Kelsey: We are encouraged by this work, and it continues to be a productive clinical exploration of the combination strategy. RevMed is also excited to announce today an expansion of our collaboration on this drug combination with Amgen with the RMC-4630-03 study. I will provide a more detailed update on this study momentarily. In addition, we plan to combine RMC-4630 with RMC-6291, our KRAS G12C ON inhibitor, and potentially other compounds from our RAS ON inhibitor collection as these become available. Finally, the TCD16210 study sponsored by Sanofi continues, evaluating RMC-4630 plus pembrolizumab. We are pleased to report today the combination will now be evaluated in an expansion cohort of patients with previously untreated advanced PD-L1 positive non-small cell lung cancer. This study could provide the foundation for a future clinical evaluation of the triplet of a RAS inhibitor, RMC-4630, and a PD-1 inhibitor. Regarding the new RMC-4630-03 study.

We are encouraged by this work and it continues to be a productive clinical exploration of the combination strategy.

Stephen M. Kelsey: In fact, we did not identify a combination ghost and schedule.

<unk> is also excited to announce today an expansion of our collaboration on this drug combination with Amgen with the RMC full six trio Oh three studies.

Stephen M. Kelsey: Acceptable Tolerability, even employing our intermittent dosing paradigm for RMC4630, indicating that the combined on-target toxicity caused by suppression of RAF signaling in normal tissues caused by these two...

I will provide a more detailed update on this study momentarily.

Steve Kelsey: In addition, we plan to combine RMC-4630 with RMC-6291, our KRAS G12C ON inhibitor, and potentially other compounds from our RAS(ON) inhibitor collection as these become available. Finally, the TCD16210 study sponsored by Sanofi continues, evaluating RMC-4630 plus pembrolizumab. We are pleased to report today the combination will now be evaluated in an expansion cohort of patients with previously untreated advanced PD-L1-positive non-small cell lung cancer.

In addition, we plan to combine RMC full succeed with RMC six to nine one I'll pay last year 12 C. One inhibitor.

Stephen M. Kelsey: Caused by these two agents together, presents too big a hurdle to justify advancing this approach. Again, this outcome reiterates our prime combination hypothesis for treating RAFs-addicted cancers, which is combining IMC4630 or other RAFs companion inhibitors with direct RAFs inhibitors. Unknown Speaker 0

There's potentially other compounds from our RAF inhibitor collection as these become available.

Finally, the T. C. D 16 to 10 study sponsored by Sanofi continues evaluating RMC full six three hours plus pad in burleson.

We are pleased to report today, the combination will now be evaluated in an expansion cohort of patients with previously untreated advanced PD lone positive non small cell lung cancer.

Stephen M. Kelsey: and that strategy will be our highest priority going forward.

Stephen M. Kelsey: In view of the response rates, emerging drug resistance profiles, and resistance mechanisms for the leading KRAS G12C off inhibitors,

Steve Kelsey: This study could provide the foundation for a future clinical evaluation of the triplet of a RAS inhibitor, RMC-4630, and a PD-1 inhibitor. Regarding the new RMC-4630-03 study.

This study could provide the foundation for future clinical evaluation of the triplet. So the Ras inhibitor RMC for <unk> and a PD one inhibitor.

Stephen M. Kelsey: We continue to have conviction about combining RMC 4630 with...

Stephen M. Kelsey: X-ray with direct trace inhibitors.

Stephen M. Kelsey: Since, to our understanding, all clinical problems.

Regarding the new RMC for <unk> III study.

Steve Kelsey: Informed by preclinical data, the CodeBreaK 101c work to date, and important learnings in the field over the last few years since the CodeBreaK protocol was written, the RMC-4630-03 study was designed as a global phase 2 study of the combination of sotorasib plus RMC-4630 in advanced KRAS G12C non-small cell lung cancer that have not previously received a KRAS G12C inhibitor. It is intended to establish the extent and nature of additional clinical benefit from combining these two agents and to inform the design of a possible registrational trial. While the 03 study is complementary to CodeBreaK 101c, it has several important differences. The RMC-4630-03 study will enroll approximately 46 non-small cell lung cancer subjects with 2 cohorts that are defined by co-mutations that may affect the outcome to either KRAS inhibitor or SHP2 inhibition.

Steve Kelsey: Informed by preclinical data, the CodeBreaK 101C work to date, and important learnings in the field over the last few years since the CodeBreaK protocol was written, the RMC-4630-03 study was designed as a global phase 2 study of the combination of sotorasib plus RMC-4630 in advanced KRAS G12C non-small cell lung cancer that have not previously received a KRAS G12C inhibitor.

Stephen M. Kelsey: Unknown Executive, Chris Shibutani, Erin Graves, Wei Chang, Jack Anders, We have no reason to believe that combining RMC4630 with a RAS mutant-selective inhibitor would be compromised by additive dose-limiting toxicity. Amgen continues to enroll the COVID Break 101 Subpart C study of satoracid with RMC4630 in advanced non-small cell lung cancer, colorectal cancer, As noted earlier in the quarter, the dose escalation work continues evaluating RMC4630 at the target dose of 200 milligrams daily on a day one, day two weekly schedule, the full dose used by us in monotherapy.

Informed by preclinical data.

The code break one I wanted to see work to date and important learnings in the field over the last few years since the Covid break protocol was written.

The RMC 463 of the <unk> III study was designed as a global phase two study.

The combination of Setara surplus RMC full six trio and advanced pay Ross <unk> non small cell lung cancer that have not previously received a <unk> inhibitor.

It is intended to establish the extent and nature of additional clinical benefit.

Combining these two agents.

And to inform the design of a possible registrational trial.

While the <unk> III study is complementary to calibrate what I wanted to see it has several important differences.

The RMC for 603 study will enroll approximately 46 non small cell lung cancer subjects with two cohorts that are defined by <unk> mutations that may affect the outcome to either pay rasp inhibitor or ship to the ambition.

Stephen M. Kelsey: in combination with Sotiris at 960 milligrams daily.

Stephen M. Kelsey: A combination dose for expansion is expected to be achieved by Amgen in the second half of this year.

Steve Kelsey: First cohort will have KRAS G12C positive tumors without co-mutations, and the second cohort will have KRAS G12C positive tumors with co-mutations, such as KEAP1 or STK11 mutations. This will allow us to better define who may most benefit from this promising combination strategy. Unlike CodeBreaK 101, the study will restrict eligibility to second and third line therapy, and it will enroll outside the United States as well as within the United States. RevMed is sponsoring and executing this study under its global partnership with Sanofi, with clinical supply of sotorasib provided by Amgen for the ex-US sites where the drug is not yet approved, which is expected to be a major source of enrollment now that sotorasib has been approved in the United States.

First cohort will have <unk> 12, see positive tumors with <unk> mutations and the second cohort will have <unk> positive tumors with <unk> mutations such as <unk> or SD Wan 11 mutations.

Stephen M. Kelsey: We are encouraged by this work, and it continues to be a productive clinical exploration of the combination strategy.

Stephen M. Kelsey: RedMed is also excited to announce today an expansion of our collaboration.

This will allow us to better define who may most benefit from this promising combination strategy.

Stephen M. Kelsey: 46303 study. I will provide a more detailed update on this study momentarily.

Unlike co Brightwater one the study will restrict eligibility to second and third line therapy.

Stephen M. Kelsey: In addition, we plan to combine RMC4630 with RMC6291, our KRAS-G12C ON inhibitor.

And it will enroll outside the United States as well as well as within the United States.

Steve Kelsey: RevMed is sponsoring and executing this study under its global partnership with Sanofi, with clinical supply of sotorasib provided by Amgen for the ex-US sites where the drug is not yet approved, which is expected to be a major source of enrollment now that sotorasib has been approved in the United States.

We have made is sponsoring and executing this study under its global partnership with Sanofi.

Stephen M. Kelsey: inhibitor, and potentially other compounds from our RAS-on-inhibitor collection as these become available. Finally, the TCD 16.2.10 study sponsored by Sanofi continues evaluating INC4630 plus Pembrolizumab.

With clinical suppliers to tourists it provided by Amgen for the ex U S sites, where the drug is not yet approved which is expected to be a major source of enrollment Niobrara software has been approved in the United States.

Steve Kelsey: For data analysis and full interpretation, we will have the ability to draw from both CodeBreaK 101c results and the 03 study results. We view RMC-4630-03 as an important and exciting clinical study. We are preparing to launch the study, and we expect the first patients to be enrolled in the H2 of this year and to have preliminary findings by the end of 2022. Back to you, Mark.

Steve Kelsey: For data analysis and full interpretation, we will have the ability to draw from both CodeBreaK 101C results and the RMC-4630-03 study results. We view RMC-4630-03 as an important and exciting clinical study. We are preparing to launch the study, and we expect the first patients to be enrolled in H2 of this year and to have preliminary findings by the end of 2022. Back to you, Mark.

Stephen M. Kelsey: We are pleased to report that the combination will now be evaluated and...

For data analysis and full interpretation, we will have the ability to draw from both Coke Brightwater I want to see results and the <unk> study results.

unknown: Transcripts provided by Transcription Outsourcing, LLC.

Stephen M. Kelsey: PDL-1 positive non-small cell lung cancer. This study could provide the foundation for a future clinical evaluation of the triplets of a RAS inhibitor, RMC4630, and a PD-1 inhibitor. Regarding the new RNC 4630-03 study.

We view RMC pool sits railroad three as an important and exciting clinical study.

We are preparing to launch this study and we expect the first patient to be enrolled in the second half of this year and to have preliminary findings by the end of 2022.

Mark Goldsmith: Thank you, Steve. Today, we highlighted recent progress regarding several important assets in our strategic development stage pipeline, addressing key drivers of RAS addiction and drug resistance, and provided further visibility into the remarkable drug discovery advances within our RAS(ON) inhibitor program that will help power advancing additional research stage assets into development. In addition, our mTORC1 selective inhibitor, RMC-5552, continues advancing in monotherapy dose escalation, and our SOS1 selective inhibitor, RMC-5845, is on track to be IND-ready by the end of this year. Slide 41 outlines our corporate milestones. I'd like to highlight several of these in particular. In our RAS(ON) inhibitor pipeline, we continue to anticipate IND filings for both RMC-6291 and RMC-6236 in H1 2022 and selection of a third RAS(ON) inhibitor development candidate later this year.

Two months.

Thank you Steve.

Today, we highlighted recent progress regarding several important assets in our strategic development stage pipeline addressing key drivers of Ras addiction, and drug resistance and provided further visibility into the remarkable drug discovery advances within our rason inhibitor program that will help power advancing additional research.

Stephen M. Kelsey: Influenced by preclinical data, the Code Break 101C working to date, and important learnings in the field over the last few years since the Code Break protocol was recognized, the RMC 463003 study was designed as a global phase 2 study.

Mark Goldsmith: In addition, our mTORC1 selective inhibitor, RMC-5552, continues advancing in monotherapy dose escalation, and our SOS1 selective inhibitor, RMC-5845, is on track to be IND-ready by the end of this year. Slide 41 outlines our corporate milestones. I'd like to highlight several of these in particular. In our RAS(ON) inhibitor pipeline, we continue to anticipate IND filings for both RMC-6291 and RMC-6236 in H1 2022 and selection of a third RAS(ON) inhibitor development candidate later this year.

<unk> assets into development.

In addition, our <unk> selective inhibitor RMC $5.55 to continue advancing in monotherapy dose escalation.

And our source one selective inhibitor RMC 5845 is on track to be IND ready by the end of this year.

Stephen M. Kelsey: of the combination of satoracid plus RMC4630 in advanced KRAS G12C non-small cell lung cancer that has not previously received a KRAS inhibitor

Slide 41 outlines our corporate milestones I'd like to highlight several of these in particular.

Stephen M. Kelsey: It is intended to establish the extent and nature of additional clinical features.

Ras on inhibitor pipeline, we continue to anticipate IND filings for both RMC $6.91, and RMC 63, six in the first half of 2022.

Stephen M. Kelsey: and to inform the design of a possible registration trial.

Stephen M. Kelsey: While the O3 study is complementary to CoV-101c, it has several limitations.

And selection of a third rason inhibitor development candidate later this year.

Stephen M. Kelsey: The RMC 46303 study will enroll approximately 46 non-small cell lung cancer subjects, with two cohorts that are defined by co-mutations that may affect the outcome to either K-Ras inhibitor or SHIP2 inhibition. The first cohort will have KRAS G12C positive tumors without commutations, and the second cohort will have KRAS G12C positive tumors with commutations, such as KIP-1 or STK-11 mutation This will allow us to better define who may most benefit from this promising combination strategy. However, unlike COBRATE-101, this study will restrict eligibility.

Mark Goldsmith: For RMC-4630, later this year, we anticipate selection by Amgen of a dose for further study with sotorasib in CodeBreaK 101 and to begin dosing patients in our new 03 study with sotorasib. I'll now turn things over to Jack Anders to review our financial results. Jack?

For RMC for <unk> later this year, we anticipate selection by Amgen a dose for further study with <unk> could break 101.

And to begin dosing patients in our new <unk> III study with soda rapid.

I'll now turn things over to Jack Anders to review our financial results Jack.

Jack Anders: Thank you, Mark, and good afternoon, everyone. We ended the quarter with $646 million in cash equivalents, and investments. Revenue for Q2 2021 was $8.7 million and consists entirely of revenue under our collaboration agreement with Sanofi. Total operating expenses for Q2 2021 increased to $53.2 million, largely driven by R&D expenses, which were $45.9 million during the quarter. Net loss for Q2 2021 was $44.3 million or $0.60 per share. Turning to financial guidance, we continue to expect full-year GAAP net loss to be between $170 million and $190 million, which includes estimated non-cash stock-based compensation expense of approximately $20 million.

Thank you Mark and good afternoon, everyone.

We ended the quarter with $646 million in cash cash equivalents and investments.

Revenue for the second quarter of 2021 was $8.7 million and consist entirely of revenue under our collaboration agreement with Sanofi.

Total operating expenses for the second quarter of 2021 increased to $53.2 million largely driven by R&D expenses, which were $45.9 million during the quarter.

Stephen M. Kelsey: Eligibility for Second and Third Line Therapy, and

Stephen M. Kelsey: And it will enroll patients outside the United States as well as within the United States. WebMed is sponsoring and executing this study under its global partnership with, with clinical supplier Sitorusib provided by Amgen for the ex-U.S. sites where the drug is not yet approved, which is expected to be a major source of enrollment now that software has been approved in the United States. For data analysis and full interpretation, we will have the ability to draw from both COBRATE-101C results and the O3 study results.

Net loss for the second quarter of 2021 was $44.3 million or <unk> 60 per share.

Jack Anders: Turning to financial guidance, we continue to expect full year GAAP net loss to be between $170 million and $190 million, which includes estimated non-cash stock-based compensation expense of approximately $20 million.

Turning to financial guidance, we continue to expect full year GAAP net loss to be between 170 and $190 million.

Which includes estimated noncash stock based compensation expense of approximately $20 million.

Jack Anders: Our GAAP net loss for H1 2021 was $81 million, and we expect net loss to increase during H2 of the year, primarily driven by increases in operating expenses as we advance our pre-clinical and clinical programs. With that, I'll now turn the call back over to Mark.

Our GAAP net loss for the first half of 2021 was $81 million.

Stephen M. Kelsey: We view RMC 46303 as an important and exciting clinical study. We are preparing...

And we expect net loss to increase during the second half of the year.

Primarily driven by increases in operating expenses as we advance our preclinical and clinical programs.

Stephen M. Kelsey: Clinical Study. We are preparing to launch the study, and we expect the first patients to be enrolled in the second half of this year and to have preliminary findings by the end of 2022.

And with that I'll now turn the call back over to Mark.

Mark Goldsmith: Thank you, Jack. We believe that RevMed is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients. We have a compelling strategy, a growing set of exciting product assets, and a strong balance sheet. We're proud of the tireless commitment to patients by our organization and are grateful to the patients, their families, and the many partners who work with us for providing RevMed with the opportunity to advance our unique pipeline of RAS(ON) inhibitors and RAS companion inhibitors, which we believe may transform the treatment of RAS-addicted cancers in the future. This concludes our prepared remarks for today. I'll now turn the call over to the operator for the Q&A session. Operator?

Thank you Jack.

We believe that resonate is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients. We have a compelling strategy a growing set of exciting product assets and our strong balance sheet. We're proud of the tireless commitment to patients by our organization and are grateful to the patients and their families and the many.

Mark A. Goldsmith: Today we highlighted recent progress regarding several important assets in our strategic development stage pipeline, addressing key drivers of RAS addiction and drug resistance, and provided further visibility into the remarkable drug discovery advances within our RAS on inhibitor program that will help power advancing additional research stage assets into development. In addition, our mTORC1 selective inhibitor, RMC5552, continues advancing in monotherapy dose escalation, and our SOS1 selective inhibitor, RMC5845, is on track to be IMD-ready by the end of this year. Slide 41 outlines our corporate milestones. I'd like to highlight several of these in particular.

Mark Goldsmith: We're proud of the tireless commitment to patients by our organization and are grateful to the patients, their families, and the many partners who work with us for providing RevMed with the opportunity to advance our unique pipeline of RAS(ON) inhibitors and RAS companion inhibitors, which we believe may transform the treatment of RAS-addicted cancers in the future. This concludes our prepared remarks for today. I'll now turn the call over to the operator for the Q&A session. Operator?

<unk>, who worked with us for providing resonated with the opportunity to advance our unique pipeline of <unk> inhibitors in Ras companion inhibitors, which we believe may transform the treatment of Ras addicted cancers in the future.

This concludes our prepared remarks for today and I'll now turn the call over to the operator for the Q&A session operator.

Operator 2: Thank you. As a reminder to ask a question, please press the star key followed by one on your touch-tone telephone. To withdraw your question, press the pound key. Again, that's star one to ask the question. Please stand by while we compile the Q&A roster. Our first question comes from the line of Chris Shibutani with Goldman Sachs. Your line is open.

Operator: Thank you. As a reminder to ask a question, please press the star key followed by one on your touchtone telephone. To withdraw your question, press the pound key. Again, that's star one to ask the question. Please stand by while we compile the Q&A roster. Our first question comes from the line of Chris Shibutani with Goldman Sachs. Your line is open.

Thank you.

As a reminder to ask a question. Please press the star key followed by want when your touch tone telephone.

Withdraw your question press the pound key again Thats star one to ask a question. Please standby, while we compile the Q&A roster.

Our first question comes from the line of Chris <unk>.

Jack Anders: In our RAS-ON inhibitor pipeline, we continue to anticipate IND filings for both RMC6291 and RMC6236 in the first half of 2022 and selection of a third RAS-on inhibitor development candidate later this year. For RMC4630, later this year, we anticipate selection by Amgen of a dose for further study with sodoracib in code break 101 and to begin dosing patients in our new O3 study with I'll now turn things over to Jack Anders to review our financial results.

Tiny with Goldman Sachs. Your line is open.

Chris Shibutani: Yes. Hi, thanks very much for the questions. I want to get a sense for timelines for clinical data. A lot of progress and updates with your clinical planning here, obviously. With the study that you have with the sotorasib, this RMC-4630-03 study, it looks as if we're gonna get the preliminary findings in H2 2022. Can you help put that timeline in context with your confidence in starting the phase 2 now? Also, will we be able to get a sense for what phase 1 data looks like?

Chris Shibutani: Yes. Hi, thanks very much for the questions. Want to get a sense for timelines for clinical data. A lot of progress and updates with your clinical planning here, obviously. With the study that you have with the sotorasib, this 03 study, it looks as if we're gonna get the preliminary findings in H2 2022. Can you help put that timeline in context with your confidence in starting the phase 2 now? Also, will we be able to get a sense for what phase 1 data looks like?

Yes, hi, thanks, very much for the questions.

Want to get a sense for timelines for clinical data and a lot of progress and updates with your clinical planning here obviously.

With the study that you have with the tourists. This <unk> III study.

It looks as if we're going to get the preliminary findings in the second half of next year 2022 can you help put that timeline in context with.

Your confidence in starting the phase two now and also.

So.

Jack Anders: Thank you, Mark, and good afternoon, everyone. We ended the quarter with $646 million in cash, cash equivalents, and investments. Revenue for the second quarter of 2021 was $8.7 million and consists entirely of revenue under our collaboration agreement with Sinovac. Total operating expenses for the second quarter of 2021 increased. 53.2 million, largely driven by R&D expenses, which were $45.9 million during the quarter. The net loss for the second quarter of 2021 was $44.3 million, or $0.60 per share.

Will we be able to get a sense for what phase one data looks like.

Mark Goldsmith: Thanks, Chris. This is Mark Goldsmith. Thanks for asking your questions. Good to hear from you. I think I'll ask Steve Kelsey to comment. There were several pieces built into that question. Maybe Steve can tackle them for you.

Thanks, Chris.

Thanks for asking your question sitting here from you I think I'll ask Steve Kelsey to comment there were several cases built into that question.

On Florida.

Steve Kelsey: Yeah. Thanks, Chris. I'll try to answer your questions in a logical sequence if I can. Firstly, the 03 study to which we refer is complementary to the Amgen CodeBreaK 101c study. The totality of the data will be evaluated together, and we expect, as we said, the first readout actually towards the end of next year. The Phase 1 data to which you allude, there is going to be a very brief safety run-in for the 03 study, where we are compelled to do that because a recommended Phase 2 dose schedule has not yet been defined with that we can legitimately and ethically start the 03 study with.

Steve Kelsey: Yeah. Thanks, Chris. I'll try to answer your questions in a logical sequence if I can. Firstly, the RMC-4630-03 study to which we refer is complementary to the Amgen CodeBreaK 101C study. The totality of the data will be evaluated together, and we expect, as we said, the first readout actually towards the end of next year.

Yes, Thanks, Chris.

I'm trying to ask.

Last question.

Sure.

Uh huh.

Firstly.

The other three studies.

Rich.

Yes.

Is complementary to the <unk> study.

And so.

The data the totality of the space.

<unk> GAAP.

And as.

As we said.

Towards the end of next year.

Jack Anders: Turning to financial guidance, we continue to expect full-year gap net loss to be between $170 and $190 million, which includes estimated non-cash stock-based compensation expense of approximately $20. Our gap net loss for the first half of 2021 was $81 million, and we expect net loss to increase during the second half of the year, primarily driven by increases in operating expenses as we advance our preclinical and clinical programs. And with that, I'll now turn the call back over to Mark.

Steve Kelsey: The Phase 1 data to which you allude, there is going to be a very brief safety run-in for the RMC-4630-03 study, where we are compelled to do that because a recommended Phase 2 dose schedule has not yet been defined without that we can legitimately and ethically start the RMC-4630-03 study with.

The.

Phase one days, which.

That is going to be a.

Very great safety run ins as we study.

In house to do that.

Because a recommended phase two dose and schedule has not yet been defined we can do that.

<unk>.

As we saw in interesting ways.

Steve Kelsey: Obviously, we will be able to use that for the expansion of the 03 study. What we cannot do is comment on when Amgen will release data from the Phase 1 component of the CodeBreaK 101c study other than we are guiding to the fact that they will select a dose in H2 of this year. What we can't tell you is when they will disclose that.

Steve Kelsey: Obviously, we will be able to use that for the expansion of the 03 study. What we cannot do is comment on when Amgen will release data from the phase I component of the CodeBreaK 101C study other than we are guiding to the fact that they will select a dose in H2 this year. What we can't tell you is when they will disclose that.

And obviously, we will be able to.

Yes.

The expansion study what we do is comment on when and you do release data from the studies won't components of the Cobra worldwide C study all of that we are guiding to the Pfizer will select.

Jack Anders: Thank you, Jack. We believe that ResMed is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients. We have a compelling strategy, a growing set of exciting product assets, and a strong balance sheet. We're proud of the tireless commitment to patients by our organization and are grateful to the patients and their families and the many partners who work with us for providing ResMed with the opportunity to advance our unique pipeline of RAS-on inhibitors and RAS companion inhibitors, which we believe may transform the treatment of RAS-addicted cancers in the future. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session. Operator?

In the second half of this year.

Thompson.

Discuss.

Chris Shibutani: Okay, that's helpful. With the studies that have been discontinued with the Amgen program, can you provide us with a preliminary sense for what impact you feel the design of the studies may have factored into this outcome and the decision?

Okay. That's helpful.

With the studies that have been discontinued.

With the Amgen program can you provide us with a preliminary sense for what impact you feel the design of the studies may have factor into this.

The outcome in the decision.

Mark Goldsmith: Just to clarify, you're talking about the cobimetinib and osimertinib studies, the 02 studies?

Just to clarify you are talking about the Kobe.

Chris Shibutani: Yes, that's correct. Yeah.

<unk> plus <unk>.

Yes, that's correct yeah.

Mark Goldsmith: I'm not sure. Steve, do you wanna comment on that? I'm not sure what design of the studies, what aspect of design you were referring to. It's really the choice of drugs that we're combining with there, but maybe Steve can clarify.

I'm not sure Steve you want to comment on that Im not sure with design of the studies what aspects of the design youre, referring to is really the choices.

Operator: Thank you. As a reminder to ask the

Operator: Please press the star key followed by 1 on your touch tone telephone. To withdraw your question, press the pound key. Again, that's star 1 to ask the question. Please stand by while we compile the Q&A roster.

Growth.

We're combining with there, but maybe you can clarify.

Steve Kelsey: Yeah, I think there's 2 components to the question. One is what decision are we making and why are we making it? Then the second is how the design of both the combo MEK inhibitor combination and the RAS(ON) combination contributed to the fact that we didn't see as encouraging efficacy as we want to see moving forward. Let's be clear about the reasons why we're not moving forward with those two combinations. The first and most compelling one is that the efficacy profile wasn't sufficiently compelling to justify moving forward.

Steve Kelsey: Yeah, I think there's two components to the question. One is what decision are we making and why are we making it? The second is how the design of both the combo MEK inhibitor combination and the RAS(ON) combination contributed to the fact that we didn't see as encouraging efficacy as we want to see moving forward. Let's be clear about the reasons why we're not moving forward with those two combinations. The first and most compelling one is that the efficacy profile wasn't sufficiently compelling to justify moving forward.

Yes.

Two questions.

Question, one is what Rob just one decision only Nike and why are we making.

And then the second is how the design of the both the cutting.

Operator: How we compiled the Q&A roster

Method, a culmination of the ultimate combination cautious view.

Operator: Our first question comes from the line of Chris Shibutani with Goldman Sachs. Your line is open.

Sure.

<unk>.

Didn't see as encouraging efficacy so we will see the floor.

Chris Shibutani: Yes, hi. Thanks very much for the questions. I want to get a sense of timelines for clinical data. There will obviously be a lot of progress and updates with your clinical planning here. With the study that you have with the TORACEB, this O3 study, it looks as if we're going to get the preliminary findings in the second half of next year, 2022. Can you help put that timeline in context with your confidence in starting Phase II now? And also, will we be able to get a sense for what the Phase I data looks like?

So let's be clear.

<unk>.

The reasons why we are not moving forward with those two combinations.

And I'll ask another one is that the efficacy profile sufficiently compelling to justify moving forward, but there is a.

Steve Kelsey: There is also a large component of prioritization here as well, that we, you know, we have been very publicly moving towards combining the companion inhibitors that we have, which include RMC-4630, with RAS-directed therapies that we and others are making. That's an important part of our consideration here. It's really about what do we think, where do we think the best place to go for RAS-addicted cancers and patients with RAS-addicted cancers is, as much as it is the data for the sake of the study. I don't think there was any design fault with the studies. We think we have comprehensively tested the hypothesis, at least as far as we can with a MEK inhibitor, combo MEK inhibitor. The data is fairly, in our opinion, conclusive in that respect.

Steve Kelsey: There is a large component of prioritization here as well, that we, you know, we have been very publicly moving towards combining the companion inhibitors that we have, which include RMC-4630, with RAS-directed therapies that we and others are making. And that's an important part of our consideration here. It's really about what do we think, where do we think the best place to go for RAS addicted cancers and patients with RAS addicted cancers is, as much as it is the data for sake of the study.

There's also a large component of the prioritization here as well.

We have the.

Very calculated moving towards combining the companion of datasets that we have.

Which include our sequels.

With less direct therapies.

Mark A. Goldsmith: Yeah, thanks Chris. I'll try to answer your questions.

Hey.

And that's an important part of our consideration.

Consideration here is really about what can we say where do we think the best places.

Mark A. Goldsmith: I'm going to be asking questions in a logical sequence like answer. Firstly, the O3 studies, which we refer to as the O3 studies, are complementary to the Amgen-Kerrigan-Wansi study, and so...

Yes.

Cancers in patients with prostate cancer.

As much as it is.

Steve Kelsey: I don't think there was any design fault with the studies. We think we have comprehensively tested the hypothesis, at least as far as we can with a MEK inhibitor, combo MEK inhibitor. And the data is fairly, in our opinion, conclusive in that respect.

Patients are safe.

I don't think there was any design salt Lake the studies.

Mark A. Goldsmith: The data, the totality of the data, will be evaluated together.

We tested the hypothesis.

As far as we can with a message here with some kind of event.

Mark A. Goldsmith: As we said, the first run-up is actually towards the end of next year.

Mark A. Goldsmith: There is going to be a... Very brief one.

And as the data is.

Mark A. Goldsmith: We are compelled to do that because a recommended phase 2 dose has not yet been defined. We can legitimately say

Sure.

As conclusive in that respect.

Steve Kelsey: As you are aware, we are still supporting the Netherlands Cancer Institute to do a study in combination with an ERK inhibitor in pancreatic and colon cancer. In as much as that represents a slight variation on the hypothesis, you know, we'll be interested to see the outcome from that experiment. I think we designed the best experiment we could, and we are making the decision we made for compelling reasons, both strategically and financially.

Steve Kelsey: As you are aware, we are still supporting the Netherlands Cancer Institute to do a study in combination with an ERK inhibitor in pancreatic and colon cancer. In as much as that represents a slight variation on the hypothesis, then you know, we'll be interested to see the outcome from that experiment. I think we designed the best experiment we could, and we are making the decision we made for compelling reasons, both strategically and financially.

Thank you.

Yes.

Mark A. Goldsmith: And obviously, we will be able to use that for the expansion of the ACES study. But what we cannot do is comment on when Amgen will release data from the Phase I components of the CoBreak101c study, other than we are guiding to the fact that they will select a dose in the second half of this year. But what we can't tell you is when they will disclose it.

We we are still supporting the Netherlands passengers.

I studied in combination with them.

In contrast control.

And in as much as that represents a slight variation on the hypothesis.

We will be interested to see the outcome from that experiment I think we designed the best experiment because.

And we are making the decision we made for competitive reasons both strategically.

Chris Shibutani: Okay, that's helpful. With the studies that have been discontinued with the Amgen...

Mark Goldsmith: Maybe if I could just add to that, Chris, just to see if I can get at the question that you're raising here. I think it goes back to the indirect strategy of the clamping approach, which is one that we now disfavor, and that is trying not actually inhibiting the cancer driver, but inhibiting the pathway upstream and downstream.

Okay.

And then if I could just add to that Chris just to see if I can get at the question that you're that you are raising here I think it goes back to the indirect strategy of the classic approach which is.

Chris Shibutani: Can you provide us with a preliminary sense of what impact you feel?

Chris Shibutani: Do you have a sense of how much you feel the design of the studies may have factored into this outcome and the decision? Just to clarify, are you talking about the CoV-19 and Oxymeritinib studies, the O2 studies?

One that we announced this favor and that is trying not actually exhibiting the cancer driver, but inhibiting the pathway upstream and downstream.

Mark Goldsmith: Mm-hmm.

Mark Goldsmith: That appears to deliver some benefit. There's modest benefit. We did see a PR in a KRAS G12C-positive patient, but it's just not sufficient, in our view, to justify pursuing. Furthermore, we have direct inhibitors of many different variants of RAS coming forward very shortly, as you know. That makes much more sense to us, is to combine the direct RAS inhibitor with the RAS Companion Inhibitors. After all, we call the RAS Companion Inhibitors RAS Companion Inhibitors to indicate that they'll be combined with RAS inhibitors. I think that all makes sense, but maybe that's the design feature you're asking about. The hypothesis seemed reasonable. There was clinical data to support it, and there's a serious unmet need that couldn't be satisfied by any existing compound, so we tested it.

Mark Goldsmith: That appears to deliver some benefit. There's modest benefit. We did see a PR in a KRAS G12C positive patient, but it's just not sufficient, in our view, to justify pursuing. Furthermore, we have direct inhibitors of many different variants of RAS coming forward very shortly, as you know. That makes much more sense to us, to combine the direct RAS inhibitor with the RAS Companion Inhibitor. After all, we call the RAS Companion Inhibitors to indicate that they'll be combined with RAS inhibitors.

That appears to deliver some benefit is modest benefit.

Chris Shibutani: Yes, that's correct, yeah. I'm not sure. Steve, do you want to comment on that? I'm not sure what design studies, what aspect of design you were referring to was really the choice of drugs that we're combining with there, but maybe Steve can clarify. You know, I think there are two components to the question, one is what decision are we making, and one is what decision are we making?

We didn't see a PR payoffs chipotle.

Positive patients, but it's just not sufficient in our view to justify pursuing and Furthermore, we have directly inhibitors of many different variants of drafts coming forward very shortly as you know.

So that makes much more sense to us was to combine them.

To provide a direct RAF inhibitor with with the rest of the Pan inhibitor. After all we called Ras companion inhibitors, perhaps dependent.

Mark Goldsmith: I think that all makes sense, but maybe that's the design feature you're asking about. The hypothesis seemed reasonable. There was clinical data to support it, and there's a serious unmet need that couldn't be satisfied by any existing compound, so we tested it.

Combined with <unk> inhibitors, so I think that makes sense, but maybe that's the design feature you're asking about the.

Chris Shibutani: And then the second question is how the design of both the Kirby method combination and the alternate method combination of culture would be used.

The hypothesis is reasonable there was clinical data to support it.

And there is a serious unmet need that couldnt be satisfied by any existing compound. So we tested it but.

Chris Shibutani: and the combination contributed to the fact that we... Unknown Executive, Chris Shibutani, Erin Graves, Wei Chang, Jack Anders, Erin Graves, Wei

Mark Goldsmith: We don't think it will be. Those results are dispositive or read through to a strategy that involves a direct inhibitor plus a RAS Companion Inhibitors. I think that's really the key point maybe that you're getting to.

Mark Goldsmith: We don't think it will be. Those results are dispositive or read through to a strategy that involves a direct inhibitor plus a RAS Companion Inhibitor. I think that's really the key point maybe that you're getting to.

But we don't think it will be those results are.

This positive or read through to a strategy that involves a direct inhibitor plus a ras companion.

Really the key point.

Chris Shibutani: Yeah, I appreciate the thoughtful responses, and we'll certainly look forward to your continued progress on the wholly-owned RAS(ON) programs. Thank you.

Chris Shibutani: The reasons why we're not moving forward with those two combinations.

Youre getting.

No I appreciate the thoughtful responses and we will certainly look forward to continued progress on the wholly owned rason programs. Thank you.

Chris Shibutani: Unknown Executive, Chris Shibutani, Erin Graves, Wei Chang, Jack Anders, Wei Chang

Mark Goldsmith: Thanks, Chris.

Operator 2: Thank you. Our next question comes from the line of Marc Frahm with Cowen. Your line is open.

Operator: Thank you. Our next question comes from the line of Marc Frahm with TD Cowen. Your line is open.

Thanks, Chris.

Thank you.

Our next question comes from the line of Mark <unk> with Cowen Your line is open.

Marc Frahm: Hey, thanks for taking my questions. Maybe just to start on the 03 trial with the brief safety run-in that you discussed. Is all of it gonna be run at 200 mg day 1, day 2, or are you gonna have some dose exploration built into that run-in? Then related on that trial, just why is the right structure to move now with a RevMed sponsored trial rather than you know waiting for the formal selection of a recommended phase 2 dose within CodeBreaK and kind of keeping everything contained within that first collaboration with Amgen?

Marc Frahm: Hey, thanks for taking my questions. Maybe just to start on the 03 trial, with the brief safety run-in that you discussed. Is all of it gonna be run at 200mg Day 1, Day 2, or are you gonna have some dose exploration built into that run-in? Related to that trial, just why is the right structure to move now, with a RevMed sponsored trial rather than, you know, waiting for the formal selection of a recommended phase 2 dose within CodeBreaK and kind of keeping everything contained within that first collaboration with Amgen?

Hi, Thanks for taking my questions.

Chris Shibutani: We have been very popular moving towards combining the companion inhibitors that we have, which include RMC416.

Maybe just to start on the <unk> III trial.

A brief safety run in that you discussed is that it's all going to be run at 200 milligrams day. One day, two or are you going to have some dose exploration built into that.

Chris Shibutani: We are with Restorative Therapies.

Chris Shibutani: of the Week, and others. Thank you. And that's an important part of our consideration here; it's really about...

Into that run in and then related on that trial is just what is the right structure to move now with Revlimid sponsored trial rather than.

Chris Shibutani: What do we think? Where do we think the best place to go is?

Chris Shibutani: RAS Addictive Cancers and Patients with RAS Addictive Cancers is, as much as it is the data per se from the study.

Waiting for the formal selection of a.

Chris Shibutani: [inaudible]

Our recommended phase two dose within Covid break and kind of keeping everything contained within that first collaboration with Amgen.

Chris Shibutani: of the hypothesis, at least as far as we can with a mechanism, a coded mechanism.

Mark Goldsmith: Yeah. Thanks, Mark. Appreciate those questions. I think I'm gonna comment on the second question, and then Steve can take a crack at the first one, and you can add to the second one if he wants, which is why do it now? I think it's important to emphasize that this is a study specifically of lung cancer patients as opposed to the exploratory ongoing CodeBreaK 101c study. We feel there's sufficient information now to really go after that. There is some overlap with CodeBreaK 101c, but this is a more advanced design. It builds on things that we've learned over the last couple of years that we didn't know when the CodeBreaK study was designed. We think it's also urgent to get to the answers to the questions.

Mark Goldsmith: Yeah. Thanks, Mark. I appreciate those questions. I think I'm gonna comment on the second question, and then Steve can take a crack at the first one, and you can add to the second one if he wants, which is why do it now? I think it's important to emphasize that this is a study specifically of lung cancer patients as opposed to the exploratory ongoing CodeBreaK 101C study. We feel there's sufficient information now to really go after that.

Yes, Thanks, Mark I appreciate you for those questions I think I'm going to comment on the second question and then Steve can take a crack at the first of all I can answer the second whether it be loss, which is why why do it now.

Chris Shibutani: And the data is, in our opinion, conclusive in that respect. And, as you are aware... We are still supporting the Melbourne Cancer Institute through a...

And to emphasize that this is a study specifically of lung cancer patients as opposed to the exploratory ongoing for <unk> 101 C study.

Chris Shibutani: And we are making the decision we made for compelling reasons, both strategically and

And we feel there are sufficient information now really go after that.

Mark Goldsmith: There is some overlap with CodeBreaK 101C, but this is a more advanced design. It builds on things that we've learned over the last couple of years that we didn't know when the CodeBreaK study was designed. We think it's also urgent to get to the answers to the questions.

Chris Shibutani: We did the best experiment we could, and we are making the decision we made for compelling reasons, both strategically and quantitatively. And maybe I could just add to that, Chris, just to see if I...

There is some overlap with COVID-19 breakdown on Wednesday, but this is a more advanced designs and builds on things that we've learned over the last couple of years that we didn't know when the Covid study was designed.

And we think that's also urgent.

Mark Goldsmith: The question that we're posing here has to do in part with the co-mutations that Steve alluded to. We think it makes sense to move forward, and there will be just a little bit of overlap in time there, but it will give us the advantage of getting to the answer as robustly as possible and as quickly as possible with regard to lung cancer. Steve, you can comment on that. You can comment on the first question, whatever you'd like.

Mark Goldsmith: The question that we're posing here has to do in part with the co-mutations that Steve alluded to. We think it makes sense to move forward. There will be just a little bit of overlap in time there, but it will give us the advantage of getting to the answer as robustly as possible and as quickly as possible with regard to lung cancer. Steve, you can comment on that. You can comment on the first question, whatever you'd like.

To get to the answers to the questions and the question that we're closing here has to do in part with the co mutations as Steve alluded to so we think it makes sense to move forward.

Chris Shibutani: Some benefit, there's a modest benefit. We didn't see a PR in the KRS-GCoV positive patients, but it's just not sufficient in our view to justify continuing. And furthermore, we have direct inhibitors of many different variants of RAS coming forward very shortly, as you know, and so that makes much more sense to us to combine them, to combine a direct RAS inhibitor with a RAS-companion inhibitor, and after all, we call RAS-companion inhibitors RAS-companion inhibitors to indicate that they'll be combined with RAS inhibitors.

And.

There will be just a little bit of overlap in time, there, but it will give us the advantage of getting to the answer.

Lastly, as possible as quickly as possible with regard to lung cancer.

You can comment on that you can comment on the first question what everybody.

Steve Kelsey: I think you've answered the second part of the question, Mark, and unless Mark has a follow-up question, we'll happily address it. With regards to the, you know, the dose exploration at the beginning, it's not really a dose exploration. I mean, we basically have two choices, 140 milligrams day one, day two, or 200 milligrams day one, day two.

Okay.

Second.

Question.

Small.

Sure.

The address is.

With regards to the.

Exploration of the gig is not really a dose exploration.

They have two choices.

What makes it work.

Mark Goldsmith: You know, as we said, we know, and I think we publicly disclosed where Amgen are in CodeBreaK 101c with regard to dose of RMC-4630 in combination with their full doses of sotorasib. We fully expect to move forward with those two components of the study at what we call the target dose of RMC-4630, which is 200mg, day one, day two. With the current timing and just the way that the CodeBreaK 101c study is at the moment, we're obliged to build a short safety run-in into our study. It's more of an operational detail than it is a real sort of dose exploration.

Mark Goldsmith: You know, as we said, we know, and I think we publicly disclosed where Amgen is in CodeBreaK 101C with regard to dose of RMC-4630 in combination with their full doses of sotorasib. We fully expect to move forward with those two components of the study at the, what we call the target dose of RMC-4630, which is 200mg, day one, day two. With the current timing and the, just the way that the CodeBreaK 101C study is at the moment, we're obliged to build a short safety run-in to our study. It's more of an operational detail than it is a real sort of dose exploration.

So.

Chris Shibutani: So I think that all makes sense, but maybe that's the design feature you're asking about. The hypothesis seemed reasonable. There was clinical data to support it, and there's a serious unmet need that couldn't be satisfied by any existing compounds, so we tested it, but we don't think it will be those results.

When.

As we've said, we know and I think we publicly disclosed.

111 <unk>.

Doses RMC dosing of <unk> in combination with vessel versus sell through us.

We fully expect to move forward with the phase II.

Chris Shibutani: I appreciate the thoughtful responses, and we'll certainly look forward to your continued progress on the wholly owned RASAN programs. Thank you.

This study at the what we what we call recall.

<unk> 200 milligrams.

Marc Alan Frahm: Our next question comes from the line of Marc Frahm with Cohen.

On day, one so with.

Marc Alan Frahm: Marc Frahm with Cohen. Your line is open. Thanks for taking my questions. Maybe just to start on the O3 trial, but the brief safety run-in that you discussed, is that?

With the current timing.

<unk>.

Just the way.

Co vary wildly study is.

Is where.

We are obliged to bill.

Sure.

It is all study so.

Marc Alan Frahm: Is all of it going to be run at 200mg day 1, day 2?

It's more of an operational detail.

Marc Alan Frahm: Day 1, Day 2, or are you going to have some dose exploration built into that run-in? And then, related to that trial, why is the right structure to move now with a RevMed-sponsored trial rather than wait for the formal selection of a recommended Phase 2 dose within Code Break and kind of keep everything contained within that first collaboration with Amgen? Yeah, thanks, Marc.

Mark Goldsmith: you know, we went on, then we'll go back and revisit it. I would be surprised if we don't end up using our target dose in combination with the 96mg of sotorasib.

Exploration.

Mark Goldsmith: You know, we went on, then we'll go back and revisit it. I would be surprised if we don't end up using our target dose in combination with the 96 milligrams of sotorasib.

Well no.

I'll go back and revisit.

I will argue these processes.

Using our top dose in combination with <unk>.

John.

Yes.

Marc Frahm: Okay. Thanks. That's very helpful. Maybe a bigger picture question, just given the kind of totality of the updates today, what have you kind of learned about the level of maybe wild-type RAS inhibition that's acceptable and kind of how that makes you think about designing your multi-RAS inhibitors on it. Kind of how much spillover effect either the multi-RAS or the targeted ones are allowed or kind of allowed to have before their acceptable profile to move in when you ultimately wanna use them in combinations?

Marc Frahm: Okay. Thanks. That's very helpful. And then maybe a bigger picture question, just given the kind of totality of the updates today, what have you kind of learned about the level of maybe wild-type RAS inhibition that's acceptable and kind of how that makes you think about designing your multi-RAS inhibitors on it? Kind of how much spillover effect either the multi-RAS or the targeted ones are allowed or kind of allowed to have before their acceptable profile to move in when you ultimately wanna use them in combinations?

Okay. Thanks.

Very helpful.

And then maybe a bigger picture question, just given the totality of the updates today.

What are you kind of learned about the level of wild type Ras inhibition, that's acceptable and how that makes you think about designing your multi ras inhibitors on kind of how much spillover effect, either the multi ras or the targeted ones are allowed.

Mark A. Goldsmith: I appreciate those questions. I think I'm going to comment on the second question and then Steve can take a crack at the first one, and you can add to the second one if you want, which is why why do it now? I think it's important to emphasize that this is a study specifically of lung cancer patients as opposed to the ongoing exploratory ongoing co-grade 101c study. And we feel there's sufficient information now to really go after that. There is some overlap with Code Break 101C, but this is a more advanced design.

A allowed to have before they are acceptable profile to move in when you ultimately want to be using a <unk> combination.

Mark Goldsmith: Thanks, Mark. Let me just add something to that previous discussion about timing. It just also occurs to me that it's important to mention. Amgen is collaborating with us on this RMC-4630-03 study. They view it as an expansion, a complement to the current CodeBreaK 101c study, just as we do, as does Sanofi. We have, you know, three companies all getting together agreeing on that concept. Based on that, there's no reason not to proceed with it. As Steve said, we're so close to finalization of dose, that there's no reason to wait.

Mark Goldsmith: Thanks, Mark. Let me just add something to that previous discussion about timing. It just also occurs to me that it's important to mention. Amgen is collaborating with us on this 03 study. They view it as an expansion of complement to the current CodeBreaK 101C study, just as we do, as does Sanofi. We have, you know, three companies all getting together agreeing on that concept. Based on that, there's no reason not to proceed with it. As Steve said, we're so close to finalization of dose that there's no reason to wait.

Thanks, Mark let me just add something to that previous discussion about timing and just also occurs to me. This is important too to diminish.

To mention.

<unk> is collaborating with us on this <unk> III study.

Just view it as an extension of the expansion of compliment to the current <unk> study.

As we do as dose therapy. So we have three companies all getting together reign on that concept and based on that.

Mark A. Goldsmith: It builds on things that we've learned over the last couple of years that we didn't know when the Code Break study was designed. And we think it's also urgent to get to the answers to the questions. And the question that we're posing here has to do, in part, with the co-mutations that Steve alluded to. So we think it makes sense to move forward. And there will be just a little bit of overlap in time there, but it will give us the advantage of getting to the answer as robustly as possible and as quickly as possible with regard to lung cancer. Steve, you can comment on that; you can comment on the first question, whatever you'd like.

There's no reason not to proceed with it and as Steve said, we're so close to finalization of dose.

Mark Goldsmith: Now with regard to what have we learned, again, maybe I'll just take a crack at this, which is we already knew that SHP2 inhibition has a tolerability constraint because of its effect in normal tissues. There's nothing selective about its action in tumor cells, as you know. We designed the intermittent dosing regimen, which we still have a lot of confidence in, as a way to take advantage of tumor cells being able to tip into apoptosis if they're covered deeply enough and long enough, but they don't require continuous coverage. We're trying to create a pharmacologic way of manipulating tumor cells versus normal cells. There's a limit to that. The limit to that is probably 200 milligrams day one, day two, you know, or thereabout in a dosing regimen.

There's no reason to wait.

Mark Goldsmith: Now with regard to what have we learned, again, maybe I'll just take a crack at this, which is, we already knew that SHP2 inhibition has a tolerability constraint because of its effect in normal tissues. There's nothing selective about its action in tumor cells, as you know. We designed the intermittent dosing regimen, which we still have a lot of confidence in, as a way to take advantage of tumor cells being able to tip into apoptosis if they're covered deeply enough and long enough, but they don't require continuous coverage.

Now with regard to what have we learned.

Maybe I'll just take a crack at this switches.

We already do that <unk> inhibition.

S. A tolerability constrained because of its affected normal tissues theres nothing selective about action in two yourselves as you know.

We designed the intermittent dosing regimen, which we still have a lot of confidence in as a way to take advantage of.

Tumor cells being able to ticket apoptosis covered deeply on long enough. They don't require continuous coverage. So we're trying to create a pharmacologic waste manipulating tumor cells versus normal cells, but there's a limit to that.

Mark Goldsmith: We're trying to create a pharmacologic way of manipulating tumor cells versus normal cells. There's a limit to that. The limit to that is probably 200 milligrams day one, day two, you know, or thereabout, in a dosing regimen.

The limit that is probably 200 milligrams to one pay too.

Thereabouts.

Stephen M. Kelsey: I think you've answered the second part of the question, and that's Mark's follow-up question. We'll happily address it, but with regard to the, you know, the dose expiration at the beginning, it's not really a dose expiration. I mean, we basically have two choices, 140 milligrams of A1, B2, or 200 milligrams of A1, B2. We're currently, as we said, and I think we've publicly disclosed where our antigens are in CoV-101C with regard to the dose of RMC4630 in combination with that full dose of sulphuric acid.

Mark Goldsmith: We have seen objective responses with that sort of regimen. It's clearly a very active agent with our compound at that, you know, that kind of regimen. We're also having to take into account the landscape. When there are G12C specific, you know, mutant-specific inhibitors that are in play, as Lumakras is now approved, and there will be others coming, we have to make sure that what we're doing is additive in terms of clinical benefit, and not sub what you can achieve with those targeted mutant-selective agents. I think we're still net of all that is we're still quite confident that SHP2 inhibitor brings antitumor activity. There's just no doubt about that now.

Mark Goldsmith: We have seen objective responses with that sort of regimen. It's clearly a very active agent with our compound at that, you know, that kind of regimen.

And the dosing regimen, and we have seen objective responses with that sort of regimen. So it's clearly very active agents with our compounds.

That kind of regimen, but.

Mark Goldsmith: We're also having to take into account the landscape. When there are G12C specific, you know, mutant-specific inhibitors that are in play, as Lumakras is now approved, and there will be others coming, we have to make sure that what we're doing is additive in terms of clinical benefit, and not suboptimal what you can achieve with those targeted mutant-selective agents. I think net-net of all that, we're still quite confident that SHP2 inhibitor brings antitumor activity. There's just no doubt about that now.

We're also having to take into account the landscape and when there are <unk> specific.

Specific inhibitors that are in play as when craft is now approved and there will be others coming.

We have to make sure that what we're doing is attitude in terms of clinical benefit.

Not not so what you can achieve with those targeted.

Fluctuations and so.

I think we're so net net all of that is we're still quite confident that ship two different grades of antitumor activity. There's just no doubt about that now.

Mark Goldsmith: When dosed in the ways that we dose it, and we fully expect that it'll show additivity, but that's why we have to do the clinical studies when we combine it with RAS inhibitors. With regard to read-through to RMC-6291, which is the G12C selective inhibitor, I don't think there's any read-through whatsoever that we're aware of to a mutant selective inhibitor like G12C selective inhibitor that we're aware of. With regards to RMC-6236, which is a multi-RAS inhibitor, I think you're right in principle, you know, to raise that question. I think we had already learned what we needed to learn before. I don't think this changes that anything was changed by the results that we just described.

Stephen M. Kelsey: So we fully expect to move forward with the Phase II component of this study at the, what we call the target dose of RMC4630, which is 200 milligrams, day one, day two. With the current timing and the, just the way that the CoV-101C study is at the moment, we're obliged to build a short safety bucket into our study. So it's more of an operational detail, but it is a real sort of dose expiration. You know, we've gone a long way, and I'll...

And when dosed in a way so doses and we fully expect that it'll show activity, but that's why we have to do the clinical studies when we combined with <unk> inhibitors.

With regard to read through to RMB 691, which is the <unk> selective inhibitor I don't think theres any reasonable whatsoever that we're aware of to view selective inhibitor why did she fell see selective inhibitor.

Mark Goldsmith: With regards to RMC-6236, which is a multi-RAS inhibitor, I think you're right in principle, you know, to raise that question. I think we had already learned what we needed to learn before. I don't think this changes that anything was changed by the results that we just described.

That we're aware of with regard to a RMB 63, six which is <unk>.

Congrats inhibitor I think youre right in principle to raise that question.

I think we had already learned what we needed to learn before I don't think this changes if anything is changed by the results that we just described.

Stephen M. Kelsey: I would be surprised if we don't end up using non-targeted dosing.

Stephen M. Kelsey: We don't end up using our target base in co-operation with them.

Mark Goldsmith: That there is a limit to how much you can dose that, how continuously you can inhibit all RAS targets. That's for sure. We also know that RAS-addicted tumors are particularly sensitive to inhibition of the RAS driver, and that it is possible to achieve quite deep antitumor effects. We show this, as you know, across multiple preclinical models that we never achieved with a SHP2 inhibitor alone or a SHP2 inhibitor even when combined with a MEK inhibitor. I think the tolerability limits are there, but in the right context and when combined, you know, specifically with inhibiting the mutant driver, even if it's not a mutant selective inhibitor, one can achieve quite profound effects.

Mark Goldsmith: That is that there is a limit to how much you can dose that, how continuously you can inhibit all RAS targets. That's for sure. But we also know that RAS-addicted tumors are particularly sensitive to inhibition of the RAS driver, and that it is possible to achieve quite deep antitumor effects. We show this, as you know, across multiple preclinical models that we never achieved with a SHP2 inhibitor alone or a SHP2 inhibitor even when combined with a MEK inhibitor.

That is that there is a limit to how much you can build a SaaS.

Marc Alan Frahm: Okay, thanks, that's very helpful. And then maybe a bigger picture question, just given the kind of totality of the updates today, what have you kind of learned?

Continuously you can debate all Ras targets.

That's for sure.

But we also know that rapidly the tumors are particularly sensitive to inhibition of the Ras driver.

And then it is possible to achieve quite deep.

Marc Alan Frahm: Maybe a bigger picture question, just given the totality of the updates today, what have you learned about the level of wild-type RAS inhibition that's acceptable and how that makes you think about designing your multi-RAS inhibitors on and how much spillover effect either the multi-RAS or the targeted ones are allowed to have before they're an acceptable profile to move in when you ultimately want to use them in combination. Thanks, Marc.

Tumor effects and we showed as you know across multiple preclinical models that we never achieved with the ship two inhibitor alone Forrester two inhibitor, even when combined with a message in there. So I think the tolerability limits.

Mark Goldsmith: I think the tolerability limits are there, but in the right context and when combined specifically with inhibiting the mutant driver, even if it's not a mutant selective inhibitor, one can achieve quite profound effects.

Are there.

In the right context, and when combined spin.

Specifically inhibiting.

The driver even if the Saturday selective inhibitor, one can achieve quite profound effects on as you know there's precedent with average receiver.

Mark Goldsmith: As you know, there's precedent for that with Tasigna, EGFR receptor antagonists, and so on that have had profound impact in tumors at tolerable levels. I think we feel very good about RMC-6236. We continue to evaluate it, but everything continues going in the same direction. We feel terrific about RMC-6291. Then the combination strategy of combining a companion inhibitor with the RAS inhibitor is on the forefront of our thinking. The RMC-4630-03 study, I think, is the first example where we really get to deploy that fully, as we prepare to bring forward the rest of the RAS inhibitor pipeline.

Mark Goldsmith: As you know, there's precedent for that with Tasigna, EGFR receptor antagonists, and so on that have had profound impact in tumors at tolerable levels. I think we feel very good about RMC-6236. We continue to evaluate it, but everything continues going in the same direction. We feel terrific about RMC-6291. Then the combination strategy of combining a companion inhibitor with the RAS inhibitor is on the forefront of our thinking. The 03 study, I think, is the first example where we really get to deploy that fully, as we prepare to bring forward the rest of the RAS inhibitor pipeline.

Jeff receptor antagonist and so on the.

Mark A. Goldsmith: Let me just add something to that previous discussion about timing. It just occurred to me that this is important to mention. Amgen is collaborating with us on this O3 study. They view it as an extension of, expansion of, and complement to the current COBRIC-101C study, just as we do, and so does Sanofi. So, we have, you know, three companies all getting together and agreeing on that concept. And based on that, there's no reason not to proceed with it. As Steve said, we're so close to the finalization of those, so there's no reason to wait.

Profound impacts.

<unk>.

In tumors.

At tolerable levels. So I think we feel very good about RMB 63, six we continue to evaluate it but everything <unk> interaction, we feel terrific about RMB 69, one and then the combination strategy of combining our companion inhibitor with the RAF inhibitor.

On the forefront.

Our thinking and so the <unk> study I think is the first example, where we really get to deploy that fully.

As we prepare to bring forward the rest of the Ras inhibitor pipeline.

Marc Frahm: Okay. Thanks for that. Very helpful.

Okay. Thanks, that's very helpful.

Operator 2: Thank you. Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is open.

Operator: Thank you. Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is open.

Thank you.

Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is open.

Michael Schmidt: Hey, guys. Thanks for taking my questions. I had one regarding the Keytruda combination with RMC-4630. I guess nice to see that you're moving forward here with a phase 2. You know, first question is was it driven predominantly by safety and, you know, mechanistic rationale or also by clinical efficacy data? And then perhaps if you could speak to your decision to move into PD-L1 positive patients in this initial phase 2 study and how we should think about a potential longer-term registration path for this combination.

Michael Schmidt: Hey, guys. Thanks for taking my questions. Yeah, I had one regarding the Keytruda combination with RMC-4630. I guess nice to see that you're moving forward here with a phase 2. You know, first question is was it driven predominantly by safety and, you know, mechanistic rationale or also by clinical efficacy data? And then perhaps if you could speak to your decision to move into PD-L1 positive patients in this initial phase 2 study and how we should think about a potential, you know, longer-term registration path for this combination.

Hey, guys. Thanks for taking my questions.

I had one regarding the Keytruda combination with Ara C 46.30.

Mark A. Goldsmith: Now, with regard to what we have learned? Again, maybe I'll just take a crack at this, which is... We already knew that SIP-2 inhibition has a tolerability constraint because of its effect in normal tissues. There's nothing selective about its action in tumor cells, as you know. We designed the intermittent dosing regimen, which we still have a lot of confidence in, as a way to take advantage of tumor cells being able to tip into apoptosis if they're covered deeply enough and long enough, but they don't require continuous coverage. And so we're trying to create a pharmacologic way of manipulating tumor cells versus normal cells. But there's a limit to that.

Nice to see that you're moving forward here with a phase two.

<unk>.

First question is what was driven predominantly by safety and.

Mechanistic rationale or also by clinical efficacy data in <unk> and then perhaps if you could.

Speak to the decision to move into PD one positive.

Patients in this initial phase III study and how we should think about a potential.

Longer term our registration path for this combination.

Mark A. Goldsmith: And the limit to that is probably 200 milligrams to one day or thereabouts in a dosing regimen. And we have seen objective responses with that sort of regimen. So it's clearly a very active agent with our compound at that, you know, that kind of regimen. But we're also having to take into account the landscape.

Mark Goldsmith: Thanks, Michael. Let me just give a quick preamble and then Steve, I think, can really address the meat of your question. I think the preamble is, we can't disclose anything about the dose escalation work that Sanofi did. They're the sponsor of that study, so you know, when they decide to disclose it, they will. We can't really address your carefully worded question about it was the tolerability or efficacy that drove it. It was primarily intended as a safety and dose escalation study. You know, that was the purpose of it. What's now going to be tested is, as you point out, in PD-L1 positive lung cancer and particularly first-line treatment, so previously untreated patients, which is an exciting move, and maybe Steve can speak to that.

Thanks, Michael Let me just get a quick preamble and then Steve I think you can really address the meat of your question I think the preamble is we can't disclose anything about the <unk>.

Dose escalation, where we did.

There was a sponsor that study so.

When they when they decided to dispose of it. So we can't really address your carefully worded question about tolerability or or efficacy that drove it but but.

Mark A. Goldsmith: And when there are G12 seeds specific. You know, mutant-specific inhibitors that are in play, as LumaCraft has now approved, and there will be others coming, we have to make sure that what we're doing is additive in terms of clinical benefit and not sub what you can achieve with those targeted mutant-selective agents. And so I think we're still, net of all that is, we're still quite confident that SHP2 inhibitor brings anti-tumor activity. There's just no doubt about that now.

Was primarily intended as a safety and dose escalation study that was the purpose of it but what's now going to be tested as you pointed out.

Mark Goldsmith: What's now going to be tested is, as you point out, in PD-L1 positive lung cancer and particularly first-line treatment, so previously untreated patients, which is an exciting move, and maybe Steve can speak to that.

In PD lone positive lung cancer, and particularly first line treatment. So previously untreated pay.

Patients, which is an exciting move and maybe Steve.

Steve Kelsey: Sure. I think it helps to explain where we think we may end up in the positive study, because I think that will explain the rationale behind the study in the first place. If it turns out that adding the SHP2 inhibitor to pembrolizumab in the context of PD-L1 positive non-small cell lung cancer, which by the way does include RAS mutant non-small cell lung cancer, then it really leaves us with two large opportunities. One is obviously that there are a very limited number of drugs that improve outcomes over and above checkpoint inhibitors alone without significantly increasing the toxicity.

Steve Kelsey: Sure. I think it helps to explain where we think we may end up in the positive study, because I think that will explain the rationale behind the study in the first place. If it turns out that adding the SHP-2 inhibitor to pembrolizumab in the context of PD-L1 positive non-small cell lung cancer, which by the way does include RAS mutant non-small cell lung cancer, then we really it leaves us with two large opportunities. One is obviously that there are a very limited number of drugs that improve outcomes over above checkpoint inhibitors alone without significantly increasing the toxicity.

Ken can speak to that.

Sure.

I think.

Helps to explain why we think can be my end.

Sorry, because I think that was the rationale behind the study in the first place.

Mark A. Goldsmith: And when dosed in the ways that we dose it, and we fully expect that it will show additivity, but that's why we have to do the clinical studies when we combine it with RAS inhibitors. With regard to read-through to RMC6291, which is the G12C selective inhibitor, I don't think there's any read-through whatsoever that we're aware of to a mutant-selective inhibitor like G12C With regard to RMC6236, which is a multi-RAS inhibitor, I think you're right in principle to raise that question. However, I think we have already learned what we needed to learn before.

Yes.

<unk>.

H eight terms.

But adding to ship soon.

Remember this is not in the context of the PD lone positive non small cell lung cancer, which by the way. It does include Ras mutant non small cell lung cancer.

Then we really it leaves us with true.

Large opportunities one is obviously.

That's the.

There are a very limited number of drugs that improve outcomes opened about checkpoint inhibitors.

Significantly cruising the toxicity.

Steve Kelsey: Obviously, if SHP2 inhibitor can do that, then that presents a huge opportunity, not just in lung cancer, but in a lot of other tumors where pembrolizumab and other PD-1 or PD-L1 inhibitors are used. The second and probably the, from our perspective, the primary driver when we set about doing this is the fact that checkpoint inhibitors are currently standard of care for RAS mutant lung cancer. We do foresee a future state where the doublet chemotherapy for RAS mutant lung cancer is replaced by the combination of a RAS-directed inhibitor, whether it's a G12C inhibitor or one of our other RAS inhibitors for other RAS mutations, in combination with a companion inhibitor like RMC-4630 and then plus pembrolizumab. Now that requires us to demonstrate that each doublet component of that triplet is tolerable.

And do not prevent.

Mark A. Goldsmith: I don't think this changes anything, that anything has changed by the results that we just described. That is, there is a limit to how much you can dose that, and how continuously you can inhibit all RAS targets. That's for sure, but we also know that RAS-infected tumors are particularly sensitive to inhibition of the RAS driver, and that it is possible to achieve quite deep anti-tumor effects, and we show this, as you know, across multiple preclinical models, that we never achieve with a SHIP-2 inhibitor alone or a SHIP-2 inhibitor even when combined with a MEK inhibitor. So I think the tolerability limit is there. But in the right context, and when combined, you know, specifically with inhibiting agents, as we prepare to bring forward the rest of the rafts into their piping.

A huge opportunity not just in lung cancer or other tumors.

We have another PD one PD lone.

The second is appropriate for losses, such as the primary driver of what we said I believe this is the fact that checkpoint inhibitors as it currently stands the test of rescue lung cancer.

Steve Kelsey: We do foresee a future state where the doublet chemotherapy for RAS mutant lung cancer is replaced by the combination of a RAS-directed inhibitor, whether it's a G12C inhibitor or one of our other RAS inhibitors for other RAS mutations, in combination with a companion inhibitor like RMC-4630 and then plus pembrolizumab. Now that requires us to demonstrate that each doublet component of that triplet is tolerable.

We do foresee a future where the doublet chemotherapy for Ras mutant lung cancer is replaced by a combination of a rash the rest of it is whether it's a regional say negligible.

One of our other Ras inhibitors or other mutations in combination with a component here.

Right.

And then there isn't that close.

To demonstrate leach components, each dominant component of that triplet is tolerable and.

Steve Kelsey: That's the primary intent of that study, which, you know, we have declared a recommended Phase 2 dose and schedule for moving into the Phase 2 expansion of that study. Unfortunately, we're not going to tell you what it is at the moment, but I think when eventually you will learn and, then it will become clear what the tolerability profile looks like. All we can say at the moment is the tolerability profile is perfectly acceptable and encouraging enough for us to want to move forward with Phase 2 efficacy testing. There is a very mechanistic basis for doing it as well. Again, going back, right back to the very beginning.

Steve Kelsey: That's the primary intent of that study, which, you know, we have declared a recommended phase 2 dose and schedule for moving into the phase 2 expansion of that study. Unfortunately, we're not going to tell you what it is at the moment, but I think when eventually you will learn and then it will become clear what the tolerability profile looks like. All we can say at the moment is the tolerability profile is perfectly acceptable and encouraging enough for us to want to move forward with phase 2 efficacy testing. There is a very mechanistic basis for doing it as well. Again, going back, right back to the very beginning.

And that's the primary in terms of that study, which we have we have declared a recommended phase two dose and schedule.

Michael Werner Schmidt: Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is open.

Into the phase two expansion of us Unfortunately.

Michael Werner Schmidt: Hey guys, thanks for taking my questions. I had one regarding the Keytruda combination with RMC 4630.

Well it is a environment.

Great.

Eventually you will.

<unk>.

And it will become clear what the Tolerability profile.

So I hope, we can say the amount of business all of this profile.

Michael Werner Schmidt: I guess it's nice to see that you're moving forward here with a Phase II. You know, the first question is, was it driven predominantly by safety and, you know, mechanistic, rational, or also by clinical efficacy data? And then perhaps you could speak to the decision to move into PD-L1 positive patients in this initial phase 2 study and how we should think about a potential longer-term registration path for this combination. Thanks.

Perfect.

Optical and encouraging enough first wanted to absorb.

C testing.

Very mechanistic basis as well.

Steve Kelsey: In fact, a paper published by Ira Mellman of Genentech back in 2017 showed very clearly that one of the roles of SHP2 is to regulate checkpoint signaling. There's a huge rationale for a SHP2 inhibitor augmenting the effects of checkpoint inhibition. We have also subsequently demonstrated, both in pre-clinical models and in patients, that SHP2 inhibition activates both the innate and adaptive immune system in a way which should be beneficial in an anti-tumor effect. It should be helpful rather than a hindrance.

Steve Kelsey: In fact, a paper published by Ira Mellman of Genentech back in 2017 showed very clearly that one of the roles of SHP-2 is to regulate checkpoint signaling. There's a huge rationale for a SHP-2 inhibitor augmenting the effects of checkpoint inhibition. We have also subsequently demonstrated, both in pre-clinical models and in patients, that SHP-2 inhibition activates both the innate and adaptive immune system in a way which should be beneficial in an anti-tumor effect. It should be helpful rather than a hindrance.

Got it going go back right back very beginning in a paper published by our melanoma Gen set back in 2017.

It showed very clearly one of the roles of shifts.

<unk> checkpoint signaling.

And so there's a huge rationale for a shift to enhance the effects of checkpoint inhibition, we have a whole set of subsequently demonstrates.

Michael Werner Schmidt: Faith to study and how we should think about it. I think the preamble is that we can't disclose anything about the dose escalation work that SAMHSA did. They're the sponsor of that study, so, you know, when they decide to disclose it, they will. So we can't really address your carefully worded question about whether it was tolerability or efficacy that drove it. But it was primarily intended as a safety and dose escalation study. You know, that was the purpose of it. But what's now going to be tested is, as you point out, in PD-L1 positive lung cancer, and particularly as first-line treatment, so previously untreated patients, which is an exciting move. And maybe Steve can speak to that.

Increasingly patients.

Patients shift to a division.

CNA.

After the immune system and the way we should be.

Sure Angie.

June that architecture should be it should be helpful rather than a hindrance.

Steve Kelsey: When you compound the mechanistic basis of SHP2 inhibition as demonstrated in the PDE studies from our clinical trials, the fact that checkpoint inhibitors are standard of care for RAS mutant lung cancer, and the opportunity beyond RAS mutant lung cancer, I think it presents a very compelling place for us to do a study.

Steve Kelsey: When you compound the mechanistic basis of SHP2 inhibition as demonstrated in the PD-1 studies from our clinical trials, the fact that checkpoint inhibitors are standard of care for RAS mutant lung cancer and the opportunity beyond RAS mutant lung cancer, I think it presents a very compelling place for us to do a study.

When you compile the mechanistic basis salt ship to innovation as demonstrated in the Ped studies from our clinical trials.

The facts the checkpoint inhibitors as a standard of tenant the rash.

Michael Werner Schmidt: I think it is...

Michael Werner Schmidt: helps to explain where we think we may end up in the event of a positive study.

So on the opportunity beyond Ras mutant lung cancer, I think that's very compelling.

Michael Werner Schmidt: Because I think that would explain the rationale behind the study in the first place.

Place for us to do this stuff.

Michael Werner Schmidt: If it turns out that adding the chitin inhibitor to Ambryl is valid,

Michael Schmidt: Got it. Okay. Yep, just wanted to get your thoughts on Amgen's recent decision to also study sotorasib with SHP2 inhibitor, actually. Just curious if you have any thoughts on that and perhaps conversely-

Michael Schmidt: Got it. Okay. Yep, just wanted to get your thoughts on Amgen's recent decision to also study sotorasib with the SHP2 inhibitor, actually. Just curious if you have any thoughts on that and perhaps conversely-

Eddie.

Got it Okay and then on.

Michael Werner Schmidt: and Robert Zmab in the context of PD-L1 positive non-small cell lung cancer, which by the way does include RAS mutant non-small cell lung cancer.

Just wanted to get your thoughts on amgen's reasonably close to also study.

Or asset with Novartis shipped to an ever actually just curious if you have any thoughts on that and perhaps Conversely.

Michael Werner Schmidt: Then we really, it leaves us with two larger questions.

Michael Schmidt: Have plans to evaluate RMC-4630 with Mirati's KRAS inhibitor.

Michael Werner Schmidt: Not all chances, but one is obviously there.

<unk> plans to evaluate 46.30 with Novartis.

Michael Werner Schmidt: There are a very limited number of drugs that improve outcomes over time.

Operator.

Mark Goldsmith: Yeah. I think for us, the main thing it suggests is that Amgen continues to have a high interest in SHP2 as a target and using it as a co-target along with the mutant driver, RAS mutant driver. So I think that's a very, you know, positive signal. As to why they chose specifically TNO155 or something else, I couldn't speak to that at all. You know, it obviously is a leading SHP2 inhibitor. So, you know, it may be as simple as that. You know, what they've indicated publicly, I'll just reiterate sort of my interpretation of David Reese's comments, which are that they think it's an important target. They wanna make sure that the Lumakras franchise, which is rapidly building, has access to whatever makes it to the finish line.

Michael Werner Schmidt: Unknown Executive, Chris Shibutani, Erin Graves, Wei Chang, Jack Anders, Wei Chang

Yes.

I think for us to maintain our suggestions that Amgen continues to have a high interest in ship to as a target.

And using and using it as a co target along with with the mutant driver revenue driver.

Michael Werner Schmidt: We're not just dealing with lung cancer; there are a lot of other tumors where...

So I think thats, a very positive signal.

Michael Werner Schmidt: Chief as well, and there's like another, uh, P.D. one or P.D.A. one. Unknown Executive, Chris Shibutani, Erin Graves, Wei Chang, Jack Anders, Wei Chang

As to why they chose specifically by.

Five or.

Something else I couldn't speak to that at all.

Obviously as a leading ship two inhibitor.

Mark Goldsmith: You know, it may be as simple as that. You know, what they've indicated publicly, I'll just reiterate sort of my interpretation of David Reese's comments, which are that they think it's an important target. They wanna make sure that the Lumakras franchise, which is rapidly building, has access to whatever makes it to the finish line.

So.

There is.

Michael Werner Schmidt: And we do foresee a future state where the double echelon...

Maybe simple as that.

Yes.

Michael Werner Schmidt: Therapy for abstinence and lung cancer is replaced by

They have indicated publicly I'll just reiterate my interpretation of data recent comments, which are that they think it's an important target they want to make sure that the wound <unk> franchise, which is rapidly building has access to whatever makes it to the finish line.

Michael Werner Schmidt: Unknown Executive, Chris Shibutani, Erin Graves, Wei Chang, Jack Anders, Wei Chang

Mark Goldsmith: that they have no particular concerns about RMC-4630 and continue to support CodeBreaK 101c and are excited about it. What he couldn't say then, but now you can read into it, is that they're also excited about the RMC-4630-03 study that of course they knew we were about to announce, but he couldn't speak to that then. I don't think it reads at all negatively on RMC-4630. If anything, it reads positively on it. We've always suggested that everybody would dance with everybody else when it comes to these sorts of companion inhibitors. You know, until the music's over, until we know all the answers, there's a dance to be danced.

Michael Werner Schmidt: and one of our other RAS inhibitors for other RAS mutations.

Mark Goldsmith: that they have no particular concerns about RMC-4630, and continue to support CodeBreaK 101C and are excited about it. What he couldn't say then, but now you can read into it, is that they're also excited about the 03 study that of course they knew we were about to announce, but he couldn't speak to that then. I don't think it reads at all negatively on RMC-4630.

But they have no particular concerns about RMC for <unk>.

Michael Werner Schmidt: In combination with a companion inhibitor like RMC4630.

And continue to support Covid break 100, once a year and are excited about it.

Michael Werner Schmidt: Now that requires us to demonstrate that each component.

But it couldnt say that but now you can read it.

Michael Werner Schmidt: Each dominant component of that triplet is tolerable, and that's the most important thing.

Two it is that they're also excited about resetting.

They knew we were about to announce that he couldn't speak to that and so I don't think it reached at all negatively on RMC 463 Ho.

Michael Werner Schmidt: [inaudible]

Michael Werner Schmidt: We have declared a recommended Phase 2 dose and scheduled to move into the Phase 2 expansion of that study. Unfortunately, I'm not going to tell you what it is at the moment, but I think eventually you will learn. And then it will become clear what the tolerance profile looks like. But what we can say at the moment is the tolerance profile is perfectly acceptable and encouraging enough for us to want to move forward with Phase 2 efficacy testing.

Mark Goldsmith: If anything, it reads positively on it. We've always suggested that everybody would dance with everybody else when it comes to these sorts of companion inhibitors. You know, until the music's over, until we know all the answers, there's a dance to be danced.

Anything you'd be positively on it.

And.

We've always suggested that.

Everybody with dance with everybody else when it comes to these sorts of companion inhibitors.

Until the music's over until we know all the answers.

Mark Goldsmith: People are gonna, you know, switch around, try different partners, and we've been doing that. We'll continue doing that. I suspect everybody will do that. That makes perfect sense in a rational approach to drug development.

Michael Werner Schmidt: There is a very mechanistic basis for doing it as well.

Advance to the dance and so people are going to.

Michael Werner Schmidt: I like that the very beginning of that paper published by Iron Element and Genentech back in 2017, showed very clearly that one of the roles of SHIP2 is to regulate checkpoint signals. And so there's a huge rationale for a shift to the inhibitor, augmenting the effects of checkpoint inhibition. We have also subsequently demonstrated both in preclinical models and in...

Switch around private <unk> partners.

We've been doing that we'll continue doing that.

And I suspect everybody will do that because that makes perfect sense.

National approach too.

Michael Schmidt: Yeah, that makes a lot of sense to me. Well, thanks for your comments there, Mark, and thanks for taking my question.

No.

Yes that makes a lot of sense to me well. Thanks for all your comments about my opinion, thanks, taking my questions.

Mark Goldsmith: Thank you.

Operator 2: Thank you. Our next question comes from the line of Jonathan Chang with SVB Leerink. Your line is open.

Operator: Thank you. Our next question comes from the line of Jonathan Chang with SVB Leerink. Your line is open.

Thank you.

Our next question comes from the line of Jonathan Chang with SBB Leerink. Your line is open.

Michael Werner Schmidt: [inaudible]

Michael Werner Schmidt: It should be helpful rather than a hindrance.

Faisal Rashid: Hi, guys. This is Faisal Rashid on for Jonathan Chang. Thanks for taking my question. For RMC-5845, the SOS1, just a clarification. Is this an asset that would be considered for, like, a potential out-licensing, or is this simply a delay in a potential IND filing? I guess a related question, are there any features of the molecule itself that kind of played into the decision, or was it just the other priorities? Thank you.

Michael Werner Schmidt: When you compound the mechanistic basis of ship-to-inhibition...

Hi, guys first with the feet on for Jonathan Chang. Thanks for taking my question.

Michael Werner Schmidt: has demonstrated in the PDE studies from our clinical trials.

Our RMC 50.845, the source one just a clarification is this an asset that would be considered for like a potential out licensing or is this simply a delay in a potential IND filing and then I guess the related question are there any features of the molecule itself that kind of played the decision or was it just the priority.

Michael Werner Schmidt: The fact that Checkpoint Inhibits is our standard...

Michael Werner Schmidt: The Care for Raspy Lung Cancer and the opportunity beyond raspy lung cancer, I think it's a very compelling place for us to do a study. Got it. Okay.

Michael Werner Schmidt: It's a very compelling place for us to do a study.

Michael Werner Schmidt: It should do and will actually. Just curious if you have any thoughts on that and, perhaps conversely, have plans to evaluate 4630 with more.

Mark Goldsmith: Yeah, thanks for your question. I don't think that there are specific features of the molecule that are affecting that decision. I think it's primarily a prioritization decision. You know, we're moving two compounds into the clinic next year. We already have two compounds in the clinic. We said that there's at least another one coming and several more behind that. You know, over the next 12 months, we've got our hands quite full and RMC-6291 is entering a crowded space, and RMC-6236 is entering a very large space. Those are pretty big programs. We just announced the 03 program, which is gonna be a significant commitment of resources. I think it's really more a timing question, and we will evaluate.

Thank you.

Michael Werner Schmidt: 4630 with Maradi. Thank you. Yeah. I think for us, the main thing it suggests is that Amgen continues to have a high interest in CHIP-2 as a target and using it as a co-target along with the mutant driver, the rat mutant driver. So I think that's a very positive signal as to why they chose specifically TN0155 or something else. I couldn't speak to that at all.

Yes, thanks for the question.

<unk>.

I don't think that there are specific.

<unk> features of the molecule that are affecting that decision I think it's primarily a prioritization decision. We're moving two compounds into the clinic next year.

We already have two compounds in the clinic.

We said that there's at least another one coming in several more behind that so.

Mark Goldsmith: You know, over the next 12 months, we've got our hands quite full and RMC-6291 is entering a crowded space, and RMC-6236 is entering a very large space. Those are pretty big programs. We just announced the RMC-4630-03 program, which is gonna be a significant commitment of resources. I think it's really more a timing question, and we will evaluate.

Over the next 12 months, we got our hands quite fallen at RMB 69, one is entering a crowded space and RMC 63, six is entering a very large space. So those are those are pretty big programs and we just announced the <unk> III program, which is going to be a significant commitment of resources. So.

Michael Werner Schmidt: You know, it obviously is a leading shift to inhibitors. So, you know, there's, it may be as simple as that. You know, what they've indicated publicly, I'll just reiterate sort of my interpretation of David Reese's comments, which are that they think it's an important target. They want to make sure that the Winnipress franchise, which is rapidly building, has access to whatever makes it to the finish line, but that they have no particular concerns about RMC 4630 and continue to support Code Break 101-Z and are excited about it.

I think it's really more more a timing question and we will evaluate we'll continue evaluating what's the right timing for moving that forward and if and when that's what we'll do but I don't think I would anticipate any sort of out licensing.

Mark Goldsmith: We'll continue evaluating what's the right timing for moving that forward and if and when, that's what we'll do. I don't think I would anticipate any sort of out-licensing. I'm not sure why we would do that since we have an integrated approach to RAS-driven tumors, and having a good quality SOS1 inhibitor is part of that approach. It's not on the point of the spear, but it's part of our overall integrated approach.

Im not sure why we would do that since we have an integrated approach to Ras driven tumors and having a good quality source one inhibitors as part of that approach is.

It's not on the point of the sphere, but as part of our overall integrated approach.

Michael Werner Schmidt: And what he couldn't say then, but now you can read into it, is that they're also excited about the O3 study that, of course, they knew we were about to announce, but he couldn't speak to that then.

Faisal Rashid: Got it. Thank you for taking the question.

Got it thank you for taking my question.

Mark Goldsmith: Thank you.

Operator 2: Thank you. Our final question comes from the line of Eric Joseph with J.P. Morgan. Your line is open.

Operator: Thank you. Our final question comes from the line of Eric Joseph with JP Morgan. Your line is open.

Thank you.

Our final question comes from the line of Eric Joseph from Jpmorgan. Your line is open.

Eric Joseph: Hi, good evening. Thanks for taking the question. Just to follow up on the 03 study, I'm curious to get a maybe a bit of a sense of the strategic rationale to pursue lung cancer as opposed to perhaps colorectal, given the sort of the relatively higher unmet need and the lack of objective responses there. I guess was this decision based on anything that you've seen thus far in CodeBreaK 101, and is combination potential in colorectal cancer something that might still be on the table?

Eric Joseph: Hi, good evening. Thanks for taking the question. Just to follow up on the 03 study, I'm curious to get a maybe a bit of a sense of the strategic rationale to pursue lung cancer as opposed to perhaps colorectal, given the relatively higher unmet need and the lack of objective responses there. I guess was this decision based on anything that you've seen thus far in CodeBreaK 101, and is combination potential in colorectal cancer something that might still be on the table?

Michael Werner Schmidt: Everybody would dance with everybody else when it comes to these sorts of companion inhibitors. You know, until the music's over, until we know all the answers, there's a dance to be danced. And so people are going to, you know, switch around and try different partners. And we've been doing that. We'll continue doing that. And I suspect everybody will do that. That makes perfect sense in a rational approach to...

Good evening and thanks for taking the question.

Just a follow up on the <unk> III study.

To get to.

Maybe a bit of a sense of the strategic rationale to pursue lung cancer as opposed to perhaps colorectal given the.

The relatively higher unmet need and the lack of objective responses there.

I guess was this decision basically anything that you've seen thus far in co break.

Michael Werner Schmidt: Yeah, that makes a lot of sense to me. Well, thanks for your comments there, Marc.

One is combination potential in colorectal cancer or something that might still be on the table.

Michael Werner Schmidt: Thank you for your comments there, Mark, and thank you for taking my question.

Mark Goldsmith: Thanks for your question. I think Steve's got some comments to make on that.

Thanks for your question.

Jonathan Chang: Our next question comes from the line of Jonathan Chang with SBB Lebrink. Your line is open.

I think he's got some comments to make on that yes.

Steve Kelsey: Yeah, let's start with the colon cancer bit first. Absolutely, it's on the table. The reason for focusing on non-small cell lung cancer, I think, is really twofold. One is we were swayed to some extent by the data that was presented at AACR and then published in the New England Journal of Medicine about the mechanisms by which tumors escape from KRAS G12C OFF inhibitors. I think if you look at that data, the potential for a SHP2 inhibitor to intervene meaningfully in the effects of a KRAS G12C OFF inhibitor or at least augment the effect and mitigate resistance is potentially greater in non-small cell lung cancer.

Steve Kelsey: Yeah, let's start with the colon cancer bit first. Absolutely, it's on the table. The reason for focusing on non-small cell lung cancer, I think, is really twofold. One is, we were swayed to some extent by the data that was presented at AACR and then published in the New England Journal of Medicine about the mechanisms by which tumors escape from KRAS G12C OFF inhibitors. I think if you look at that data, the potential for a SHP2 inhibitor to intervene meaningfully in the effects of a KRAS G12C OFF inhibitor or at least augment the effect and against resistance is potentially greater in non-small cell lung cancer.

Let's start with let's start with the colon cancer.

Faisal Ali Khurshid: Hi guys, this is Faisal Khurshid on behalf of Jonathan Chang. Thanks for taking my question. For RMC5845, the SOS1, just a clarification, is this an acid that would be considered for potential out licensing? Or is this simply a delay in a potential IND filing? And then, I guess a related question, are there any features of the molecule itself that kind of played into the decision? Or was it just the other priorities? Thank you. Yeah, thanks for your question.

Absolutely on the table.

The.

The reason for focusing on non small cell lung cancer.

<unk> is is really twofold one is.

We was way.

To some extent.

Thanks.

As.

Presented at ACR, and then operation in Europe.

Given the events in the eyes of the mechanisms by which tumors escape from <unk> often and this is I think if you look at that data.

The potential for a shift to inhibit <unk> meaningfully in the <unk> and the effects of a <unk> inhibitor are already sold and the effect of not forget ecosystems.

Faisal Ali Khurshid: I don't think that they're specific features of the molecules that are affecting that decision. I think it's primarily a prioritization decision. You know, we're moving two compounds into the clinic next year. We already have two compounds in the clinic. We've said that there's at least another one coming, and several more behind that. So, you know, over the next 12 months, we've got our hands quite full. And RMC6291 is entering a crowded space, and RMC6236 is entering a very large space. So those are pretty big programs.

Steve Kelsey: Secondly, we know the objective response rate to single agent sotorasib is a little bit higher, and that actually, oddly enough, if you're comparing makes it easier to detect a difference if you're dealing with double versus single. I think there's a very good reason. Thirdly, we wanted to focus our attention on a single disease and make sure we got the right answer. Absolutely doesn't say anything negative about the potential for four-six-three-oh in colon cancer. I think there's every expectation that at some point in the future, we will be doing that combination as well.

Hi, Grayson and non small cell lung cancer. Secondly, we know the objective response rate simulations with <unk> is a little bit higher.

That actually oddly enough.

Comparing mix makes it easiest new types of differences.

With all of those things so.

So I think Thats a very good reason thirdly, we wanted to focus our attention on a single disease make sure. We've got the right answer, but absolutely absolutely doesn't say anything negative about the potential for forces kind of I'll pass it on I think.

There's every expectation that at some point.

In the future, we will be doing a combination of all that.

Mark Goldsmith: If I could add to that, Eric, the CodeBreaK 101c study continues, and it is an exploratory study looking at multiple histotypes. We're gonna continue to get information out of that. Also, highlight that in the formal part of the presentation, we did show an example of a colorectal cancer tumor line that was relatively unresponsive or had low response to RMC-6291 alone, but when combined with the inhibitor, actually developed quite deep regressions. I think we're still quite committed to other things as well. At this point, you sort of break off of the broad multi-tumor approach and start delving down one at a time. The first approval for Lumakras, of course, is in non-small cell lung cancer.

Mark Goldsmith: If I could add to that, Eric, the CodeBreaK 101C study continues, and it is an exploratory study looking at multiple histotypes. We're gonna continue to get information out of that. Highlight that in the formal part of the presentation, we did show an example of a colorectal cancer tumor line that was relatively unresponsive or had low response to RMC-6291 alone, but when combined with the inhibitor, actually developed quite deep regressions. I think we're still quite committed to other things as well.

Faisal Ali Khurshid: And we just announced the O3 program, which is going to be a significant commitment of resources. So I think it's really more of a timing question. And we will evaluate, we'll continue evaluating what's the right timing for moving that forward, and if and when we do, that's what we'll do. But I don't think I would anticipate any sort of out-licensing. I'm not sure why we would do that since we have an integrated approach to RAS-driven tumors. And having a good quality SOS-1 inhibitor is part of that approach. It's not at the point of the sphere, but it's part of our overall integrated approach.

If I could add to that Eric the Colgate <unk> study continues and it is an exploratory study is looking at multiple tissue types that we're going to continue to get information out of that.

Also.

Highlight that in the formal part of the presentation. We did show. An example of colorectal cancers tumor ly that was relatively unresponsive or had low response to RMC six to nine months alone, but when combined with shifting inhibitor actually develop.

Quite deep.

And so I think we're still quite committed to others other things as well but.

Mark Goldsmith: At this point, you sort of break off of the broad multi-tumor approach and start delving down one at a time. The first approval for Lumakras, of course, is in non-small cell lung cancer.

At this point do you sort of break off with a broad multi tumor approach and start delving down one at a time in the first approval for the crash courses in.

Mark Goldsmith: If we're looking for a place where we can make a difference and just build on improved treatment regimen, that would be the place to start. By no means, as Steve said, are we excluding other opportunities.

Wholesale lung cancer. So if we're looking for a place where we can make a difference and.

Faisal Ali Khurshid: Got it. Thank you for taking the questions. Thank you. Our final question comes from the line of Eric Joseph with J.P. Morgan. The line is open.

This build on improved treatment regimen that would be the place to start.

By no means as Steve said, our we excluding other opportunities.

Eric William Joseph: Hi, good evening. Thanks for taking the time to ask the question. Just to follow up on the O3 study, I'm curious to get a bit of a sense of the strategic rationale to pursue lung cancer as opposed to perhaps colorectal cancer, given the sort of the relatively higher unmet need and the lack of objective responses there. I guess, was this decision based on anything that you've seen thus far in Code Break 101 and is, Combination potential and colorectal cancer is something that might still be on

Eric Joseph: Okay. Okay, great. With respect to the RAS(ON) portfolio, it looks like you're deciding between two targets, and naming a third development candidate between KRAS G12D and KRAS G13C. Just kind of curious to get a sense of your thinking that remains in deciding between sort of which you nominate here. I guess how far apart are these compounds, I guess, in their preclinical development? Should we be thinking about multiple development candidates coming to the fore being named over the next year or so?

Eric Joseph: Okay. Okay, great. With respect to the RAS(ON) portfolio, it looks like you're deciding between two targets, and naming a third development candidate between G12D and G13C. Just kind of curious to get a sense of your thinking that remains in deciding between sort of which you nominate here. I guess how far apart are these compounds, I guess, in their preclinical development? Should we be thinking about multiple development candidates coming to the fore being named over the next year or so?

Okay, Okay great.

And with respect to the Ras on portfolio it looks like you're deciding between two.

<unk> targets.

A third development candidate between RASK.

<unk> see.

Just kind of.

Curious to get a sense of your thinking.

That remains in deciding between sort of which you nominate here and I guess, how far apart are these compounds I guess in there.

Eric William Joseph: Thanks for your question. I think Steve's got some comments to make on that.

Preclinical development it should be just thinking about multiple development candidates coming through before being named over the next year or so.

Stephen M. Kelsey: Yeah, let's start with the Kellogg hats a bit first.

Stephen M. Kelsey: Absolutely. It's on the table.

Mark Goldsmith: Yeah. I wouldn't read too much into that. That's the question of sort of the complex strategic decision about which one to move forward. We basically have a bunch of teams competing with each other to put forth the best package when they've got the package together, and when they've got a package, we'll look at it and consider whether to approve moving forward with it. It's not as if we ask one team to slow down and another team to speed up. I mean, everybody's moving as fast as they can. We also didn't explicitly say that we'll be choosing between G12D or G13C for this decision. We just said those are two that we've disclosed that are in late lead optimization, and we expect to select a next development candidate coming up.

Stephen M. Kelsey: The reason for focusing on non-small cell lung cancer is, I think, really twofold.

Yes.

I wouldn't read too much into that but the question is sort of the.

The complex strategic decision about which way to move forward, we basically have a bunch of teams competing with each other to put forth. The best package when they've got the package together and when they've got a package will look at and consider whether to approve moving forward with it. So it's not as if we ask lumping to slow down and other things to speed up I mean, everybody is moving faster.

Stephen M. Kelsey: One is that we were swayed to some extent by the data that was presented at AACR and then published in the New England Journal of Medicine about the mechanism.

Stephen M. Kelsey: [inaudible]

Stephen M. Kelsey: The potential for a SHIP-2 inhibitor to intervene meaningfully in the effect of a KRS-G-Torx-C-Op inhibitor or at least augment the effect of aggregating resistance is potentially greater in non-smart cell lung cancer. Secondly, we know the objective response rate to single agents of tyrosine is a little bit higher, and that actually, oddly enough, if you're comparing, makes

Mark Goldsmith: We also didn't explicitly say that we'll be choosing between G12D or G13C for this decision. We just said those are two that we've disclosed that are in late lead optimization, and we expect to select a next development candidate coming up.

Can we.

We also didn't explicitly said that we will be choosing between <unk> 12 to <unk> <unk>.

For for this decision. We just said those are two that we've disclosed that are in late lead optimization that we expect to select a.

Mark Goldsmith: You know, in principle, there could be other options on the table too. I wouldn't read too much into the, you know, whatever comes out of that. We'll move things forward as swiftly as we can. If one gets named and the other one doesn't, at some point thereafter, not too far after, the other one I'm sure will get named. These programs are moving along well, as are unnamed target programs that are continuing to work their way through.

The next development candidate coming up but.

First of all it could be other options on the table too.

So I would agree.

Shouldn't read too much into that.

Stephen M. Kelsey: makes it easy, and you have to stick tight.

Whenever it comes out of that and we're moving forward as quickly as we can if one just staying with yellow it doesn't at some point thereafter, not too far after the other one I'm sure we will get names in each of these programs are moving along well as our unmanned target programs.

Stephen M. Kelsey: So I think that's a very good reason. Thirdly, we wanted to focus our attention on a single disease and make sure we got the right answer. But it absolutely doesn't say anything negative about the potential for 4-6-3-0 and colon cancer. And I think there's every expectation that at some point in the future, we will be doing that combination as well. And if I could add to that, Eric, the COCHRATE.1c study continues, and it is an exploratory study looking at multiple histotypes.

That are continuing to work their way through.

Eric Joseph: Okay. All right. I'll try not to overinterpret, I guess, from the slides going forward. Thanks for taking the questions.

Eric Joseph: Okay. All right. I'll try not to overinterpret, I guess, from the slides going forward. Thanks. Thanks for taking the questions.

Okay, Alright, alright.

Try not to over interpret that.

Going forward. Thanks.

Mark Goldsmith: Yeah. All right.

For taking my questions.

Operator 2: Thank you. As there are no more questions in the queue, I will turn the call back over to Dr. Goldsmith for his closing remarks.

Operator: Thank you. As there are no more questions in the queue, I will turn the call back over to Dr. Goldsmith for his closing remarks.

Alright.

Thank you.

And there are no more questions in the queue.

Stephen M. Kelsey: So we're going to continue to get information out of that. But I'd also highlight that in the formal part of the presentation, we did show an example of a colorectal cancer tumor line that was relatively unresponsive or had a low response to RMC6291 alone, which combined with shift inhibitor actually developed quite deep regressions. And so I think we're still quite committed to other things as well. But at this point, you sort of break off from the broad, multi-tumor approach and start delving down one at a time. And the first approval for LUMOCRAS, of course, is in.

I'd turn the call back over to Dr. Smith for his closing remarks.

Mark Goldsmith: Thank you, operator, and thank you to our analysts who just participated in the Q&A and to everyone for participating today and for your continued support of Revolution Medicines.

Thank you operator, and thank you too.

Alex So just participated in the Q&A and to everyone for participating today and for your continued support of our bullishness.

Operator 2: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Operator: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation you may now disconnect.

[music].

Stephen M. Kelsey: Okay, okay, great. And with respect to the Razon portfolio, it looks like you're deciding between two targets and naming a third development candidate between G12D and G13C. Curious to get a sense of your thinking, that remains in deciding between the sort of which you you nominate here. And I guess how far apart these compounds are in their preclinical development should be thinking about multiple development candidates coming to the fore and being named over the next year or so. Yeah,

Okay.

Yes.

Sure.

[music].

Okay.

[music].

Okay.

Yes.

[music].

Eric William Joseph: Yeah, I wouldn't read too much into that. That's the question of sort of a complex strategic decision about which one to move forward with. We basically have a bunch of teams competing with each other to put forward the best package when they've got the package together. And when they've got the package, we'll look at it and consider whether to approve moving forward with it. So it's not as if we ask one team to slow down and another team to speed up. I mean, everybody's moving as fast as they can.

Eric William Joseph: We also didn't explicitly say that we'll be choosing between G12B or G13B for this decision. We just said those are two that we've disclosed that are in late lead optimization, and we expect to select a next development candidate coming up. You know, in principle, there could be other options on the table, too. So I wouldn't read too much into the, you know, whatever comes out of that. And we'll move things forward as quickly as we can.

Eric William Joseph: If one gets named and the other one doesn't, at some point thereafter, not too far after, the other one, I'm sure, will get named. And these programs are moving along well, as are unnamed target programs that are continuing to work their way forward. Okay, all right.

Eric William Joseph: Okay. All right. All right. I'll guess from the slides going forward. Thanks for taking the questions.

Operator: As there are no more questions in the queue, I will...

Mark A. Goldsmith: In the Queue, I will turn the call back over to Dr. Goldsmith for his closing remarks. Thank you, Operator, and thank you to our analysts who just participated in the Q&A and to everyone for participating today and for your continued support of Revolution Medicine.

Operator: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

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Operator: Good day, ladies and gentlemen, and welcome to the Revolution Medicine second quarter fiscal 2021 financial results conference call and webcast. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will have a question and answer session. To ask a question at that time, please press star followed by the number on your touchtone telephone. Please stand by, as today's conference call is being recorded. If anyone has difficulty hearing the conference, please press star zero for the operator. I would now like to hand the conference over to Peg Horn, Revolution's Chief Operating Officer, for opening remarks. Peg, you may begin.

Margaret A. Horn: Good afternoon everyone, and thank you all for joining us today. Joining me on today's call are Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer, Dr. Steve Kelsey, the company's President of Research and Development, and Jack Anders, our Senior Vice President of Finance and Principal Accounting Officer. As we begin, I'd like to caution you that our presentation today will contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act regarding the current beliefs of the company.

Margaret A. Horn: Company.

Margaret A. Horn: During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call. With that, I will turn the call over to Dr. Mark Goldsmith, Revolutions Chairman and Chief Executive Officer. Thank you and good afternoon.

Mark A. Goldsmith: Welcome to our Q2 earnings call. This is Revolution Medicine's first earnings call, and we look forward to having this opportunity to connect with our investors on a regular basis. After our prepared remarks today, we will host a Q&A session.

Mark A. Goldsmith: Treatment for RAS-addicted cancers reached an important milestone in Q2 with the first FDA approval of a targeted medicine for lung cancer carrying the KRAS-G12C mutation, Amgen's Lumicras or Sotiracib. Likewise, R&D at Revolution Medicines continued making excellent progress, reinforcing our belief that the company's innovative and cohesive asset portfolio can drive rational, mechanism-based, and beneficial combination Our ambition is to serve remaining and significant unmet needs for patients with K-RAS G12C positive tumors, and even larger opportunities to benefit those with cancers driven by other non-G12C RAS variants, as shown on slide 4.

Mark A. Goldsmith: Today we will highlight important progress we've made on our exciting tri-complex RAS-ON inhibitors that extends the momentum we've described previously. We will also provide an update on several aspects of RMC4630, an advanced and important asset in our RAS companion inhibitor portfolio. We will report on two combination drug strategies that have been under evaluation in the RMC-4630-02 study. The so-called clamping approach with our SHIP-2 inhibitor RMC4630 in combination with the MEK inhibitor CoB-Metnib directed against advanced RAS-addicted cancers lacking a targeted RAS inhibitor. And a second approach with RMC4630 combined with the EGF receptor inhibitor Osimertinib aiming to enhance clinical benefit in EGF receptor mutant lung cancer.

Operator 1: Good day, ladies and gentlemen, and welcome to the Revolution Medicines Q2 Fiscal 2021 Financial Results Conference Call and Webcast. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will have a question-and-answer session. To ask a question at that time, please press star followed by the one on your touchtone telephone. Please be advised that today's conference call is being recorded. If anyone has difficulty hearing the conference, please press star zero for operator assistance. I would now like to hand the conference over to Peg Horn, Revolution's Chief Operating Officer, for opening remarks. Peg, you may begin.

Good day, ladies and gentlemen, and welcome to the Revolution Medicine second quarter fiscal 2021 financial results conference call and webcast.

Mark A. Goldsmith: We will also explain our continued commitment to treatment strategies combining a direct RAS inhibitor with RMC4630. And we'll announce an exciting high-priority combination study sponsored by Revolution Medicines evaluating RMC4630 in combination with sodoracid in KRAS G12C positive lung cancer under a new clinical trial collaboration and supply agreement with Amgen that builds on and is a complement to the Code Break 101 trial exploring this combination across multiple cancer The ARMC 4630-03 study is designed to allow us to better define patients who may most benefit from the combination of our SHIP-2 inhibitor with the KRAS G12C inhibitor through analysis of cohorts with and without certain mutations. Steve Kelsey, Revolution's President of R&D, will provide more information on the new O3 study and our other clinical programs after I provide an update on our RAS-ON inhibitors.

At this time, all participants on a listen only mode.

Following managements prepared remarks, we will have a question and answer session.

Ask the question at that time, Please press star followed by the one on your Touchtone telephone.

Usually about the today's conference call is being recorded.

If anyone has difficulty hearing the conference. Please press star zero for operator.

I would now like to hand, the conference over to Pat Horn Revolutions, Chief operating officer for opening remarks, Craig you may begin.

Good afternoon, everyone and thank you all for joining US today joining me on today's call are Dr. Mark Goldsmith revelations, Chairman and Chief Executive Officer, Dr. Steve Kelsey, the Companys, President research and development and Jack Anders Our senior Vice President of Finance and principal accounting officer.

Peg Horn: I encourage you to review the legal disclaimer slide we are presenting today as well as all of the company's filings with the SEC concerning these other matters. During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call. With that, I will turn the call over to Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer. Mark?

During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call.

With that I will turn the call over to Dr. Mark Goldsmith Revolutions, Chairman and Chief Executive Officer Mark.

Mark Goldsmith: Thank you and good afternoon. Welcome to our Q2 earnings call. This is Revolution Medicines' first earnings call, and we look forward to having this opportunity to connect with our investors on a regular basis. After our prepared remarks today, we will host a Q&A session. Treatment for RAS-addicted cancers reached an important milestone in Q2 with the first FDA approval of a targeted medicine for lung cancer carrying the KRAS G12C mutation, Amgen's Lumakras or sotorasib. Likewise, R&D at Revolution Medicines continued making excellent progress, reinforcing our belief that the company's innovative and cohesive asset portfolio can drive rational, mechanism-based, and beneficial combination treatments for patients with RAS-addicted cancers. Our ambition is to serve remaining and significant unmet needs for patients with KRAS G12C-positive tumors. Even larger opportunities to benefit those with cancers driven by other non-G12C RAS variants as shown on slide 4.

Treatment for rapid they could cancers reached an important milestone in Q2 with the first FDA approval of a targeted medicine for lung cancer carrying the <unk> mutation, Amgen, Luna crafts or soda or asset.

Mark A. Goldsmith: These experiments are part of a growing body of evidence that RMC6291 has best-in-class potential among KRAS G12C inhibitors. Also, in Q2, various newly emergent RAS or RAS pathway mutations were reported in 39% of patients exhibiting resistance to treatment without a Grasib, and the described mutations provide a critical roadmap for treatment approaches to combat these mechanisms of clinical failure. As shown in this table on slide 14, the company has expanded on initial results published in Cancer Discovery by Dr. Ryan Corcoran's team at the Massachusetts General Hospital and Harvard Medical School by demonstrating that RMC6291 is active against all second-site resistance mutations reported thus far from patients treated with Adagracib.

Mark Goldsmith: Today, we will highlight important progress we've made on our exciting tri-complex RAS(ON) inhibitors that extends the momentum we've described previously. We will also provide an update on several aspects of RMC-4630, an advanced and important asset in our RAS Companion Inhibitors portfolio. We will report on two combination drug strategies that have been under evaluation in the RMC-4630-02 study, the so-called clamping approach with our SHP2 inhibitor RMC-4630 in combination with the MEK inhibitor cobimetinib, directed against advanced RAS-addicted cancers lacking a targeted RAS inhibitor, and a second approach with RMC-4630, combined with the EGFR inhibitor osimertinib, aiming to enhance clinical benefit in EGFR mutant lung cancer.

Today, we will highlight important progress we've made on our exciting try complex Ras on inhibitors that extends the momentum. We've described previously we.

We will also provide an update on several aspects of RMC for 63 O and advanced an important asset in our Ras companion inhibitor portfolio.

We will report on to combination drug strategies that have been under evaluation in the RMC 463002 study.

The so-called clamping approach with our ship two inhibitor RMC for <unk> in combination with the <unk> inhibitor Kobe net nib directed against advanced Ras addicted cancers, lacking a targeted Ras inhibitor.

And a second approach with RMC for <unk> combined with the EGF receptor inhibitor Aussie merit to nib, aiming to enhance clinical benefit and EGF receptor mutant lung cancer.

Mark Goldsmith: We will also explain our continued commitment to treatment strategies, combining a direct RAS inhibitor with RMC-4630, and will announce an exciting high priority combination study sponsored by Revolution Medicines evaluating RMC-4630 in combination with sotorasib in KRAS G12C-positive lung cancer under a new clinical trial collaboration and supply agreement with Amgen that builds on, and is a complement to, the CodeBreaK 101 trial exploring this combination across multiple cancer types. The RMC-4630-03 study is designed to allow us to better define patients who may most benefit from the combination of our SHP2 inhibitor with the KRAS G12C inhibitor through analysis of cohorts with and without certain co-mutations.

Mark A. Goldsmith: As many of these mutations also confer resistance to sodoracid and other KRAS G12C-off inhibitors, the activity of RMC6291 in this setting illustrates a distinguishing property of the molecule that may be useful for preventing or treating the emergence of these resistance mutations. RMC 6291 continues on track in its IND Enabling Development Program toward its expected IND filing in the first half of 2020-2022.

We will also explain our continued commitment to treatment strategies, combining a direct Ras inhibitor with RMC 46 REO.

And we will announce an exciting high priority combination study sponsored by Revolution medicines evaluating RMC for six trio in combination with <unk> acid and <unk> positive lung cancer under a new clinical trial collaboration and supply agreement with Amgen that builds on and is a complement to the code break.

<unk> hundred one trial exploring this combination across multiple cancer types.

The RMC for six Rio <unk> III study is designed to allow us to better define patients who made most benefit from the combination of our ship two inhibitor with a <unk> inhibitor through analysis of cohorts with and without certain Commutations Steve.

Mark Goldsmith: Steve Kelsey, Revolution's President of R&D, will provide more information on the new 03 study and our other clinical programs after I provide an update on our RAS(ON) inhibitors. For KRAS G12C positive lung cancer and colorectal cancer in particular, we continue to believe there's an opportunity to increase clinical response rates and/or durability as suggested by this table on slide 5, summarizing some key outcomes reported with first generation KRAS G12C off inhibitors so far that show both the clinical benefit of targeted drug and areas of ongoing opportunities. With these unmet needs in mind, we are pursuing development of several new RAS(ON) inhibitors. A key element of the strategy for our KRAS G12C on inhibitor is consistent with the successful generational paradigm established previously with advanced generation targeted inhibitors for tumors with EGF receptor mutations.

Steve Kelsey revolutions President of R&D will provide more information on the new <unk> III study and our other clinical programs. After I provide an update on our Ras on inhibitors.

For K, Ras <unk> positive lung cancer and colorectal cancer in particular, we continue to believe there is an opportunity to increase clinical response rates <unk> durability as suggested by this table on slide five summarizing some key outcomes reported with first generation <unk>.

<unk> inhibitor, so far that show, both the clinical benefit of targeted drug and areas of ongoing opportunities.

With these unmet needs in mind, we are pursuing development of several new Ras on inhibitors.

A key element of the strategy for our <unk> inhibitor is consistent with the successful generational paradigm established previously with advanced generation targeted inhibitors for tumors.

Mark A. Goldsmith: Among the multiple resistance mechanisms, resistance mutations in adegraf-subtreated patients that were reported in Q2, a notable group of emergent RAS variants was described that are expected to be insensitive to KRAS G12C off-inhibitors and to RMC6291. As shown on slide 22, these mutations include new substitutions at KRAS G12 in the upper panel, KRAS G13 in the lower panel, and NRAS Q61 also in the lower right panel.

With EGF receptor mutations.

Mark Goldsmith: In Q1 2021, we had introduced the compelling profile of the development candidate RMC-6291, our first in class potent oral and selective tri-complex inhibitor for KRAS G12C, as summarized on slide 10. Expanding from earlier examples shown previously, in Q2, we reported additional examples of deeper, more uniform, and/or more sustained antitumor effects in xenograft KRAS G12C cancer models compared to a first generation RAS off inhibitor. These experiments are part of a growing body of evidence that RMC-6291 has best in class potential among KRAS G12C inhibitors. Also in Q2, various newly emergent RAS or RAS pathway mutations were reported in 39% of patients exhibiting resistance to treatment with adagrasib, and the described mutations provide a critical roadmap for treatment approaches to combat these mechanisms of clinical failure.

Expanding from earlier examples shown previously in Q2, we reported additional examples of deeper more uniform, Andrew or a more sustained anti tumor effects in xenograft <unk> cancer models compared to a first generation <unk> inhibitor.

These experiments are part of a growing body of evidence that RMC 69, one has best in class potential among <unk> <unk> inhibitors.

Mark Goldsmith: As shown in this table on slide 14, the company has expanded on initial results published in Cancer Discovery by Dr. Ryan Corcoran's team at the Massachusetts General Hospital and Harvard Medical School by demonstrating that RMC-6291 is active against all second site resistance mutations reported thus far from patients treated with adagrasib. As many of these mutations also confer resistance to sotorasib and other KRAS G12C off inhibitors, the activity of RMC-6291 in this setting illustrates a distinguishing property of the molecule that may be useful for preventing or treating emergence of these resistance mutations. RMC-6291 continues on track in its IND enabling development program toward its expected IND filing in the first half of 2022.

Operator: As shown in this table on slide 14, the company has expanded on initial results published in Cancer Discovery by Dr. Ryan Corcoran's team at the Massachusetts General Hospital and Harvard Medical School by demonstrating that RMC-6291 is active against all second site resistance mutations reported thus far from patients treated with adagrasib. As many of these mutations also confer resistance to sotorasib and other KRAS G12C OFF inhibitors, the activity of RMC-6291 in this setting illustrates a distinguishing property of the molecule that may be useful for preventing or treating emergence of these resistance mutations. RMC-6291 continues on track in its IND enabling development program toward its expected IND filing in H1 2022.

As shown in this table on slide 14. The company has expanded on initial results published in cancer discovery by Dr. Ryan Corker and his team at the Massachusetts General Hospital and Harvard Medical School.

By demonstrating that RMC 69, one is active against all second sight resistance mutations reported thus far from patients treated with that aggressive.

As many of these mutations also confer resistance to <unk> and other <unk> inhibitors. The activity of <unk> 69, one in this setting illustrates a distinguishing property of the molecule that may be useful for preventing or treating emergence of these resistance mutations RMC 69, one continues on.

Tracking its IND, enabling development program toward its expected IND filing in the first half of 2000.2022.

Mark Goldsmith: We also showed additional progress in addressing non-G12C oncogenic RAS variants, which account for approximately 85% of all incident RAS-addicted cancers and for which no targeted treatments are available. Earlier in 2021, we had described the compelling profile of our second development candidate, RMC-6236, a first-in-class potent oral RAS-selective tri-complex inhibitor for multiple variants of RAS as summarized on slide 17. Expanding from earlier examples of KRAS G12V and KRAS G12D cancer models shown previously, in Q2 we described additional preclinical data in a growing body of evidence that RMC-6236 has first-in-class and best-in-class potential for treating KRAS G12V and/or KRAS G12D tumors across multiple histotypes.

Mark Goldsmith: We also showed additional progress in addressing non-G12C oncogenic RAS variants, which account for approximately 85% of all incident RAS addicted cancers and for which no targeted treatments are available. Earlier in 2021, we had described the compelling profile of our second development candidate, RMC-6236, a first in class potent oral and RAS selective tri-complex inhibitor for multiple variants of RAS as summarized on slide 17. Expanding from earlier examples of KRAS G12V and KRAS G12D cancer models shown previously, in Q2 we described additional preclinical data in a growing body of evidence that RMC-6236 has first in class and best in class potential for treating KRAS G12V and/or KRAS G12D tumors across multiple histotypes.

We also showed additional progress in addressing non GE <unk> oncogenic, Ras variants, which account for approximately 85% of all incident, Ras addicted cancers and for which no targeted treatments are available.

Expanding from earlier examples of K, Ras <unk> V and <unk> 12 D cancer models shown previously in Q2, we described additional preclinical data and the growing body of evidence that RMB 63, 6% as first in class and best in class potential for treating <unk> and or <unk>.

<unk> tumors across multiple hyster types.

Mark A. Goldsmith: Today we'd like to show you some new evidence of our drug discovery capabilities by focusing briefly on two programs we've disclosed for late lead optimization, KRAS-G13C and KRAS-G12D. Shown on the left of slide 29 is a graphical surface representation of the SW1-2 region of the RAS-ON protein, which shows that amino acids 12, highlighted in blue, and 13, highlighted in red, lie adjacent to each other in the protein, and both are very close to the Ras-on inhibitor binding site, highlighted in dark pink.

Mark Goldsmith: Among the multiple resistance mechanisms, resistance mutations in adagrasib-treated patients that were reported in Q2, a notable group of emergent RAS variants was described that are expected to be insensitive to KRAS G12C OFF inhibitors and to RMC-6291. As shown on slide 22, these mutations include new substitutions at KRAS G12 in the upper panel, KRAS G13 in the lower panel, and NRAS Q61 also in the lower right panel. Importantly, we've now shown in preclinical experiments that RMC-6236 is active against all of these clinically observed variants, as well as a broader panel of KRAS G12 mutants that to date haven't been described in patients. Hence, these findings indicate that RMC-6236 has important properties that may be useful for preventing or treating emergence of these RAS oncogene switch resistance mutations.

Among the multiple resistance mechanisms resistance mutations in <unk> treated patients that were reported in Q2.

Notable group of emergent <unk> variance was described that are expected to be insensitive to <unk> inhibitors, and two RMC $6.91.

As shown on slide 2022 Slide 22. These mutations include new substitution that <unk> 12 in the upper panel.

<unk> 13 in the lower panel and <unk> 61 also in the lower right panel.

Importantly, we've now shown in preclinical experiments that RMC 63, six is active against all of these clinically observed variance as well as a broader panel of <unk> 12 mutants.

Mark A. Goldsmith: Our previous work enabled RMC6291 to selectively engage the oncogenic cysteine at position 12 in the mutant KRAS-G12C on-protein, as indicated by the upward shift of the KRAS-G12C protein band in the cross-linking experiment on the left. We have now been able to engineer new RAS-on inhibitor compounds that covalently engage the specific oncogenic cysteine at position 13 in the mutant k-RAS G13C on protein, as indicated by the upward shift of the KRAS G13C protein in the middle panel.

To date haven't been described in patients.

These findings indicate that RMC 63, 6% as important properties that may be useful for preventing or treating emergence of these ras oncogene switch resistance mutations.

Mark Goldsmith: In Q2, we also reported information about the potential for additive benefit in combinations of either RMC-6291 or RMC-6236 with a checkpoint inhibitor. For example, shown on the left of slide 26, in immunocompetent mice grafted with the syngeneic RAS mutant tumor, RMC-6236 induced a favorable transformation of the tumor immune microenvironment, characterized by an increase in infiltrating CD8 T-cells and a decrease in immune suppressive M2 macrophages. As shown on the right, RMC-6236 alone was quite active against growth of these syngeneic tumor grafts, including inducing a number of complete responses. An anti-PD-1 antibody alone was active as well, but the two together led to complete responses in all animals.

Mark Goldsmith: In Q2, we also reported information about the potential for additive benefit in combinations of either RMC-6291 or RMC-6236 with a checkpoint inhibitor. For example, shown on the left of slide 26, in immunocompetent mice engrafted with the syngeneic RAS mutant tumor, RMC-6236 induced a favorable transformation of the tumor immune microenvironment, characterized by an increase in infiltrating CD8 T cells and a decrease in immunosuppressive M2 macrophages. As shown on the right, RMC-6236 alone was quite active against growth of these syngeneic tumor grafts, including inducing a number of complete responses. An anti-PD-1 antibody alone was active as well, but the two together led to complete responses in all animals.

In Q2, we also reported information about the potential for additive benefit and combinations of either RMC 60, 91, or RMC 63, six with a checkpoint inhibitor.

For example, as shown on the left of slide 26, and immuno competent mice and grafted with <unk> Ras mutant tumor.

RMC 63, six induced a favorable transformation of the tumor immune microenvironment characterized by an increase in infiltrating CDA T cells and a decrease in immune suppressive <unk> macrophages as shown on the right RMC $63 six alone was quite active against growth of these <unk> Mcgrath.

Including inducing a number of complete responses.

And anti PD, one antibody alone was active as well, but the two together led to complete responses in all animals.

Mark Goldsmith: These results are encouraging about the potential clinical benefit of combining our RAS(ON) inhibitors with PD-1 inhibitors in treating anti-PD-1 sensitive tumors. Like RMC-6291, RMC-6236 continues on track in IND-enabling development, and we continue making very good progress on advancing additional mutant-selective RAS(ON) inhibitors. Our corporate goal is to select a third development candidate this year to advance into IND-enabling development and others subsequently. Today, we'd like to show you some new evidence of our drug discovery capabilities by focusing briefly on two programs we've disclosed in late lead optimization, KRAS G13C and KRAS G12D.

These results are encouraging about the potential clinical benefit of combining our rason inhibitors with PD one inhibitors in treating anti PD one sensitive tumors.

Mike RMC 69, one RMC 63, six continues on track and IND, enabling development and we continue making very good progress on advancing additional mutant selective Ras on inhibitors. Our corporate goal is to select a third development candidate this year to advance into IND, enabling development and other subsequent.

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Today, we'd like to show you some new evidence of our drug discovery capabilities by focusing briefly on two programs. We disclosed in late lead optimization K Ras G 13 fee and K Ras <unk>.

Mark Goldsmith: Shown on the left of slide 29 is a graphical surface representation of the switch one-two region of the RAS(ON) protein, which shows that amino acids 12, highlighted in blue, and 13, highlighted in red, lie adjacent to each other in the protein, and both are very close to the RAS(ON) inhibitor binding site, highlighted in dark pink. Our previous work enabled RMC-6291 to selectively engage the oncogenic cysteine at position 12 in the mutant KRAS G12C RAS(ON) protein, as indicated by the upward shift of the KRAS G12C protein band in the cross-linking experiment on the left. We've now been able to engineer new RAS(ON) inhibitor compounds that covalently engage the specific oncogenic cysteine at position 13 in the mutant KRAS G13C RAS(ON) protein, as indicated by the upward shift of the KRAS G13C protein in the middle panel.

Mark Goldsmith: Shown on the left of slide 29 is a graphical surface representation of the Switch I/II region of the RAS(ON) protein, which shows that amino acids 12, highlighted in blue, and 13, highlighted in red, lie adjacent to each other in the protein, and both are very close to the RAS(ON) inhibitor binding site, highlighted in dark pink. Our previous work enabled RMC-6291 to selectively engage the oncogenic cysteine at position 12 in the mutant KRAS G12C(ON) protein, as indicated by the upward shift of the KRAS G12C protein band in the cross-linking experiment on the left. We've now been able to engineer new RAS(ON) inhibitor compounds that covalently engage the specific oncogenic cysteine at position 13 in the mutant KRAS G13C(ON) protein, as indicated by the upward shift of the KRAS G13C protein in the middle panel.

Shown on the left of Slide 29 is a graphical surface representation of the switch one two region of the Ras on protein.

Which shows that amino acids 12 highlighted in blue and 13 highlighted in red by adjacent to each other in the protein and both are very close to the rasp inhibitor binding site highlighted in dark pink.

Our previous work enabled RMC $6.91 to selectively engage the oncogenic 15 at position 12 in the mutant <unk> protein as indicated by the upward shift of the <unk> protein band and the cross linking experiment on the left.

Mark A. Goldsmith: We're very proud of both of these quite differentiated chemical series that enable potent and highly mutant selective inhibition of oncogenic RAS signaling. Indeed, as shown here, each of these compounds shows impressive tumor cell growth inhibition in the corresponding genetic context as anticipated by the specific cross-linking pattern shown above. These laboratory-based feeds offer further insight into the groundbreaking drug design and execution capabilities deployed as we continue expanding our portfolio of ason inhibitor assets, and we look forward to providing further updates as these programs reach further milestones.

We've now been able to engineer new Ras on inhibitor compounds that covalently engaged the specific oncogenic existing app position 13 in the mutant <unk> protein.

As indicated by the upward shift of the <unk> protein in the middle panel.

Mark Goldsmith: Further, the exquisite molecular control we bring to the design of these remarkable compounds enables selective covalent binding to the cysteine 13 variant by one compound without detectable binding to the cysteine 12 variant. Or conversely, selective covalent binding to the cysteine 12 variant by another compound without covalent binding to the cysteine 13 variant, despite the similar positions of the cysteines at positions 12 and 13 in these RAS variants. Thus, the covalent warheads in these compounds are tuned to work only when positioned precisely and optimally with the free thiol group of the particular cysteine residue for which they are designed, a degree of on-target selectivity that is very encouraging. We also report today that we have extended covalent chemistry beyond cysteines to the oncogenic aspartic acid in the KRAS G12D ON variant, an exciting innovation and major achievement.

Further the exquisite molecular control, we bring to the design of these remarkable compounds enables selective covalent binding to the <unk> 13 variant by one compound without detectable binding to the sustained 12 variant or Conversely, selective covalent binding to the sustained 12 variant bye.

Mark A. Goldsmith: We'd also like to provide an update on the good progress within our RAS companion inhibitor pipeline. Previously, we identified combinations with RAS inhibitors as a core strategic element of our SHIP-2 inhibitor program, and we remain optimistic about this strategy. To illustrate this concept, we recently shared data on this example of a drug-resistant KRAS G12C colorectal tumor xenograft in slide 32. In contrast to another colorectal cancer model we showed previously that is highly sensitive to single agent RMC6291, this particular colorectal cancer model exhibits only a modest growth inhibition response to RMC6291 monotherapy in the blue line, which we believe relates to the role of wild type or normal RAS proteins in supporting the growth of these tumors.

Another compound without covalent binding to the sustained 13 variant despite the similar positions of the fifteens acquisitions 12, and 13 in these rats variance.

Thus the covalent warheads and these compounds are tuned to work only when positioned precisely and op optimally with the free file group of the particular cysteine residue for which they are designed a degree of on target activity that is very encouraging.

We also reported today that we have extended covalent chemistry beyond <unk> to the oncogenic aspartic acid in the K Ras <unk> D on variant and exciting innovation and major achievement.

Mark Goldsmith: Shown on the right of slide 29 is a representative compound that binds and cross-links to the KRAS G12D ON variant, as indicated by the upward shift of the KRAS G12D protein. Important evidence of the selectivity of this engagement is the absence of significant cross-linking to its close cousin, the KRAS G13D variant, despite the close proximity of aspartate 12 and aspartate 13 to one another. We're very proud of both of these quite differentiated chemical series that enable potent and highly mutant-selective inhibition of oncogenic RAS signaling. Indeed, as shown here, each of these compounds shows impressive tumor cell growth inhibition in the corresponding genetic context, as anticipated by the specific cross-linking pattern shown above.

Shown on the right of Slide 29 is a representative compound it binds in cross links to the <unk> on variant.

As indicated by the upward shift of the <unk> protein.

Important evidence of the selectivity of this engagement is the absence of significant cross linking to its close cousin the K Ras G 13, the variant despite the close proximity of our sparked a 12 and a <unk> <unk> to one another.

Mark A. Goldsmith: Notably, combining our SHIP2 inhibitor RMC4550, a tool compound we often use for preclinical research, with RMC6291 induced deep and sustained regressions in the tumor xenografts, as shown on slide 32. Hence, while RMC6291 itself has a superior preclinical profile to first-generation KRAS G12C inhibitors, as measured in a variety of models we've shown previously We believe that combining such agents in the clinic will prove to be a compelling therapeutic strategy, and now I'll turn things over to Dr. Steve Kelsey, our President of R&D, to bring you up to date on these efforts.

We're very proud of both of these quite differentiated chemical series that enable potent and highly selective inhibition of oncogenic Ras signaling.

Indeed as shown here each of these compounds shows impressive tumor cell growth inhibition and the corresponding genetic context as anticipated by the specific cross linking pattern shown above.

Mark Goldsmith: These laboratory-based feats offer further insight into the groundbreaking drug design and execution capabilities deployed as we continue expanding our portfolio of RAS(ON) inhibitor assets, and we look forward to providing further updates as these programs reach further milestones. We'd also like to provide an update on the good progress within our RAS Companion Inhibitor pipeline. Previously, we identified combinations with RAS inhibitors as a core strategic element of our SHP2 inhibitor program, and we remain optimistic about this strategy.

These laboratory based feeds offer further insight into the groundbreaking drug design and execution capabilities deployed as we continue expanding our portfolio of rason inhibitor assets and we look forward to providing further updates as these programs reach further milestones.

Stephen M. Kelsey: In monotherapy clinical studies to date, RMC4630, our clinical stage CHIP2 inhibitor, compares favorably with competitors and is well set up for continued evaluation of potential combination benefits with RAS. Notable features of our RMC4630 program include the use of an innovative intermittent dosing regimen.

We'd also like to provide an update on the good progress within our Ras companion inhibitor pipeline previously we identified combinations with RAF inhibitors as a core strategic elements of our ship to inhibitor program and we remain optimistic about this strategy.

Mark Goldsmith: To illustrate this concept, we recently shared data on this example of a drug-resistant KRAS G12C colorectal tumor xenograft in slide 32. In contrast to another colorectal cancer model we showed previously that is highly sensitive to single agent RMC-6291, this particular colorectal cancer model exhibits only a modest growth inhibition response to RMC-6291 monotherapy in the blue line, which we believe relates to the role of wild type or normal RAS proteins in supporting growth of these tumors. Notably, combining our SHP2 inhibitor RMC-4550, a tool compound we often use for preclinical research, with RMC-6291 induced deep and sustained regressions in the tumor xenografts as shown on slide 32.

To illustrate this concept we recently shared data on this example of a drug resistant K Ras <unk> colorectal tumors xenograft and slide 32.

In contrast to another colorectal cancer model. We showed previously that is highly sensitive to single agent RMC $6.91. This particular colorectal cancer model exhibits only a modest growth inhibition response to RMC 60, 91, mono therapy, and the Blue line, which we believe relates to the role of wild type or nor.

Stephen M. Kelsey: We have a dosing schedule to optimize for activity and tolerability.

Stephen M. Kelsey: An Absence of Cardiac and Liver Dose-Limiting Toxicities in the Dose-Escalation World, focusing on patients with RAS mutant tumors, observed clinical activity with best responses including partial response and complete response

Immel Ras proteins and supporting growth of these tumors.

Notably combining our ship two inhibitor RMC 45, five O a tool compound we often used for preclinical research with RMC 60, 91 induced deep and sustained regressions in the tumor xenograft as shown on slide 32.

Stephen M. Kelsey: Observed reduction in driver oncogene frequency detected in circulating tumor DNA samples, and evidence of favorable modulation of the tumor immune microenvironment in tumor samples from treated patients at Q2 of the annual ASCO meeting. Another prominent ship-to-inhibitor program, TNO 155 by Nevada, presented its first monotherapy clinical data that showed a different clinical strategy and dosing paradigm with less encouraging output so far. We continue to believe.

Mark Goldsmith: Hence, while RMC-6291 itself has a superior preclinical profile to first generation KRAS G12C inhibitors as measured in a variety of models we've shown previously, additional antitumor impact can be obtained by the additive contribution of our SHP2 inhibitor. We believe that combining such agents in the clinic will prove to be a compelling therapeutic strategy. Now I'll turn things over to Dr. Steve Kelsey, our President of R&D, to bring you up to date on these efforts.

Hence while RMC 69, one itself has the superior preclinical profile to first generation <unk> inhibitors as measured in a variety of models. We've shown previously additional antitumor impact can be obtained by the additive contribution of our ship two inhibitor.

We believe that combining such agents in the clinic will prove to be a compelling therapeutic strategy and now I'll turn things over to Dr. Steve Kelsey.

Our president of R&D to bring you up to date on these efforts.

Steve Kelsey: Thank you, Mark. In monotherapy clinical studies to date, RMC-4630, our clinical-stage SHP2 inhibitor, compares favorably with competitors and is well set up for continued evaluation of potential combination benefits with RAS inhibitors. Notable features of our RMC-4630 program include the use of an innovative intermittent dosing schedule to optimize for activity and tolerability, an absence of cardiac and liver dose limiting toxicities in the dose escalation work, a focus on patients with RAS mutant tumors, observed clinical activity with best responses, including partial response and a complete response, observed reduction in driver oncogene frequency detected in circulating tumor DNA samples, and evidence of favorable modulation of the tumor immune microenvironment in tumor samples from treated patients.

Steve Kelsey: Thank you, Mark. In monotherapy clinical studies to date, RMC-4630, our clinical stage SHP2 inhibitor, compares favorably with competitors and is well set up for continued evaluation of potential combination benefits with RAS inhibitors. Notable features of our RMC-4630 program include the use of an innovative intermittent dosing schedule to optimize for activity and tolerability, an absence of cardiac and liver dose limiting toxicities in the dose escalation work, a focus on patients with RAS mutant tumors, observed clinical activity with best responses, including partial response and a complete response, observed reduction in driver oncogene frequency detected in circulating tumor DNA samples, and evidence of favorable modulation of the tumor immune microenvironment in tumor samples from treated patients.

Thank you Mark.

Stephen M. Kelsey: We believe that RMC-4630 has the potential to be a class-leading SHP2 inhibitor and, thereby, a class-leading RAS companion.

In monotherapy clinical studies to date RMC fulfills all clear.

Nickel stage shifting inhibitor compares favorably with competitive.

And as well setup for continued evaluation of potential combination benefits with RAF inhibitors.

Stephen M. Kelsey: Rusk, Companion, and Hibbert. The earliest combination studies we were able to begin, before RAS inhibitors were available for clinical testing, were combinations with inhibitors of two other targets in the RAS signaling pathway.

Notable features of our RMC for <unk> III program include the use of an innovative.

Dosing schedule to optimize for activity and Tolerability.

Stephen M. Kelsey: Mech and EGFR, and today we provide an update on both. In the absence of direct inhibitors for most RAS mutants, our first approach was to try to clamp them.

In absence of cardiac liver dose limiting toxicities in the dose escalation work.

Our focus on patients with Ras mutant tumors.

Stephen M. Kelsey: Transcribed by https://otter.ai with Covimatinib, a MEK inhibitor which suppresses the bottom of the signaling cascade or downstream of that, based on preclinical work from several groups, including ourselves.

Observed clinical activity with best responses, including partial response and the complete response.

Observed reduction in drive oncogene frequency detected in circulating tumor DNA sample.

Stephen M. Kelsey: had suggested modest but undoubtedly combinatorial antitumor potential for this approach, which we felt merited further investigation.

And evidence of favorable modulation of the tumor immune microenvironment in tune of samples from treated patients.

Steve Kelsey: In Q2, at the annual ASCO meeting, another prominent SHP2 inhibitor program, TNO155 by Novartis, presented its first monotherapy clinical data that showed a different clinical strategy and dosing paradigm with less encouraging output so far. We continue to believe that RMC-4630 has the potential to be a class-leading SHP2 inhibitor and thereby a class-leading RAS companion inhibitor. The earliest combination studies we were able to begin before RAS inhibitors were available for clinical testing were combinations with inhibitors of two other targets in the RAS signaling pathway, MEK and EGFR, and today we provide an update on both.

Steve Kelsey: In Q2, at the annual ASCO meeting, another prominent SHP2 inhibitor program, TNO155 by Novartis, presented its first monotherapy clinical data that showed a different clinical strategy and dosing paradigm with less encouraging output so far. We continue to believe that RMC-4630 has the potential to be a class-leading SHP2 inhibitor and thereby a class-leading RAS Companion Inhibitor. The earliest combination studies we were able to begin before RAS inhibitors were available for clinical testing were combinations with inhibitors of two other targets in the RAS signaling pathway, MEK and EGFR, and today we provide an update on both.

Stephen M. Kelsey: Evaluation in the Context of Serious Unmet Needs. In the RNC 4630-02 study, a group of patients with rasputin non-small cell lung cancer were treated with the RMC4.

In Q2 of the annual Astro meeting.

Another prominent ship two inhibitor program TNI 155 by Novartis presented at first monotherapy clinical data that showed a different clinical strategy and the dosing paradigm with less encouraging.

Stephen M. Kelsey: Diarrhoea MC 4630 plus COVID-19 combination, using the recommended phase two dosing schedule that we described last fall.

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We continue to believe that RMC for Breo has the potential to be a class leading ship two inhibitor and thereby a class leading Ras companion inhibitor.

Stephen M. Kelsey: 11 subjects were valuable for efficacy.

Stephen M. Kelsey: We observed acceptable tolerability, and one patient with a KRAS G12V tumor mutation and gene amplification of that mutation exhibited a confirmed partial response, with an almost 45% tumor volume reduction. In a group of patients with RAS mutant colorectal cancer, we had 25 efficacy-evaluable subjects. Here, too, we observed acceptable tolerability, but the best clinical response was stable disease.

The earliest combination studies, we were able to begin the <unk>.

Full rasp inhibitors were available for clinical testing.

Where combinations with inhibitors of two other targets in the Ras signaling pathway Mec and Egfr.

Today, we provide an update on both.

Steve Kelsey: In the absence of direct inhibitors for most RAS mutants, our first approach was to try to clamp the RAS pathway by combining our inhibitor of SHP2, RMC-4630, which suppresses the top of the signaling cascade or upstream of RAS with cobimetinib, a MEK inhibitor which suppresses the bottom of the signaling cascade or downstream of RAS. Preclinical work from several groups, including ourselves, had suggested modest but undoubtedly combinatorial antitumor potential for this approach, which we felt merited clinical evaluation in the context of serious unmet needs. In the RMC-4630-02 study, a group of patients with RAS mutant non-small cell lung cancer were treated with the RMC-4630 plus cobimetinib combination using the recommended phase 2 dosing schedule that we had described last fall. 11 subjects were evaluable for efficacy.

In the absence of direct inhibitors, but most Ras mutants I'll first approach was to try to plan the Ras pathway by combining our inhibitor of ship to RMB 46, three O, which suppresses the top of the signaling cascade or upstream a bra.

Stephen M. Kelsey: Together, these results are encouraging in that they further support the anti-tumor activity of RMC4630 in a way that can deliver clinical results.

With Koby majnoon in.

Mec inhibitor, which suppresses the Baltimore this segment on the Cascade or guidance stream, Nebraska.

Preclinical work from several groups, including ourselves.

Stephen M. Kelsey: Over Clinical Benefits in RAS-Driven Cancers

Suggested modest, but undoubtedly combinatorial antitumor potential for this approach.

Stephen M. Kelsey: and can be combined tolerably with other drugs.

Stephen M. Kelsey: However, the combination also showed insufficient clinical benefit.

Which we felt merited clinical evaluation in the context with serious unmet needs.

Stephen M. Kelsey: Clinical Benefits to justify advancing this approach.

In the <unk> two study.

Stephen M. Kelsey: To us, this strongly points us back to the primary hypothesis for RAS-addicted cancers.

A group of patients with Ras mutant non small cell lung counts so were treated with <unk> 463 hundred plus COVID-19 that new combination.

Stephen M. Kelsey: which is to focus our efforts on using RMC 4630 as a companion for

Using the recommended phase II dose and the schedule that we have described last fall.

Stephen M. Kelsey: for Direct Ras Inhibitors. Our second and quite different approach was to try to enhance the clinical benefit of a best-in-class receptitizer.

11 subjects were evaluable for efficacy.

Steve Kelsey: We observed acceptable tolerability and one patient with a KRAS G12V tumor mutation and gene amplification of that mutation exhibited a confirmed partial response with an almost 45% tumor volume reduction. In a group of patients with RAS mutant colorectal cancer, we had 25 efficacy evaluable subjects. Here, too, we observed acceptable tolerability, but the best clinical response was stable disease. Together, these results are encouraging in that they further support the antitumor activity of RMC-4630 in a way that can deliver clinical benefit in RAS driven cancers and can be combined tolerably with other drugs. However, the combination also showed insufficient clinical benefit to justify advancing this approach. To us, it strongly points us back to the primary hypothesis for RAS addicted cancers, which is to focus our efforts on using RMC-4630 as a companion for direct RAS inhibitors.

The acceptable Tolerability and one patients with a K Ras G 12, b tumor mutation and gene amplification of that mutation exhibited a confirmed partial response with an almost 45% tumor volume reduction.

Stephen M. Kelsey: Receptorizing Kinase Inhibitor, Ozimertinib

Stephen M. Kelsey: by including RMC 4630 to suppress adaptive resistance mechanisms that may eventually reduce

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And a group of patients with Ras mutant colorectal cancer.

22, five efficacy evaluable subjects here.

Stephen M. Kelsey: Preclinical work has supported the antitumor potential of this probe.

Here too we observe acceptable tolerability.

The best clinical response or stable disease.

Stephen M. Kelsey: which we felt merited a clinical evaluation. We had previously communicated with them, but we were not confident.

Together. These results are encouraging and that further support the antitumor activity of RMC for trio.

In a way that can deliver clinical benefits in Ras driven cancers.

Stephen M. Kelsey: These two agents, with well-recognized on-pathway side effects, could be combined clinically, a precedent set by the combination of osimertinib with the MEK inhibitor, and indeed last quarter, we reported intolerability at the

And can be combined tolerably with other drugs.

The combination also showed any sufficient clinical benefit to justify advancing this approach.

So us strongly point despite the primary hypothesis for rest of active campuses, which is to focus our efforts on using <unk> for fixed trailer was a companion for direct rasp inhibitors.

Stephen M. Kelsey: at the early dose levels in the RMC 463002 study.

Stephen M. Kelsey: In fact, we did not identify a combination dosing schedule with acceptable...

Steve Kelsey: Our second and quite different approach was to try to enhance the clinical benefit of a best-in-class receptor tyrosine kinase inhibitor osimertinib by including RMC-4630 to suppress adaptive resistance mechanisms that may eventually reduce the efficacy of the EGFR inhibitor upon long-term treatment. Preclinical work had supported the antitumor potential for this approach, which we felt merited clinical evaluation. We had previously communicated that we were not confident these two agents with well-recognized on-pathway side effects could be combined clinically, a precedent set by the combination of olaparib with the MEK inhibitors. Indeed, last quarter, we reported intolerability at the early dose levels in the RMC-4630-02 study.

Our second didn't quite different approach was to try to enhance the clinical benefit of the best in class receptor tyrosine kinase inhibitor.

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Stephen M. Kelsey: indicating that the combined on-target toxicity caused by suppression of RAF signaling in normal tissues caused by these two agents together presents too big a hurdle to justify advancing this approach. Again, this outcome reiterates our prime combination hypothesis for treating RAS-addicted cancers, which is combining RMC4630 or other RAS companion inhibitors with direct RAS inhibitors.

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By including RMC 463, O to suppress adaptive resistance mechanisms that may eventually reduce the efficacy of the Egfr inhibitor.

<unk> long term treatments.

Preclinical work has supported the antechamber potential for this approach, which we felt merits of clinical evaluation.

We had previously communicated that we were not confident these two agents with well recognized on pathway side effects can be combined clinically.

Stephen M. Kelsey: And that strategy will be our highest priority going forward.

<unk> set by the combination of all of the Merck with the Mac inhibitors.

Stephen M. Kelsey: In view of the response rates, emerging drug resistance profiles, and resistance mechanisms for the leading KRAS G12C off inhibitors,

And indeed last quarter, we reported in Tolerability.

Early dose levels in the <unk> study.

Steve Kelsey: In fact, we did not identify a combination dosing schedule with acceptable tolerability, even employing our intermittent dosing paradigm for RMC-4630, indicating that the combined on-target toxicity caused by suppression of RAS signaling in normal tissues caused by these two agents together presents too big a hurdle to justify advancing this approach. Again, this outcome reiterates our prime combination hypothesis for treating RAS-addicted cancers, which is combining RMC-4630 or other RAS companion inhibitors with direct RAS inhibitors. That strategy will be our highest priority going forwards. In view of the response rates, emerging drug resistance profiles, and resistance mechanisms for the leading KRAS G12C off inhibitors, we continue to have conviction about combining RMC-4630 with direct RAS inhibitors.

Steve Kelsey: In fact, we did not identify a combination dosing schedule with acceptable tolerability, even employing our intermittent dosing paradigm for RMC-4630, indicating that the combined on-target toxicity caused by suppression of RAS signaling in normal tissues caused by these two agents together presents too big a hurdle to justify advancing this approach. Again, this outcome reiterates our prime combination hypothesis for treating RAS-addicted cancers, which is combining RMC-4630 or other RAS companion inhibitors with direct RAS inhibitors. That strategy will be our highest priority going forwards. In view of the response rates, emerging drug resistance profiles, and resistance mechanisms for the leading KRAS G12C (OFF) inhibitors, we continue to have conviction about combining RMC-4630 with direct RAS inhibitors.

In fact, we did not identify a combination dose and schedule with acceptable tolerability, even employing our intermittent dosing paradigm for RMC full six three of <unk>.

Stephen M. Kelsey: We continue to have conviction about combining RMC4630 with direct trace inhibitors.

Stephen M. Kelsey: Since, to our understanding, All clinical toxicities driving our selection of the recommended phase 2 dose of RMC4630 have been attributable to RAS pathway effects in normal tissue, we have no reason to believe that combining RMC4630 with a RAS mutant-selective inhibitor would be compromised by additive dose-limiting toxicity. Amgen continues to enroll the COVID break 101.

Indicating that when combined on target toxicity caused by suppression of Ras signaling in normal tissues caused by these two agents together presents too big a hurdle to justify bumps in this approach.

Okay. This high income reiterate subprime combination hypothesis for treating Rhapsody, two campuses, which is combining arms for <unk> breo or other Ras companion inhibitors with direct rasp inhibitors.

Stephen M. Kelsey: Subpart C Study of Saptoracid with RMC 4630

And that strategy will be our highest priority going forwards.

Stephen M. Kelsey: in Advanced Non-Small Cell Lung Cancer, colorectal cancer, and other solid tumors. As noted earlier in the quarter, the dose escalation work continues evaluating RMC4630 at the target dose of 200 milligrams daily on a day one, day two weekly schedule, the full dose used by us in monotherapy in combination with suctyroses.

In view of the response rates emerging drug resistance profiles and resistance mechanisms for the leading <unk> often visitors.

We continue to have conviction about combining RMC fall through with direct rasp inhibitors.

Steve Kelsey: Since, to our understanding, all clinical toxicities driving our selection of the recommended phase 2 dose of RMC-4630 have been attributable to RAS pathway effects in normal tissues, we have no reason to believe that combining RMC-4630 with a RAS mutant selective inhibitor would be compromised by additive dose-limiting toxicities. Amgen continues to enroll the CodeBreaK 101 subpart C study of sotorasib with RMC-4630 in advanced non-small cell lung cancer, colorectal cancer, and other solid tumors. As noted earlier in the quarter, the dose escalation work continues, evaluating RMC-4630 at the target dose of 200 milligrams daily on a day one, day two weekly schedule. The full dose used by us in monotherapy in combination with sotorasib at 960 milligrams daily.

Steve Kelsey: Since, to our understanding, all clinical toxicities driving our selection of the recommended phase 2 dose of RMC-4630 have been attributable to RAS pathway effects in normal tissues, we have no reason to believe that combining RMC-4630 with a RAS mutant selective inhibitor would be compromised by additive dose-limiting toxicities. Amgen continues to enroll the CodeBreaK 101 Subpart C study of sotorasib with RMC-4630 in advanced non-small cell lung cancer, colorectal cancer, and other solid tumors. As noted earlier in the quarter, the dose escalation work continues, evaluating RMC-4630 at the target dose of 200mg daily on a day 1, day 2 weekly schedule. The full dose used by us in monotherapy, in combination with sotorasib at 960mg daily.

Since two our understanding.

Stephen M. Kelsey: Tarasov at 960mg daily.

All clinical toxicity driving a selection of the recommended phase two dose of RMC for <unk> have been attributable to Ras pathway effects in normal tissues.

Stephen M. Kelsey: A combination dose for expansion is expected to be achieved by Amgen in the second half of this year.

Stephen M. Kelsey: We are encouraged by this work, and it continues to be a productive clinical exploration of the combination strategy.

We have no reason to believe that combining <unk> with a <unk> selective inhibitor would be compromised by habits of dose limiting toxicities.

Stephen M. Kelsey: RedMed is also excited to announce today an expansion of our collaboration on this drug combination with Amgen in the RMC4630-O3 study. I will provide a more detailed update on this study momentarily.

Amgen continues to enroll because it breaks one O. One sub part C study of tourists with RMC for <unk> in advanced non small cell lung cancer.

Colorectal cancer and other solid tumors.

As noted earlier in the quarter.

Stephen M. Kelsey: In addition, we plan to combine RMC4630 with RMC6291, our KRAS-G12C ON inhibitor, and potentially other compounds from our RAS ON inhibitor collection as these become available. Finally, the TCD 16.2.10 study sponsored by Sanofi continues evaluating INC4630 plus Pembrolizumab. We are pleased to report today that the combination will now be evaluated in an experiment.

The dose escalation work continues evaluating RMC full 630.

Target dose of 200 milligrams daily on a day one day two week schedule.

The full dose used by us in monotherapy in combination with the tire at 960 milligrams daily.

Steve Kelsey: A combination dose for expansion is expected to be achieved by Amgen in H2 of this year. We are encouraged by this work, and it continues to be a productive clinical exploration of the combination strategy. RevMed is also excited to announce today an expansion of our collaboration on this drug combination with Amgen with the RMC-4630-03 study. I will provide a more detailed update on this study momentarily. In addition, we plan to combine RMC-4630 with RMC-6291, our KRAS G12C(ON) inhibitor, and potentially other compounds from our RAS(ON) inhibitor collection as these become available. Finally, the TCD16210 study sponsored by Sanofi continues, evaluating RMC-4630 plus pembrolizumab.

Steve Kelsey: A combination dose for expansion is expected to be achieved by Amgen in H2 of this year. We are encouraged by this work, and it continues to be a productive clinical exploration of the combination strategy. RevMed is also excited to announce today an expansion of our collaboration on this drug combination with Amgen with the RMC-4630-03 study. I will provide a more detailed update on this study momentarily. In addition, we plan to combine RMC-4630 with RMC-6291, our KRAS G12C RAS(ON) inhibitor, and potentially other compounds from our RAS(ON) inhibitor collection as these become available. Finally, the TCD16210 study sponsored by Sanofi continues, evaluating RMC-4630 plus pembrolizumab.

A combination dose for expansion is expected to be achieved by Amgen in the second half of this year.

We are encouraged by this work and it continues to be a productive clinical exploration of the combination strategy.

Stephen M. Kelsey: Expansion Cohort of Patients with Previously Untreated Advanced

Let met is also excited to announce today an expansion of our collaboration on this drug combination with Amgen with the RMC full six Breo <unk> III study.

Stephen M. Kelsey: PDL1-positive non-small cell lung cancer. This study could provide the foundation for a future clinical evaluation of the triplet of a RAS inhibitor, RMC4630, and a PD-1 inhibitor in the new RNC 463003 study.

I will provide a more detailed update on this study momentarily.

In addition, we plan to combine RMC full succeed with RMC six to nine one al Qaeda wants do 12 C. One inhibitor.

Stephen M. Kelsey: Influenced by preclinical data, the Code Break 101C worked to date, and important learnings in the field over the last few years since the Code Break protocol was recognized. The RMC 463003 study was designed as a global face-to-face study.

There's potentially other compounds from all wrap one inhibitor collection as these become available.

Finally, the TC the 16 to 10 study sponsored by Sanofi continues evaluates and RMC 463 that we hadn't burleson.

Stephen M. Kelsey: of the combination of Sitorucid plus RMC4630 in advanced KRAS G12C non-small cell lung cancer

Steve Kelsey: We are pleased to report today the combination will now be evaluated in an expansion cohort of patients with previously untreated advanced PD-L1-positive non-small cell lung cancer. This study could provide the foundation for a future clinical evaluation of the triplet of a RAS inhibitor, RMC-4630, and a PD-1 inhibitor. Regarding the new RMC-4630-03 study, informed by preclinical data, the CodeBreaK 101c work to date, and important learnings in the field over the last few years since the CodeBreaK protocol was written, the RMC-4630-03 study was designed as a global phase 2 study of the combination of sotorasib plus RMC-4630 in advanced KRAS G12C non-small cell lung cancer that have not previously received a KRAS G12C inhibitor.

Steve Kelsey: We are pleased to report today the combination will now be evaluated in an expansion cohort of patients with previously untreated advanced PD-L1-positive non-small cell lung cancer. This study could provide the foundation for a future clinical evaluation of the triplet of a RAS inhibitor, RMC-4630, and a PD-1 inhibitor. Regarding the new RMC-4630-03 study, informed by preclinical data, the CodeBreaK 101C work to date, and important learnings in the field over the last few years since the CodeBreaK protocol was written, the RMC-4630-03 study was designed as a global phase 2 study of the combination of sotorasib plus RMC-4630 in advanced KRAS G12C non-small cell lung cancer that have not previously received a KRAS G12C inhibitor.

We are pleased to report today, the combination will now be evaluated in an expansion cohort of patients with previously untreated advanced PD lone positive non small cell lung cancer.

Stephen M. Kelsey: that have not previously received a KRAS-Dutil-C inhibitor.

Stephen M. Kelsey: It is intended to establish the extent and nature of additional clinical...

This study could provide the foundation for our future clinical evaluation of the triplet. So the Ras inhibitor RMC for <unk> and a PD one inhibitor.

Stephen M. Kelsey: Additional Clinical Benefits from combining these two agents and to inform the design of a possible registrational trial.

Regarding the new RMC full 6303 studies.

Stephen M. Kelsey: While the O3 study is complementary to COBRATE-101C, it has several important differences.

Informed by preclinical data.

The code break one I wanted to see work to date and important learnings in the field over the last few years since the Covid break post COVID-19.

The RMC for <unk> III study was designed as a global phase III study.

The combination of <unk>, plus RMC full six trio and advanced pay Ross <unk> non small cell lung cancer that have not previously received a <unk> inhibitor.

Steve Kelsey: It is intended to establish the extent and nature of additional clinical benefit from combining these two agents and to inform the design of a possible registrational trial. While the 03 study is complementary to CodeBreaK 101c, it has several important differences. The RMC-4630-03 study will enroll approximately 46 non-small cell lung cancer subjects with two cohorts that are defined by co-mutations that may affect the outcome to either KRAS inhibitor or SHP2 inhibition. First cohort will have KRAS G12C positive tumors without co-mutations, and the second cohort will have KRAS G12C positive tumors with co-mutations, such as KEAP1 or STK11 mutations. This will allow us to better define who may most benefit from this promising combination strategy.

Steve Kelsey: It is intended to establish the extent and nature of additional clinical benefit from combining these two agents and to inform the design of a possible registrational trial. While the RMC-4630-03 study is complementary to CodeBreaK 101C, it has several important differences. The RMC-4630-03 study will enroll approximately 46 non-small cell lung cancer subjects with two cohorts that are defined by co-mutations that may affect the outcome to either KRAS inhibitor or SHP2 inhibition. First cohort will have KRAS G12C positive tumors without co-mutations, and the second cohort will have KRAS G12C positive tumors with co-mutations, such as KEAP1 or STK11 mutations. This will allow us to better define who may most benefit from this promising combination strategy.

Stephen M. Kelsey: have KRAS G2C positive tumors with co-mutations, such as KIP-1 or STK11 mutations. This will allow us to better define who may most benefit from this promising combination strategy.

It is intended to establish the extent and nature of additional clinical benefit.

Combining these two agents.

And to inform the design of a possible registrational trial.

While the <unk> III study is complementary to kind of break what I want to see it has several important differences.

Stephen M. Kelsey: Unlike COBRATE-101, the study will restrict eligibility to second and third-line therapy, and it will enroll patients outside the United States as well as within the United States.

The RMC forces <unk> III study will enroll approximately 46 non small cell lung cancer subjects with two cohorts that are defined by code mutations that may affect the outcome to either pay rasp inhibitor or ship to the ambition.

Stephen M. Kelsey: WebMed is sponsoring and executing this study under its global partnership with Sinovac.

First cohort will have chaos G <unk> see positive tumors without co mutations and the second cohort will have <unk> positive tumors with <unk> mutations such as <unk> or <unk>.

Stephen M. Kelsey: with clinical supplies to Torresfield provided by Amgen for the ex-U.S. sites where the drug is not yet approved, which is expected to be a major source of enrolment now that Sotirisib has been approved in the United States. For data analysis and full interpretation, we will have the ability to draw from both COBRATE-101C results and the O3 study results. We view RMC 46303 as an important and exciting clinical

11 patients.

This will allow us to better define who may most benefit from this promising combination strategy.

Steve Kelsey: Unlike CodeBreaK 101, the study will restrict eligibility to second- and third-line therapy, and it will enroll outside the United States as well as within the United States. RevMed is sponsoring and executing this study under its global partnership with Sanofi. With clinical supply of sotorasib provided by Amgen for the ex-US sites where the drug is not yet approved, which is expected to be a major source of enrollment now that sotorasib has been approved in the United States. For data analysis and full interpretation, we will have the ability to draw from both CodeBreaK 101c results and the 03 study results. We view RMC-4630-03 as an important and exciting clinical study.

Steve Kelsey: Unlike CodeBreaK 101, the study will restrict eligibility to second and third-line therapy, and it will enroll outside the United States as well as within the United States. RevMed is sponsoring and executing this study under its global partnership with Sanofi. With clinical supply of sotorasib provided by Amgen for the ex US sites where the drug is not yet approved, which is expected to be a major source of enrollment now that sotorasib has been approved in the United States. For data analysis and full interpretation, we will have the ability to draw from both CodeBreaK 101C results and the RMC-4630-03 study results. We view RMC-4630-03 as an important and exciting clinical study.

Unlike co Brightwater, one study will restrict eligibility to second and third line therapy.

And it will enroll outside the United States as well as well as within Europe.

We estimate is sponsoring and executing this study under its global partnership with Sanofi.

With clinical suppliers to tourists it provided by Amgen for the ex U S sites, where the drug is not yet approved which is expected to be a major source of enrollment now that software.

Stephen M. Kelsey: Uniting Clinical Study. We are preparing to launch the study, and we expect the first patients to be enrolled in the second half of this year and to have preliminary findings by the end of 2022.

Been approved in the United States.

So data analysis and interpretation, we will have the ability to draw from both Covid break one I want to see results and the <unk> study results.

We view RMC for <unk>, three as an important and exciting clinical study.

Mark A. Goldsmith: Today we highlighted recent progress regarding several important assets in our strategic development stage pipeline addressing key drivers of RAS addiction and drug resistance and provided further visibility into the remarkable drug discovery advances within our RAS on inhibitor program that will help power advancing additional research stage assets into development. In addition, our mTORC1-selective inhibitor, RMC5552, continues advancing in monotherapy dose escalation, and our SOS1-selective inhibitor, RMC5845, is on track to be IMD-ready by the end of this year. Slide 41 outlines our corporate milestones. I'd like to highlight several of these in particular.

Steve Kelsey: We are preparing to launch the study, and we expect the first patients to be enrolled in the H2 of this year and to have preliminary findings by the end of 2022. Back to you, Mark.

Steve Kelsey: We are preparing to launch the study, and we expect the first patients to be enrolled in H2 of this year and to have preliminary findings by the end of 2022. Back to you, Mark.

We are preparing to launch this study and we expect the first patient to be enrolled in the second half of this year and to have preliminary findings by the end of 2022.

Mark Goldsmith: Thank you, Steve. Today, we highlighted recent progress regarding several important assets in our strategic development stage pipeline, addressing key drivers of RAS addiction and drug resistance, and provided further visibility into the remarkable drug discovery advances within our RAS(ON) inhibitor program that will help power advancing additional research stage assets into development. In addition, our mTORC1 selective inhibitor, RMC-5552, continues advancing in monotherapy dose escalation, and our SOS1 selective inhibitor, RMC-5845, is on track to be IND ready by the end of this year. Slide 41 outlines our corporate milestones. I'd like to highlight several of these in particular. In our RAS(ON) inhibitor pipeline, we continue to anticipate IND filings for both RMC-6291 and RMC-6236 in H1 2022, and selection of a third RAS(ON) inhibitor development candidate later this year.

Mark Goldsmith: Thank you, Steve. Today, we highlighted recent progress regarding several important assets in our strategic development stage pipeline, addressing key drivers of RAS addiction and drug resistance, and provided further visibility into the remarkable drug discovery advances within our RAS(ON) inhibitor program that will help power advancing additional research stage assets into development. In addition, our mTORC1 selective inhibitor, RMC-5552, continues advancing in monotherapy dose escalation and our SOS1 selective inhibitor, RMC-5845, is on track to be IND ready by the end of this year. Slide 41 outlines our corporate milestones. I'd like to highlight several of these in particular. In our RAS(ON) inhibitor pipeline, we continue to anticipate IND filings for both RMC-6291 and RMC-6236 in H1 2022, and selection of a third RAS(ON) inhibitor development candidate later this year.

Back to you Mark.

Thank you Steve.

Today, we highlighted recent progress regarding several important assets in our strategic development stage pipeline addressing key drivers of RAF addiction, and drug resistance and provided further visibility into the remarkable drug discovery advances within our rasp inhibitor program that will help power advancing additional research.

Stage assets into development.

In addition, our <unk> selective inhibitor RMC $5.55 to continue advancing in monotherapy dose escalation and our source one selective inhibitor RMC five eight or five is on track to be IND ready by the end of this year.

Slide 41 outlines our corporate milestones I'd like to highlight several of these in particular.

Jack Anders: In our RAS-ON inhibitor pipeline, we continue to anticipate IND filings for both RMC6291 and RMC6236 in the first half of 2022 and selection of a third RAS-on inhibitor development candidate later this year. For RMC4630, later this year, we anticipate selection by Amgen of a dose for further study with Sotiracib in code break 101 and to begin dosing patients in our new O3 study with I'll now turn things over to Jack Anders to review our financial results.

And our RASK on inhibitor pipeline, we continue to anticipate IND filings for both RMC $6.91, and RMC 63, six in the first half of 2022.

And selection of a third rason inhibitor development candidate later this year.

Mark Goldsmith: For RMC-4630, later this year, we anticipate selection by Amgen of a dose for further study with sotorasib in CodeBreaK 101 and to begin dosing patients in our new RMC-4630-03 study with sotorasib. I'll now turn things over to Jack Anders to review our financial results. Jack?

For RMC 4630 later this year, we anticipate selection by Amgen have a dose for further study with sort of rapid been could break 101 and to begin dosing patients in our new <unk> III study with soda rapid.

I'll now turn things over to Jack Anders to review our financial results Jack.

Jack Anders: Thank you, Marc, and good afternoon, everyone. We ended the quarter with $646 million in cash, cash equivalents, and investments. Revenue for the second quarter of 2021 was $8.7 million and consists entirely of revenue under our collaboration agreement with Sinovac. Our total operating expenses for the second quarter of 2021 increased by $1.5 million. 53.2 million, largely driven by R&D expenses, which were 45.9 million during the quarter. The net loss for the second quarter of 2021 was $44.3 million, or $0.60 per share.

Jack Anders: Thank you, Mark, and good afternoon, everyone. We ended the quarter with $646 million in cash equivalents, and investments. Revenue for Q2 2021 was $8.7 million and consists entirely of revenue under our collaboration agreement with Sanofi. Total operating expenses for Q2 2021 increased to $53.2 million, largely driven by R&D expenses, which were $45.9 million during the quarter. Net loss for Q2 2021 was $44.3 million or $0.60 per share. Turning to financial guidance, we continue to expect full year GAAP net loss to be between $170 million and $190 million, which includes estimated non-cash stock-based compensation expense of approximately $20 million.

Jack Anders: Thank you, Mark, and good afternoon, everyone. We ended the quarter with $646 million in cash equivalents, and investments. Revenue for Q2 2021 was $8.7 million and consists entirely of revenue under our collaboration agreement with Sanofi. Total operating expenses for Q2 2021 increased to $53.2 million, largely driven by R&D expenses, which were $45.9 million during the quarter. Net loss for Q2 2021 was $44.3 million or $0.60 per share. Turning to financial guidance, we continue to expect full year GAAP net loss to be between $170 and $190 million, which includes estimated non-cash stock-based compensation expense of approximately $20 million.

Thank you Mark and good afternoon, everyone.

We ended the quarter with $646 million in cash cash equivalents and investments.

Revenue for the second quarter of 2021 was $8.7 million and consist entirely of revenue under our collaboration agreement with Sanofi.

Total operating expenses for the second quarter of 2021 increased to $53.2 million largely driven by R&D expenses, which were $45.9 million during the quarter.

Net loss for the second quarter of 2021 was $44.3 million or <unk> 60 per share.

Jack Anders: Turning to financial guidance, we continue to expect full-year gap net loss to be between $170 million and $190 million, which includes estimated non-cash, stock-based compensation expense of approximately $20. Our gap net loss for the first half of 2021 was $81 million, and we expect net loss to increase during the second half of the year, primarily driven by increases in operating expenses as we advance our preclinical and clinical programs. And with that, I'll now turn the call back over to Mark.

Turning to financial guidance, we continue to expect full year GAAP net loss to be between 170 and $190 million.

Which includes estimated noncash stock based compensation expense of approximately $20 million.

Jack Anders: Our GAAP net loss for H1 2021 was $81 million, and we expect net loss to increase during H2, primarily driven by increases in operating expenses as we advance our pre-clinical and clinical programs. With that, I'll now turn the call back over to Mark.

Jack Anders: Our GAAP net loss for H1 2021 was -$81 million, and we expect net loss to increase during H2 of the year, primarily driven by increases in operating expenses as we advance our pre-clinical and clinical programs. With that, I'll now turn the call back over to Mark.

Our GAAP net loss for the first half of 2021 was $81 million.

And we expect net loss to increase during the second half of the year.

Primarily driven by increases in operating expenses as we advance our preclinical and clinical programs.

And with that I'll now turn the call back over to Mark.

Mark Goldsmith: Thank you, Jack. We believe that RevMed is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients. We have a compelling strategy, a growing set of exciting product assets, and a strong balance sheet. We're proud of the tireless commitment to patients by our organization and are grateful to the patients and their families and the many partners who work with us for providing RevMed with the opportunity to advance our unique pipeline of RAS(ON) inhibitors and RAS Companion Inhibitors, which we believe may transform the treatment of RAS-addicted cancers in the future. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session. Operator?

Mark Goldsmith: Thank you, Jack. We believe that RevMed is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients. We have a compelling strategy, a growing set of exciting product assets, and a strong balance sheet. We're proud of the tireless commitment to patients by our organization and are grateful to the patients and their families and the many partners who work with us for providing RevMed with the opportunity to advance our unique pipeline of RAS(ON) inhibitors and RAS companion inhibitors, which we believe may transform the treatment of RAS-addicted cancers in the future. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session. Operator?

Thank you Jack.

We believe that resonate is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients. We have a compelling strategy a growing set of exciting product assets and a strong balance sheet. We're proud of the tireless commitment to patients by our organization and are grateful to the patients and their families and the many.

<unk>, who worked with us for providing resonated with the opportunity to advance our unique pipeline of rason inhibitors in Ras companion inhibitors, which we believe may transform the treatment of Ras addicted cancers in the future.

This concludes our prepared remarks for today and I'll now turn the call over to the operator for the Q&A session operator.

Operator 2: Thank you. As a reminder to ask a question, please press the star key followed by one on your touchtone telephone. To withdraw your question, press the pound key. Again, that's star one to ask the question. Please stand by while we compile the Q&A roster. Our first question comes from the line of Chris Shibutani with Goldman Sachs. Your line is open.

Thank you.

As a reminder to ask a question. Please press the star key followed by one on your touch tone telephone.

Withdraw your question press the pound key.

Operator: Again, that's star number one to ask the question. Please stand by while we compile the Q&A. Our first question comes from the line of Chris Shibutani.

Again, Thats star one to ask a question. Please standby, while we compile the Q&A roster.

Mark Goldsmith: Our first question comes from the line of Chris Shibutani with Goldman Sachs. Your line is open.

Chris Shibutani: Chris Shibutani with Goldman Sachs. The line is open.

Our first question comes from the line of Chris <unk>.

Chris Shibutani: Yes, hi, thanks very much for the questions. I want to get a sense for timelines for clinical data, a lot of progress and updates with your clinical planning here.

Tiny with Goldman Sachs. Your line is open.

Chris Shibutani: Yes. Hi, thanks very much for the questions. Want to get a sense for timelines for clinical data. A lot of progress and updates with your clinical planning here, obviously. With the study that you have with sotorasib, this 03 study, it looks as if we're gonna get the preliminary findings in the H2 of next year, 2022. Can you help put that timeline in context with your confidence in starting the phase 2 now? Also, will we be able to get a sense for what phase 1 data looks like?

Chris Shibutani: Yes. Hi, thanks very much for the questions. I want to get a sense for timelines for clinical data. A lot of progress and updates with your clinical planning here, obviously. With the study that you have with sotorasib, this zero three study, it looks as if we're gonna get the preliminary findings in H2 of next year, 2022. Can you help put that timeline in context with your confidence in starting the phase 2 now? Also, will we be able to get a sense for what phase 1 data looks like?

Yes, hi, thanks, very much for the questions.

Want to get a sense for timelines for clinical data a lot of progress and updates with your clinical planning here obviously.

Chris Shibutani: I want to get a sense for timelines for clinical data. There is a lot of progress and updates with your clinical planning here, obviously. With the study that you have with Toraceb, this 03 study, it looks as if we're going to get the preliminary findings in the second half of next year, 2022. Can you help put that timeline in context with your confidence in starting phase two now? And also, will we be able to get a sense for what phase one data looks like?

With the study that you have with the tourists. This <unk> III study it looks as if we're going to get the preliminary findings in the second half of next year 2022 can you help put that timeline in context with.

Your confidence in starting the phase two now and also.

So.

Will we be able to get a sense for what phase one data looks like.

Mark Goldsmith: Thanks, Chris. This is Mark Goldsmith. Thanks for asking your questions, good to hear from you. I think I'll ask Steve Kelsey to comment. There were several pieces built into that question. Maybe Steve can tackle them for you.

Thanks, Chris.

Thanks for asking your question sitting here from U S.

Steve Kelsey to comment.

Mark A. Goldsmith: Yeah, thanks Chris. I'll try to answer your questions.

There were several cases built into that question.

Florida.

Steve Kelsey: Yeah. Thanks, Chris. I'll try to answer your questions in a logical sequence if I can. Firstly, the RMC-4630-03 study to which we referred is complementary to the Amgen CodeBreaK 101c study.

Steve Kelsey: Yeah. Thanks, Chris. I'll try to answer your questions in a logical sequence if I can. Firstly, the 03 study to which we referred is complementary to the Amgen CodeBreaK 101C study.

Yes, Thanks, Chris.

China for us.

Mark A. Goldsmith: I tried to answer your questions in a logical sequence, but I can't. Firstly, the 03 studies to which we refer are complementary to the Amgen-Kerrigan-Wansi study.

Last question.

Okay.

Uh huh.

Firstly.

The other three studies, which.

Yes.

Is complementary to the Amgen tolerate philosophy study.

Mark A. Goldsmith: The data, the totality of the data, will be evaluated together.

Steve Kelsey: The data, the totality of the data will be evaluated together. We expect, as we said, first run of that to be towards the end of next year. The phase 1 data to which you allude, that there is going to be a very brief safety run for the 03 study, where we are compelled to do that because a recommended phase 2 dosing schedule has not yet been defined with that we can legitimately and ethically start the 03 study with. Obviously we will be able to use that for the expansion of the 03 study. What we cannot do is comment on when Amgen will release data from the phase 1 component of the CodeBreaK 101c study.

Steve Kelsey: The data, the totality of the data will be evaluated together. We expect, as we said, first run of that to be towards the end of next year. The phase 1 data to which you allude, that there is going to be a very brief safety run for the 03 study, where we are compelled to do that because a recommended phase 2 dosing schedule has not yet been defined, with that we can legitimately and ethically start the 03 study with. Obviously we will be able to use that for the expansion of the 03 study. What we cannot do is comment on when Amgen will release data from the phase 1 component of the CodeBreaK 101C study.

And so.

The totality of the savings will be abbvie basis again.

Mark A. Goldsmith: And we expect, as we said, the first run-up act to be towards the end of next year.

And the mix.

As we said.

Mark A. Goldsmith: Phase 1 data to which you allude that there is going to be a very brief safety run into the O3 study, where we are compelled...

Towards the end of next year.

The.

Phase one days, which is.

That is going to be a journey.

Mark A. Goldsmith: Study, where we are compelled to do that because a recommended phase two dosage schedule has not yet been defined that we can legitimately and ethically start the entry study with. And obviously, we will be able to use that for the expansion of the ACES study. What we cannot do is comment on when Angine will release data from the phase one component of the codebreak model.

Jerry three safety run ins is reached.

We all come to the house to do that.

Because a recommended phase two dose and schedule is not yet defined what we can do.

<unk>.

As a result interest.

And obviously, we will be able to.

Is that.

Essentially as you study what we do is comment on one hand you'd already basis.

Data from the study as well as components of.

Mark A. Goldsmith: One Senior Study, other than we are guiding them to the fact that they will select a dose.

The Cobra, Florida one.

Steve Kelsey: Other than we are guiding to the fact that they will select a dose in H2 of this year. What we can't tell you is when they will disclose that.

<unk> study all of us.

Mark A. Goldsmith: and the fact that they will select the nominees in the second half of this year. And what we can tell you is that they will.

Adding to the size of the slate will select the dose and.

In the second half of this year Thompson will discuss.

Chris Shibutani: Okay, that's helpful. With the studies that have been discontinued with the Amgen program,

Okay. That's helpful.

With the studies that have been discontinued.

Chris Shibutani: As we continue with the AmGen program, can you provide us with a preliminary sense for what impact you feel the design of the studies may have factored into this outcome and the decision? Just to clarify, are you talking about the COVID-19 and post-emergency studies, the O2 studies? Yes, that's correct. Yeah, I'm not sure. Steve, do you want to comment on that? I'm not sure what design studies or what aspect of design you were referring to.

With the Amgen program can you provide us with a preliminary sense for what impact do you feel the design of the studies may have factor into this.

The outcome in the decision.

Mark Goldsmith: Just to clarify, you're talking about the cobimetinib and osimertinib studies, the 02 studies?

Just to clarify you are talking about the Kobe.

Chris Shibutani: Yes. That's correct. Yeah.

Awesome.

Yes, that's correct.

Correct Yeah.

I'm not sure.

Do you want to comment on that Im not sure with design of the studies what aspects of design, you're referring to is really the choices.

Chris Shibutani: It's really the choice of drugs that we're combining with there, but maybe Steve can clarify. You know, I think there are two components to the question. One is, what decision are we making, and why are we making it?

Drugs that we're combining with there, but maybe you can clarify.

Steve Kelsey: Yeah, I think there's two components to the question. One is what decision are we making and why are we making it? The second is how the design of both the cobimetinib combination and the osimertinib combination contributed to the fact that we didn't see as encouraging efficacy as we want to see moving forward. Let's be clear about the reasons why we're not moving forward with those two combinations. The first and most compelling one is that the efficacy profile wasn't sufficiently compelling to justify moving forward. There's also a large component of prioritization here as well.

Steve Kelsey: Yeah, I think there's 2 components to the question. One is what decision are we making and why are we making it. Then the second is how the design of both the cobimetinib combination and the osimertinib combination contributed to the fact that we didn't see as encouraging efficacy as we want to see moving forward. Let's be clear about the reasons why we're not moving forward with those two combinations. The first and most compelling one is that the efficacy profile wasn't sufficiently compelling to justify moving forward. There is also a large component of prioritization here as well.

Yes.

Two questions.

Question, one is what Rob just one thought decision only 19.119.

Chris Shibutani: And then the second is the design of both the code method combination and the alternative combination of culture.

And then the second is how the design of the current.

We met the culmination of the I'll use a combination of culture.

Chris Shibutani: I didn't see as much encouraging advocacy as we want to see moving forward. So let's be clear about the... the reasons why we're not moving forward.

We.

Didn't see as encouraging efficacy signals.

So let's be clear.

The reasons why we are not moving forward with those two combinations the first and I'll ask another one is that the efficacy profile will sufficiently compelling to justify moving forward, but there.

Chris Shibutani: Moving forward with those two combinations, the first, and most compelling one, is that the efficacy profile...

Chris Shibutani: Unknown Executive, Chris Shibutani, Erin Graves, Wei Chang, Jack Anders, Wei Chang

There's also a large component of the prioritization here as well.

Steve Kelsey: That we, you know, we have been very publicly moving towards combining the companion inhibitors that we have, which include RMC-4630 with RAS-directed therapies that we and others are making. That's an important part of our consideration here. It's really about what do we think, where do we think the best place to go for RAS-addicted cancers and patients with RAS-addicted cancers is, as much as it is the data for sake of the scope. I don't think there was any design fault with the studies. We think we have comprehensively tested the hypothesis, at least as far as we can with a MEK inhibitor, cobimetinib, and the data is fairly, in our opinion, conclusive in that respect.

Steve Kelsey: That we, you know, we have been very publicly moving towards combining the companion inhibitors that we have, which include RMC-4630 with RAS-directed therapies that we and others are making. That's an important part of our consideration here. It's really about where do we think the best place to go for RAS-addicted cancers and patients with RAS-addicted cancers is, as much as it is the data for the sake of the scope. I don't think there was any design fault with the studies. We think we have comprehensively tested the hypothesis, at least as far as we can with a MEK inhibitor, cobimetinib, and the data is fairly, in our opinion, conclusive in that respect.

We have the.

Very popular moving towards combining the indicators that we see.

Chris Shibutani: combining the companion inhibitors

Chris Shibutani: we have, which include IRC 4630, with last directed therapies that we

Turning to our <unk>.

Chris Shibutani: and others. And that's an important part of our consideration here; it's really about where do we think the best place to go to fight addicted cancers and patients with addicted cancers is, as much as it is the data per se from the studies. I don't think there was any design fault with the studies; we think we have comprehensively tested the hypothesis, at least as far as we can, with a mechanism to make it work.

With last directed therapies.

Mike.

And that's an important part of it.

It's really about what can we say why do we think the best places does the rats.

This is in patients with prostate cancer.

Yes.

Is that agents are baseless.

I don't think there was any design solves split the studies.

Comprehensively testing that hypothesis.

As far as we can with a message as to some kind of event.

Chris Shibutani: with a negative for COVID-19, and the data is, in our opinion, conclusive in that respect. And, as you are aware... We are still supporting the London Cancer Institute to do a study in combination with an Erkinhead experiment in pancreatic and colon cancer. And in as much as that represents a slight variation on the hypothesis, then, you know, we'll be interested to see the outcome from that experiment. But I think we designed the best experiment we could, and we are making the decision we made for compelling reasons both strategically and quantitatively. And maybe I could just add to that, Chris, just to see if I can get at the question...

And if the data is.

In our opinion is conclusive.

Steve Kelsey: As you are aware, we are still supporting the Netherlands Cancer Institute to do a study in combination with an ERK inhibitor in pancreatic and colon cancer. In as much as that represents a slight variation on the hypothesis, then, you know, we'll be interested to see the outcome from that experiment. I think we designed the best experiment we could, and we are making the decision we made for compelling reasons, both strategically and practically.

In that respect.

Thank you.

Well.

We are still supporting the Netherlands pastures.

A study in combination with them.

Erin in pancreatic can tell paths.

And as much as that represents a slight variation on the hypothesis then.

We will be interesting to see the outcome from that experiment.

We designed the best experiment because.

And we are making the decision we made for compelling reasons both strategically.

Chris Shibutani: And maybe I could just add to that, Chris, just to see if I can get at the question that you're raising here. I think it goes back to the indirect.

Okay.

And then if I could just add to that Chris if I can get a question that you're that you are raising here.

Chris Shibutani: Strategy of the Clamping Approach, which is one that we now disfavor and that is trying not actually inhibiting the cancer driver but inhibiting the pathway upstream and downstream. And that appears to deliver some benefit, just a modest benefit. We did see a PR and a KRS-G12-E positive patient, but it's just not sufficient, in our view, to justify continuing. And furthermore, we have direct inhibitors of many different variants of RAS coming forward very shortly, as you know, and so that makes much more sense to us to combine them, to combine a direct RAS inhibitor with a RAS companion inhibitor. And after all, we call RAS companion inhibitors RAS companion inhibitors to indicate that they'll be combined with RAS inhibitors.

It goes back to the indirect strategy of the clapping approach, which is.

One that we announced this favor and that is trying not actually exhibiting the cancer driver, but inhibiting the pathway upstream and downstream.

Chris Shibutani: Mm-hmm.

Mark Goldsmith: That appears to deliver some benefit. There's modest benefit. We did see a PR in the KRAS G12C cobimetinib-positive patients, but it's just not sufficient, in our view, to justify pursuing. Furthermore, we have direct inhibitors of many different variants of RAS coming forward very shortly, as you know. That makes much more sense to us, is to combine them, to combine a direct RAS inhibitor with a RAS Companion Inhibitor. After all, we call the RAS Companion Inhibitors RAS Companion Inhibitors to indicate that they'll be combined with RAS inhibitors. I think that all makes sense, but maybe that's the design feature you're asking about. The hypothesis seemed reasonable. There was clinical data to support it, and there's a serious unmet need that couldn't be satisfied by any existing compound, so we tested it.

Mark Goldsmith: That appears to deliver some benefit. There's modest benefit. We did see a PR in the KRAS G12C cobimetinib-positive patients, but it's just not sufficient, in our view, to justify pursuing. Furthermore, we have direct inhibitors of many different variants of RAS coming forward very shortly, as you know. That makes much more sense to us, is to combine a direct RAS inhibitor with a RAS companion inhibitor. After all, we call the RAS companion inhibitors to indicate that they'll be combined with RAS inhibitors. I think that all makes sense, but maybe that's the design feature you're asking about. The hypothesis seemed reasonable. There was clinical data to support it, and there's a serious unmet need that couldn't be satisfied by any existing compound, so we tested it.

And that appears to deliver some benefit is modest benefit.

CPR CA rest of Europe.

Okay.

The patients, but there's just not sufficient in our view to justify pursuing and Furthermore, we have direct inhibitors.

Many different areas.

Coming forward very shortly as you know and so that makes much more sense to us to combine them.

To provide a direct RAF inhibitor with with the rest of the Pan inhibitor and after all we called Ras companion.

<unk> companion.

Two indicators combined with Ras inhibitor. So I think that makes sense, but maybe that's a design feature you're asking about.

The hypothesis is reasonable there was clinical data to support it.

Chris Shibutani: So, I think that all makes sense, but maybe that's the design feature you're asking about. The hypothesis being reasonable, there was clinical data to support it, and there's a serious unmet need that couldn't be satisfied by any existing compound, so we tested it. But we don't think it will be—those results are—

And there is a serious unmet need that couldnt be satisfied by any existing compound. So we tested it but.

Mark Goldsmith: We don't think it will be those results are that positive or read-through to a strategy that involves a direct inhibitor plus a RAS Companion Inhibitors. I think that's really the key point maybe that you're getting to.

Mark Goldsmith: We don't think it will be that positive or read-through to a strategy that involves a direct inhibitor plus a RAS Companion Inhibitor. I think that's really the key point, maybe that you're getting to.

But we don't think it will be those results are.

This positive or read through to a strategy that is also a direct inhibitor plus the Ras companion inhibitor I think thats really the key point, maybe that youre getting.

Chris Shibutani: Now, I appreciate the thoughtful responses, and we'll certainly look forward to your continued progress on the Holyoan Rassan program.

Chris Shibutani: Yeah, I appreciate the thoughtful responses, and we'll certainly look forward to your continued progress on the wholly-owned RAS(ON) programs. Thank you.

No I appreciate the thoughtful responses and we will certainly look forward to your continued progress on the wholly owned rason programs. Thank you.

Marc Alan Frahm: Our next question comes from the line of Marc Frahm with Cohen. Your line is open. Thanks for taking my questions. Maybe just to start on the O3 trial, but the...

Mark Goldsmith: Thanks, Chris.

Operator 2: Thank you. Our next question comes from the line of Marc Frahm with Cowen. Your line is open.

Mark Goldsmith: Thank you. Our next question comes from the line of Marc Frahm with TD Cowen. Your line is open.

Thanks, Chris.

Thank you.

Our next question comes from the line of Mark <unk> with Cowen Your line is open.

Marc Frahm: Hey, thanks for taking my questions. Maybe just to start on the RMC-4630-03 trial, but the brief safety run-in that you discussed, is all of it gonna be run at 200 milligrams day 1, day 2, or are you gonna have some dose exploration built into that run-in? Then related on that trial, just why is the right structure to move now with a RevMed sponsored trial rather than you know, waiting for the formal selection of a recommended phase 2 dose within CodeBreaK and kind of keeping everything contained within that first collaboration with Amgen?

Marc Frahm: Hey, thanks for taking my questions. Maybe just to start on the 03 trial, but the brief safety run-in that you discussed, is all of it gonna be run at 200 milligrams day one, day two, or are you gonna have some dose exploration built into that run-in? Then related on that trial, just why is the right structure to move now with a RevMed sponsored trial rather than you know waiting for the formal selection of a recommended phase 2 dose within CodeBreaK and kind of keeping everything contained within that first collaboration with Amgen?

Hi, Thanks for taking my questions.

Maybe just to start on the <unk> III trial.

Brief safety run in that you discussed is that.

unknown: [inaudible]

Marc Alan Frahm: All of it is going to be run at 200 milligrams day one, day two, or are you going to have some...

All of that going to be run at 200 milligrams a day one day two or are you going to have some dose exploration built into that.

Marc Alan Frahm: Are you going to have some dose exploration built into that run-in? And then, related to that trial, why is the right structure to move now with a RevMed-sponsored trial rather than wait for the formal selection of a recommended phase 2 dose within Code Break and kind of keep everything contained within that first collaboration with Amgen? Yeah, thanks, Marc. I appreciate those questions. I think I'm going to comment on the second question, and then Steve, you can take a crack at the first one, and you can add to the second one if you want, which is why we do it now. I think it's important to emphasize that this is a study specifically of lung cancer patients as opposed to the exploratory, ongoing CoGrade 101C study.

Into that run in and then related on that trial is just what is the right structure to move now with Revlimid sponsored trial rather than.

Waiting for the formal selection of <unk>.

Recommended phase two dose within Covid break and kind of keeping everything contained within that first collaboration with Amgen.

Mark Goldsmith: Yeah. Thanks, Mark. Appreciate those questions. I think I'm gonna comment on the second question, and then Steve can take a crack at the first one, and you can add to the second one if he wants, which is why do it now? I think it's important to emphasize that this is a study specifically of lung cancer patients as opposed to the exploratory ongoing CodeBreaK 101C study. We feel there's sufficient information now to really go after that. There is some overlap with CodeBreaK 101C, but this is a more advanced design. It builds on things that we've learned over the last couple of years that we didn't know when the CodeBreaK study was designed.

Yes.

Yeah. Thanks, Mark I appreciate you for those questions I think I'm going to comment on the second question and then Steve can take a crack at the first of all I think you can ask the second whether it be loss, which is why why do it now.

To emphasize that this is a study specifically of lung cancer patients as opposed to the exploratory ongoing for <unk> 101 C study.

Mark A. Goldsmith: We feel there's sufficient information now to really go after that. There is some overlap with Code Break 101C, but this is a more advanced design. It builds on things that we've learned over the last couple of years that we didn't know when the Code Break study was designed. And we think it's also urgent to get to the answers to the questions. And the question that we're posing here has to do in part with the co-mutations that Steve alluded to. So we think it makes sense to move forward.

And we feel there are sufficient information now really go after that.

There is some overlap with coke rate 100, Wednesday, but this is a more advanced designs and builds on things that we've learned over the last couple of years that we didn't know when the study was designed.

Mark Goldsmith: We think it's also urgent to get to the answers to the questions, and the question that we're posing here has to do in part with the co-mutations that Steve alluded to. We think it makes sense to move forward, and there will be just a little bit of overlap in time there, but it will give us the advantage of getting to the answer as robustly as possible and as quickly as possible with regard to lung cancer. Steve, you can comment on that, you can comment on the first question, whatever you'd like.

And we think Thats also urgent.

To get to the answers to the questions and the question that we're closing here has to do in part with the Covid patients as Steve alluded to so we think it makes sense to move forward.

Stephen M. Kelsey: We'll happily address it. But with regard to the...

And.

Stephen M. Kelsey: You know, the dose expiration at the beginning isn't really a dose expiration. I mean, we

There will be just a little bit of overlap in time, there, but it will give us the advantage of getting to the answer as.

Obviously as possible and as quickly as possible with regard to lung cancer.

Stephen M. Kelsey: It's not really a dose aspiration. I mean, we basically have two choices: 140 mg of A1A2 or 200 mg of A1A2. We're currently, you know, as we said, and I think we've publicly disclosed, we're amginococrate 101C with regard to the dose of RMC4630 in combination with our full dose of sulturic acid. So we fully expect to move forward with the Phase II component of this study at what we call the target dose of RMC4630, which is 200 mg of A1A2.

You can comment on that you can comment on the first question.

Steve Kelsey: I think you've answered the second part of the question, actually. Unless Mark has a follow-up question, we'll happily address it. With regard to the, you know, the dose exploration at the beginning, it's not really a dose exploration. I mean, we basically have two choices, 100 milligrams day one, day two, or 200 milligrams day one, day two. You know, as we said, we know, and I think we publicly disclosed where Amgen are in CodeBreaK 101c with regard to dose of RMC-4630 in combination with their full doses of sotorasib.

Steve Kelsey: I think you've answered the second part of the question, actually. Unless Mark has a follow-up question, we'll happily address it. With regard to the, you know, the dose exploration at the beginning, it's not really a dose exploration. I mean, we basically have two choices, 140 milligrams day one, day two, or 200 milligrams day one, day two. You know, as we said, we know, and I think we publicly disclosed where Amgen are in CodeBreaK 101C with regard to dose of RMC-4630 in combination with their full doses of sotorasib.

Okay.

Central PA.

Question.

Small follow up question.

Sure.

<unk> addresses.

With regards to the.

Exploration of the JV.

Not really a dose exploration.

They have two choices 140 milligrams.

We will soon.

Thanks.

As we've said we know.

Publicly disclose where amgen.

111.

RMC doses three other than.

Coordination with vessel versus software.

Steve Kelsey: We fully expect to move forward with the phase 2 component of this study at what we call the target dose of RMC-4630, which is 200mg day one, day two. With the current timing and just the way that the CodeBreaK 101c study is at the moment, we're obliged to build a short safety run-in into our study. It's more of an operational detail than it is a real sort of dose exploration. You know, if I'm wrong, then we'll go back and revisit it. I will be surprised if we don't end up using our target dose in combination with the 960mg of sotorasib.

Steve Kelsey: We fully expect to move forward with the phase 2 component of this study at what we call the target dose of RMC-4630, which is 200 milligrams day one, day two. With the current timing and just the way that the CodeBreaK 101C study is at the moment, we're obliged to build a short safety run-in into our study. It's more of an operational detail than it is a real sort of dose exploration. You know, if I'm wrong, then we'll go back and revisit it. I will be surprised if we don't end up using our target dose in combination with the 960 milligrams of sotorasib.

So.

We fully expect to move forward with the phase two.

Two competitor study at the weaker global economy.

<unk> 200 milligrams.

In Taiwan.

No.

With the current timing.

<unk>.

Stephen M. Kelsey: Everybody wants to study is at the moment.

Just the way.

Right.

Stephen M. Kelsey: We're obliged to build a short safety bucket into our study, so it's more of an operational detail, but it is a real sort of dense exploration.

Is.

We are obliged to bill Shaw.

Sure.

It is all study so.

It's more of an operational detail.

Stephen M. Kelsey: You know, if I'm wrong, then we'll go back and revisit it, but I would be surprised if we don't end up using the on-target dose in combination with the non-target dose.

Our best exploration.

<unk>.

Well no.

I'll go back and revisit.

I will argue these processes.

Using our top dose in combination with <unk>.

Stephen M. Kelsey: Okay, thank you, that's very helpful. And then maybe a bigger picture question, just given the totality of the update,

Okay.

Marc Frahm: Okay. Thanks. That's very helpful. Maybe a bigger picture question, just given the kind of totality of the updates today, what have you kind of learned about the level of maybe wild-type RAS inhibition that's acceptable and kinda how that makes you think about designing your multi-RAS(ON) inhibitors and kinda how much spillover effect either the multi-RAS(ON) or the targeted ones are allowed or kind of allowed to have before their acceptable profile to move in when you ultimately wanna use them in combinations?

Marc Frahm: Okay. Thanks. That's very helpful. Maybe a bigger picture question, just given the kind of totality of the updates today, what have you kind of learned about the level of maybe wild-type RAS inhibition that's acceptable and kinda how that makes you think about designing your multi-RAS inhibitors on and kinda how much spillover effect either the multi-RAS or the targeted ones are allowed or kind of allowed to have, before their acceptable profile to move in when you ultimately wanna use them in combinations?

Okay. Thanks.

Very helpful.

And then maybe a bigger picture question, just given the kind of <unk>.

Marc Alan Frahm: Thank you for your question. Given the totality of the updates today, what have you learned about the level of wild-type RAS inhibition that's acceptable and how that makes you think about designing your multi-RAS inhibitors on and how much spillover effect either the multi-RAS or the targeted ones are allowed to have before they're an acceptable profile to move in when you ultimately want to use them in combination? Thanks, Marc.

The updates today.

What are you kind of learned about the level of wild type Ras inhibition that is acceptable and how that makes you think about designing your multi ras inhibitors on kind of how much spillover effect, either the multi ras or the targeted ones are allowed.

Allowed to have before they are acceptable profile to move in when you ultimately want to be using in combination.

Mark A. Goldsmith: Let me just add something to that previous discussion about timing. It just occurred to me that this is important to mention. Amgen is collaborating with us on this O3 study. They view it as an extension of, expansion of, and complement to the current Cobrake-101c study, just as we do, as does Sanofi. So we have three companies all getting together and agreeing on that concept. And based on that, there's no reason not to proceed with it. And as Steve said, we're so close to the finalization of those, so there's no reason to wait.

Mark Goldsmith: Thanks, Mark. Let me just add something to that previous discussion about timing. It just also occurs to me that it's important to mention. Amgen is collaborating with us on this RMC-4630-03 study. They view it as an expansion of complement to the current CodeBreaK 101c study just as we do, as does Sanofi. We have, you know, three companies all getting together agreeing on that concept. Based on that, there's no reason not to proceed with it. As Steve said, we're so close to finalization of dose that there's no reason to wait. Now with regard to what have we learned, again, maybe I'll just take a crack at this, which is, we already knew that SHP2 inhibition has a tolerability constraint because of its effect in normal tissues.

Mark Goldsmith: Thanks, Mark. Let me just add something to that previous discussion about timing. It just also occurs to me that it's important to mention. Amgen is collaborating with us on this RMC-4630-03 study. They view it as an expansion, a complement to the current CodeBreaK 101C study just as we do, as does Sanofi. We have, you know, three companies all getting together agreeing on that concept. Based on that, there's no reason not to proceed with it. As Steve said, we're so close to finalization of dose, that there's no reason to wait. Now with regard to what have we learned, again, maybe I'll just take a crack at this, which is, we already knew that SHP2 inhibition has a tolerability constraint because of its effect in normal tissues.

Thanks, Mark let me just add something to that previous discussion about timing. It's just also a curse me it is important to.

As you mentioned.

<unk> is collaborating with us on.

This <unk> III study.

<unk> view it as an extension.

Compliment to the current Covid, Greg why don't <unk> study.

As we do so we have three companies all getting together again on that concept and based on that.

There's no reason not to proceed with the FCC said, we're so close to Finalization dose.

Mark A. Goldsmith: Now, with regard to what we have learned? Again, maybe I'll just take a crack at this, which is... We already know that situ inhibition has a tolerability constraint because of its effect in normal tissues. There's nothing selective about its action in tumor cells, as you know, the intermittent dosing regimen, which we still have a lot of confidence in, tumor cells being able to tip into apoptosis if they're covered deeply enough and long enough, but they don't require continuous coverage, and so we're trying to create a pharmacologic way of manipulating tumor cells versus normal cells, but there's a And the limit to that is probably 200 milligrams to one day or two, you know, or thereabouts in a dosing regimen.

There's no reason to wait.

Now with regard to what did we learn.

Maybe I'll just take a crack at this switches.

We already knew that secure inhibition.

Yes.

Mark Goldsmith: There's nothing selective about its action in tumor cells, as you know. We designed the intermittent dosing regimen, which we still have a lot of confidence in, as a way to take advantage of tumor cells being able to tip into apoptosis if they're covered deeply enough and long enough, but they don't require continuous coverage. We're trying to create a pharmacologic way of manipulating tumor cells versus normal cells. There's a limit to that. The limit to that is probably 200 milligrams day one, day two, you know, or thereabouts in a dosing regimen. We have seen objective responses with that sort of regimen. It's clearly a very active agent with our compound at that, you know, that kind of regimen. We're also having to take into account the landscape.

Mark Goldsmith: There's nothing selective about its action in tumor cells, as you know. We designed the intermittent dosing regimen, which we still have a lot of confidence in, as a way to take advantage of tumor cells being able to tip into apoptosis if they're covered deeply enough and long enough, but they don't require continuous coverage. We're trying to create a pharmacologic way of manipulating tumor cells versus normal cells. There's a limit to that. The limit to that is probably 200 milligrams day one, day two, you know, or thereabouts, in a dosing regimen. We have seen objective responses with that sort of regimen. It's clearly a very active agent with our compound at that, you know, that kind of regimen. We're also having to take into account the landscape.

All of our ability constrained because of its affected normal tissues does not be selective about action in tumor cells as you know.

We designed the intermittent dosing regimen, which we still have a lot of confidence in.

Way to take advantage of.

To yourselves being able ticket apoptosis covered deeply on long enough. They don't require continuous coverage and so we're trying to create a pharmacologic waste manipulating tumor cells versus normal cells, but there's a limit to that.

The limit that is probably 200 milligrams to one day two or thereabouts.

Mark A. Goldsmith: And we have seen objective responses with that sort of regimen. So it's clearly a very active agent with our compound at that, you know, that kind of regimen. But we're also having to take into account the landscape.

And the dosing regimen, and we have seen objective responses with that sort of regimen. So it's clearly very active agents with our compound.

That kind of regimen, but.

We're also having to take into account the landscape and when there are <unk> specific.

Mark Goldsmith: When there are G12C specific, you know, mutant-specific inhibitors that are in play, as Lumakras is now approved, and there will be others coming, we have to make sure that what we're doing is additive in terms of clinical benefit, what you can achieve with those targeted mutant selective agents. I think we're still net of all that, we're still quite confident that SHP2 inhibitor brings antitumor activity. There's just no doubt about that now. When dosed in the ways that we dose it, we fully expect that it'll show additivity, but that's why we have to do the clinical studies when we combine with the KRAS inhibitors.

Mark A. Goldsmith: And when there are G12C-specific, you know, mutant-specific inhibitors that are in play, as LumaCraft has now approved, and there will be others coming, we have to make sure that what we're doing is additive in terms of clinical benefit and not sub what you can achieve with those targeted mutant-selective agents. And so I think we're still, net of all that, quite confident that SHP2 inhibitor brings anti-t There's just no doubt about that now.

Mark Goldsmith: When there are G12C-specific, you know, mutant-specific inhibitors that are in play, as Lumakras is now approved, and there will be others coming, we have to make sure that what we're doing is additive in terms of clinical benefit, and not sub what you can achieve with those targeted, mutant selective agents. I think we're still net of all that; we're still quite confident that SHP2 inhibitor brings antitumor activity. There's just no doubt about that now. When dosed in the ways that we dose it, we fully expect that it'll show additivity, but that's why we have to do the clinical studies when we combine with the KRAS inhibitors.

Specific inhibitors that are in play as <unk> is now approved and there will be others coming.

We have to make sure that what we're doing use attitude in terms of clinical benefit.

Not not so.

As you can achieve with those targeted.

Patients and so.

So net net all of that is we're still quite confident that ship two different grades of antitumor activity. There's just no doubt about that now.

Mark A. Goldsmith: And when dosed in the ways that we dose it, and we fully expect that it will show additivity, but that's why we have to do the clinical studies when we combine it with FRAS inhibitors. With regard to read-through to RMC6291, which is the G12C-selective inhibitor, I don't think there's any read-through whatsoever that we're aware of to a mutant-selective With regard to RMC6236, which is a multi-RAS inhibitor, I think you're right in principle to raise that question. But I think we have already learned what we needed to learn before.

And windows in a way so we doses.

And.

We fully expect that it will show activity.

Why do we have to do the clinical studies, when we combined with <unk> inhibitors.

Mark Goldsmith: With regard to read-through to RMC-6291, which is the G12C selective inhibitor, I don't think there's any read-through whatsoever that we're aware of to a mutant selective inhibitor like G12C selective inhibitor that we're aware of. With regard to RMC-6236, which is a multi RAS inhibitor, I think you're right in principle, you know, to raise that question. I think we had already learned what we needed to learn before. I don't think this changes that anything was changed by the results that we just described. That is, that there is a limit to how much you can build stack, how continuously you can inhibit all RAS targets. That's for sure.

With regard to read through to <unk>.

<unk> 691, which is the G P selectin inhibitor.

I don't think there's any reason for whatsoever that we're aware of to view selective inhibitor and what well see selective inhibitor.

But we're aware of with regards to RMB 63, six which is a multi ras inhibitor I think youre right in principle to read that question.

I think we had already learned what we needed to learn before I don't think this changes if anything is changed by the results that we just decide.

Mark A. Goldsmith: I don't think that anything has changed by the results that we just described. That is, there is a limit to how much you can dose that, and how continuously you can inhibit all RAS targets. That's for sure, but we also know that rat-affected tumors are particularly sensitive to inhibition of the rat's driver, and that it is possible to achieve quite deep anti-tumor effects. And we show this, as you know, across multiple preclinical models that we never achieved with the SHIP-2 inhibitor alone or a SHIP-2 inhibitor even when combined with a MEK inhibitor. So I think the tolerability limits are there.

That is that there is a limit to how much you can do that.

Continuously you can debate all Ras targets.

Mark Goldsmith: We also know that RAS-addicted tumors are particularly sensitive to inhibition of the RAS driver, and that it is possible to achieve quite deep antitumor effects, and we show this, as you know, across multiple preclinical models, that we never achieved with a SHP2 inhibitor alone or a SHP2 inhibitor, even when combined with a MEK inhibitor. I think the tolerability limits are there, but in the right context and when combined, you know, specifically with inhibiting the mutant driver, even if it's not a mutant selective inhibitor, one can achieve quite profound effects. As you know, there's precedent for that with Tarceva and EGF receptor antagonists and so on that have had profound impact in tumors at tolerable levels. I think we feel very good about RMC-6236.

Mark Goldsmith: We also know that RAS-addicted tumors are particularly sensitive to inhibition of the RAS driver, and that it is possible to achieve quite deep antitumor effects, and we show this, as you know, across multiple preclinical models, that we never achieved with a SHP2 inhibitor alone or a SHP2 inhibitor, even when combined with a MEK inhibitor. I think the tolerability limits are there, but in the right context and when combined, you know, specifically with inhibiting the mutant driver, even if it's not a mutant selective inhibitor, one can achieve quite profound effects. As you know, there's precedent for that with Tarceva and EGFR receptor antagonists and so on that have had profound impact in tumors at tolerable levels. I think we feel very good about RMC-6236.

For sure, but we also know that rapidly if the tumors are particularly sensitive to inhibition of the Ras driver.

And that is possible to achieve quite deep antitumor effects and we show. This as you know across multiple preclinical models that we never achieved with the ship two inhibitor alone or is just two inhibitor, even when combined with the mechanism there.

The tolerability limits.

Eliana Rachel Merle: But in the right context, and when combined, you know, specifically with inhibiting the mutant driver, even if it's not a mutant-selected inhibitor, one can achieve quite profound effects. And as you know, there's precedent for that with Terciva and EJF receptor antagonists and so on that have had profound impacts in mutants and tumors at tolerable levels. So I think we feel very good about RMC6236. We continue to evaluate it, but everything continues going in the same direction.

Are there.

But in the right context, and when combined specifically.

Specifically inhibiting.

The music driver, even if the Saturday slides inhibitor, one can achieve quite profound effects on as you know there is precedence with average receiver.

<unk> receptor antagonist and so on that are.

Profound impact.

<unk>.

And tumors.

At tolerable levels. So I think we feel very good about RMB 63, six and we continue to evaluate it but everything continues lanes interaction we feel terrific about RMB 69, one and then the combination strategy of combining a comparator inhibitor with the RAF inhibitor.

Mark Goldsmith: We continue to evaluate it, but everything continues going in the same direction. We feel terrific about RMC-6291. The combination strategy of combining a companion inhibitor with a RAS inhibitor is on the forefront of our thinking. The 03 study, I think, is the first example where we really get to deploy that fully, as we prepare to bring forward the rest of the RAS inhibitor pipeline.

Eliana Rachel Merle: We feel terrific about RMC6291, and the combination strategy of combining a companion inhibitor with a RAS inhibitor is at the forefront of our thinking. And so the O3 study, I think, is the first example where we really get to deploy that fully as we prepare to bring forward the rest of the rafts into their pipes. Okay, thanks, that was very helpful. Thank you. Our next question comes from the line of Mike. High School, Eliana Merle.

In our forefront.

Our thinking and so the <unk> study I think is the first example, where we really get to deploy that forward.

As we prepare to bring forward the rest of the Ras inhibitor pipeline.

Marc Frahm: Okay. Thanks for that. Very helpful.

Okay. Thanks, that's very helpful.

Operator 2: Thank you. Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is open.

Marc Frahm: Thank you. Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is open.

Thank you.

Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is open.

Eliana Rachel Merle: Hey guys, thanks for taking my questions. I had one regarding Keytruda combination with RMC 4630. It's nice to see that you're moving forward here with phase two. You know, the first question is, was it driven predominantly by safety and, you know, mechanistic, rational, or also by clinical efficacy data?

Michael Schmidt: Hey, guys. Thanks for taking my questions. I had one regarding the Keytruda combination with RMC-4630. I guess nice to see that you, that you're moving forward here with a phase 2. You know, first question is was it driven predominantly by safety and, you know, mechanistic rationale or also by clinical efficacy data? And then perhaps if you could speak to your decision to move into PD-L1 positive patients in this initial phase 2 study and how we should think about a potential longer-term registration path for this combination.

Hey, guys. Thanks for taking my questions.

I had one regarding the Keytruda combination with IMC 46.30.

Nice to see that you're moving forward here with a phase two.

Yes.

First question is what was driven predominantly by safety and.

Mechanistic rationale or also by clinical efficacy data.

Eliana Rachel Merle: And then, perhaps, it

Eliana Rachel Merle: I will speak to you this afternoon.

And then perhaps if you could.

Eliana Rachel Merle: move into PD-L1 positive patients in this initial phase two study.

Speak to the decision to move into PD one positive.

Eliana Rachel Merle: Initial Phase 2 Study and how we should think about it, you know, long term. I think the preamble is we can't disclose anything about the dose escalation work that Sanofi did. They're the sponsor of that study, so, you know, when they decide to disclose it, they will. So we can't really address your carefully worded question about whether it was tolerability or efficacy that drove it. But it was primarily intended as a safety and dose escalation study.

Patients in this initial phase II study and how we should think about a potential.

Longer term our registration path for this combination.

Mark Goldsmith: Thanks, Michael. Let me just give a quick preamble and then Steve, I think, can really address the meat of your question. I think the preamble is, we can't disclose anything about the dose escalation work that Sanofi did. They're the sponsor of that study, so you know, when they decide to disclose it, they will. We can't really address your carefully worded question about it was the tolerability or efficacy that drove it. But it was primarily intended as a safety and dose escalation study. You know, that was the purpose of it. What's now going to be tested is, as you point out, in PD-L1 positive lung cancer and particularly first-line treatment, so previously untreated patients, which is an exciting move, and maybe Steve can speak to that.

Thanks, Michael Let me just get a quick preamble and then Steve I think you can really address the meat of your question I think that preamble is we can't disclose anything about the <unk>.

Dose escalation where that stands.

Hey, Jade.

The sponsor that study so.

When they when they decide to dispose of it. So we can't really address your carefully worded question about tolerability or or efficacy that drove it but.

It was primarily intended as a safety and dose escalation study that was the purpose of it but what's now going be tested as you pointed out.

Eliana Rachel Merle: You know, that was the purpose of it. But what's now going to be tested is, as you point out, in PD-L1 positive lung cancer, and particularly as first-line treatment, so previously untreated patients, which is an exciting move. And maybe Steve can speak to that.

In PD lone positive lung cancer, and particularly first line treatment previously untreated.

<unk>, which is an exciting move and maybe Steve.

Steve Kelsey: Sure. I think it helps to explain where we think we may end up in the event of a positive study because I think that will explain the rationale behind the study in the first place. If it turns out that adding the SHP2 inhibitor to pembrolizumab in the context of PD-L1 positive non-small cell lung cancer, which by the way does include RAS mutant non-small cell lung cancer, then we really it leaves us with two large opportunities. One is obviously that there are a very limited number of drugs that improve outcomes over and above checkpoint inhibitors alone without significantly increasing the toxicity.

Steve Kelsey: Sure. I think it helps to explain where we think we may end up in the event of a positive study because I think that will explain the rationale behind the study in the first place. If it turns out that adding the SHP2 inhibitor to pembrolizumab in the context of PD-L1 positive non-small cell lung cancer, which by the way does include RAS mutant non-small cell lung cancer, then it leaves us with two large opportunities. One is obviously that there are a very limited number of drugs that improve outcomes over and above checkpoint inhibitors alone without significantly increasing the toxicity.

And speak to that.

Eliana Rachel Merle: I think it...

Sure.

Yes.

Eliana Rachel Merle: helps to explain where we think we may end up in the event of a positive study because I think that will explain the rationale behind the study in the first place.

I think Keith.

Right.

Helps to explain where we think we may end up.

This study because I think that would explain the rationale behind.

Eliana Rachel Merle: If it turns out that adding the shift-2 inhibitor to Pembroke is

Yes.

Yeah.

H H.

Eliana Rachel Merle: Pemberton's Lab in the context of PD-L1-positive non-small cell lung cancer, which, by the way, does include RAS mutant non-small cell lung cancer.

Yes.

Adding the chute zone.

So two hamburgers.

Context of PD lone positive non small cell lung cancer, which by the way. It does include Ras mutant non small cell lung cancer.

Eliana Rachel Merle: Then we really, it leaves us in...

Eliana Rachel Merle: of the United States. Thank you. Large opportunities.

Then we really needs us.

With true.

Eliana Rachel Merle: Large opportunities. Well, one is, obviously, that there are a very limited number of drugs that improve outcomes over the blood checkpoint inhibitors alone without significantly increasing the toxicity. And obviously, if you're too limited to do that, then that presents a huge opportunity, not just in lung cancer, but in a lot of other tumors where everybody's got another PD-1 or PD-1.

Large opportunities one is obviously.

That.

There are a very limited number of jobs improved guidance comes over and above checkpoint inhibitors alone.

Significantly cruising the toxicity and defaults.

Steve Kelsey: Obviously, if SHP2 inhibitor can do that, then that presents a huge opportunity, not just in lung cancer, but in a lot of other tumors where pembrolizumab and other PD-1 or PD-L1 inhibitors are used. The second and probably the primary driver, from our perspective, when we set about doing this is the fact that checkpoint inhibitors are currently standard of care for RAS mutant lung cancer. We do foresee a future state where the doublet chemotherapy for RAS mutant lung cancer is replaced by the combination of a RAS-directed inhibitor, whether it's a G12C inhibitor or a

The new <unk>.

A huge opportunity not just in lung cancer, there are a lot of other <unk>.

So I have another PD, one PD lone.

Eliana Rachel Merle: The checkpoint inhibitors are currently the standard of care for Rasputin's lung cancer, and we do foresee a

And as I use the second.

But just trying to re driver when we set about doing this is the fact of the checkpoint inhibitors.

Eliana Rachel Merle: Transcription by https://otter.ai

As a tenant for rescue lung cancer.

And we do foresee a future study.

Eliana Rachel Merle: Chief Social Inhabitor or one of our other RAS inhibitors or other RAS inhibitors

The doublet chemotherapy for us new lung cancer is replaced by a combination of a rash the rest of it hits, whether it's equal say negligible.

Eliana Rachel Merle: In combination with a companion inhibitor like RNC4630 and then plus pedalizumab. Now that requires to demonstrate that each component, each dominant component of that triplet is tolerable. And that's the primary intent of that study, which, you know, we have...

Steve Kelsey: One of our other RAS inhibitors for other RAS mutations in combination with a companion inhibitor like RMC-4630 and then plus pembrolizumab. Now, that requires us to demonstrate that each component, each double component of that triplet is tolerable. That's the primary intent of that study, which, you know, we have declared a recommended phase 2 dose and schedule. We're moving into the phase 2 expansion of that study. Unfortunately, we're not going to tell you what it is at the moment, but I think when eventually you will learn and, then it will become clear what the tolerability profile looks like. All we can say at the moment is the tolerability profile is perfectly acceptable and encouraging enough for us to want to move forward with phase 2 efficacy testing.

Mark Goldsmith: One of our other RAS inhibitors for other RAS mutations in combination with a companion inhibitor like RMC-4630 and then plus pembrolizumab. Now, that requires us to demonstrate that each component, each double component of that triplet is tolerable. That's the primary intent of that study, which, you know, we have declared a recommended phase 2 dose and schedule. We're moving into the phase 2 expansion of that study. Unfortunately, we're not going to tell you what it is at the moment, but I think when eventually you will learn and, then it will become clear what the tolerability profile looks like. All we can say at the moment is the tolerability profile is perfectly acceptable and encouraging enough for us to want to move forward with phase 2 efficacy testing.

One of our other Ras inhibitors or other kras mutations.

In combination with a compounding inhibitor like <unk>.

And there isn't that.

Demonstrate leach components, each dominant component of that triplet is tolerable.

The primary intensive.

Eliana Rachel Merle: We have declared a recommended Phase 2 dose and scheduled the move into the Phase 2 expansion of that study.

Which.

We have we have declared a recommended phase II dose.

Schedule.

Eliana Rachel Merle: I'm not going to tell you what it is at the moment, but I think eventually you will learn, and it will be coming.

Phase two expansion of us Unfortunately.

Well in Asia.

Okay.

Eventually you will.

Eliana Rachel Merle: It will become clear what the tolerance profile looks like. All we can say at the moment is that the tolerance profile...

And.

And it will become clear what the Tolerability profile.

It looks like how we can set the amount of business all of this profile is.

Eliana Rachel Merle: It looks like all we can say at the moment is that it's all a bit strange.

Firstly access limited Hirsch and our first one to move forward to phase two efficacy.

Eliana Rachel Merle: Technology Testing. And there is a very mechanistic...

Mark Goldsmith: There is a very mechanistic basis for doing it as well. I mean, again, going back, right back to the very beginning. In fact, a paper published by Ira Mellman at Genentech back in 2017 showed very clearly that one of the roles of SHP2 is to regulate checkpoint signaling. There's a huge rationale for a SHP2 inhibitor augmenting the effects of checkpoint inhibition. We have also subsequently demonstrated, both in preclinical models and in patients, that SHP2 inhibition activates both the innate and adaptive immune system in a way which should be beneficial in an anti-tumor effect. It should be helpful rather than a hindrance.

Mark Goldsmith: There is a very mechanistic basis for doing it as well. I mean, again, going back, right back to the very beginning. In fact, a paper published by Ira Mellman at Genentech back in 2017 showed very clearly that one of the roles of SHP2 is to regulate checkpoint signaling. There's a huge rationale for a SHP2 inhibitor augmenting the effects of checkpoint inhibition. We have also subsequently demonstrated, both in preclinical models and in patients, that SHP2 inhibition activates both the innate and adaptive immune system in a way which should be beneficial. In an anti-tumor effect, it should be helpful rather than a hindrance.

Eliana Rachel Merle: as well as again going back, right back to the very beginning.

There is a very mechanistic basis as well again I'm going to go back right back beginning in a paper published by autumn element Gen set back in 2017.

Eliana Rachel Merle: In fact, a paper published by Iron Element and Genentech back in 2017.

Eliana Rachel Merle: It's shown very clearly that one of the roles of SHIP2 is to regulate checkpoints.

It shows very clearly one of the roles of shifts.

<unk> checkpoint signaling.

Eliana Rachel Merle: And so there's a huge rationale for a shift to inhibitors, augmenting the effects of checkpoint inhibition. We have also subsequently...

And so that is a huge rationale for ash.

<expletive> to enhance.

The effects of checkpoint inhibition, we have a whole set of subsequently demonstrates both increase our longstanding patients ships anyway inhibition.

Eliana Rachel Merle: demonstrated both in preclinical models and in patients that SHIP-2 inhibition activates both the innate and the adaptive immune responses.

At CNA.

After the immune system, which should be.

Eliana Rachel Merle: It should be helpful rather than a hindrance. And so when you compound the mechanistic basis of SHIP-2 inhibition as demonstrated in the PDE studies from our clinical trial, the fact that the checkpoint

Unofficial guidance.

<unk> should be it should be helpful rather than a hindrance.

Mark Goldsmith: When you compound the mechanistic basis of SHP2 inhibition, as demonstrated in the PD studies from our clinical trials, the fact that checkpoint inhibitors are standard of care for RAS mutant lung cancer and the opportunity beyond RAS mutant lung cancer, I think it presents a very compelling place for us to do a study.

Mark Goldsmith: When you compound the mechanistic basis of SHP2 inhibition, as demonstrated in the PD studies from our clinical trials, the fact that checkpoint inhibitors are standard of care for RAS mutant lung cancer, and the opportunity beyond RAS mutant lung cancer, I think it presents a very compelling place for us to do a study.

When you combine the mechanistic basis salt ship to integration.

As demonstrated in the <unk> studies from our clinical trials.

Eliana Rachel Merle: This is our standard of care.

The fact that checkpoint inhibitors as a standard of kind of a rash lung cancer and the opportunity beyond lung cancer I think that's very compelling.

Eliana Rachel Merle: Care for Rast Mutant Lung Cancer and the opportunity beyond Rast Mutant Lung Cancer, I think it's a very compelling place for us to do a study. Got it. Okay. And then

Place for us to do.

Michael Schmidt: Got it. Okay. Yep, just wanted to get your thoughts on Amgen's recent decision to also study sotorasib with Novartis SHP2 inhibitor, actually. Just curious if you have any thoughts on that and perhaps conversely have plans to evaluate RMC-4630 with Mirati's KRAS inhibitor.

Michael Schmidt: Got it. Okay. Just wanted to get your thoughts on Amgen's recent decision to also study sotorasib with Novartis SHP2 inhibitor, actually. Just curious if you have any thoughts on that and perhaps conversely have plans to evaluate RMC-4630 with Mirati's KRAS inhibitor.

Study.

Got it Okay and then on.

Eliana Rachel Merle: That's a very compelling place for us to do a study.

Just wanted to get your thoughts on amgen's reasonably sales guidance.

Eliana Rachel Merle: Actually, just curious if you have any thoughts on that and, perhaps conversely, have plans to evaluate 4630 with Mirati.

Our study filter asset with Novartis shipped to an ever actually just curious if you give any thoughts on that and perhaps Conversely.

Have plans to evaluate 46.30 with Novartis.

Eliana Rachel Merle: [inaudible]

Eliana Rachel Merle: Uh, yeah, um...

Eliana Rachel Merle: I think for us, the main thing it suggests is that Amgen continues to have a high interest in CHIP-2 as a target and using it as a co-target along with the mutant driver, the RAS mutant driver. So I think that's a very positive signal as to why they chose specifically TN0155 or something else. I couldn't speak to that at all.

Nevada.

Mark Goldsmith: Yeah. I think for us, the main thing it suggests is that Amgen continues to have a high interest in SHP2 as a target and using it as a co-target along with the mutant driver, RAS mutant driver. I think that's a very, you know, positive signal. As to why they chose specifically TNO155 or something else, I couldn't speak to that at all. You know, it obviously is a leading SHP2 inhibitor. You know, it may be as simple as that. You know, what they've indicated publicly, I'll just reiterate sort of my interpretation of David Reese's comments, which are that they think it's an important target. They wanna make sure that the Lumakras franchise, which is rapidly building, has access to whatever makes it to the finish line.

Yeah.

Mark Goldsmith: I think for us, the main thing it suggests is that Amgen continues to have a high interest in SHP2 as a target and using it as a co-target along with the mutant driver, RAS mutant driver. I think that's a very, you know, positive signal. As to why they chose specifically TNO155 or something else, I couldn't speak to that at all. You know, it obviously is a leading SHP2 inhibitor. You know, it may be as simple as that. You know, what they've indicated publicly, I'll just reiterate sort of my interpretation of David Reese's comments, which are that they think it's an important target. They wanna make sure that the Lumakras franchise, which is rapidly building, has access to whatever makes it to the finish line.

I think for US the main thing of suggestions that Amgen.

Can you just at a high interest in ship to as a target.

And using and using it as a co target along with the new driver, perhaps new driver.

So I think thats, a very positive signal.

As to why they chose specifically 155 or something else I couldn't speak to that at all.

Eliana Rachel Merle: You know, it obviously is a leading CHIP2 inhibitor. So, you know, there's, it may be as simple as that. You know, what they've indicated publicly, I'll just reiterate sort of my interpretation of David Rees' comments, which are that they think it's an important target. They want to make sure that the Limit Press franchise, which is rapidly building, has access to whatever makes it to the finish line, but that they have no particular concerns about RMC 4630 and continue to support Code Break 101-Z and are excited about it.

Obviously as a leading ship two inhibitor.

So.

It may be as simple as that.

Yes.

What they've indicated publicly I'll, just reiterate sort of my interpretation of data recent comments, which are that they think it's an important target they want to make sure that the wound <unk> franchise, which is rapidly building has access to whatever makes it to the finish line.

Mark Goldsmith: They have no particular concerns about RMC-4630, and continue to support CodeBreaK 101c and are excited about it. What he couldn't say then, but now you can read into it, is that they're also excited about the 03 study that, of course, they knew we were about to announce, but he couldn't speak to that then. I don't think it reads at all negatively on RMC-4630. If anything, it reads positively on it. We've always suggested that everybody would dance with everybody else when it comes to these sorts of companion inhibitors. You know, until the music's over, until we know all the answers, there's a dance to be danced. People are gonna, you know, switch around, try different partners.

Mark Goldsmith: that they have no particular concerns about RMC-4630 and continue to support CodeBreaK 101C and are excited about it. What he couldn't say then, but now you can read into it, is that they're also excited about the 03 study that, of course, they knew we were about to announce, but he couldn't speak to that then. I don't think it reads at all negatively on RMC-4630. If anything, it reads positively on it. We've always suggested that everybody would dance with everybody else when it comes to these sorts of companion inhibitors. You know, until the music's over, until we know all the answers, there's a dance to be danced. People are gonna, you know, switch around, try different partners.

But that they have no particular concerns about RMB 460 <unk>.

And continue to support Covid break 100, once a year and are excited about it and.

But I couldn't say that but now you can read into it is that they're also excited about the <unk> study that of course, they knew we were about to announce but even speak to that debt. So I don't think at least at all negatively on RMC for <unk> III.

Eliana Rachel Merle: And what he couldn't say then, but now you can read into it, is that they're also excited about the O3 study that, of course, they knew we were about to announce, but he couldn't speak to that then.

Anything you would read positively on it.

And.

Eliana Rachel Merle: Everybody will dance with everybody else when it comes to these sorts of companion inhibitors. You know, until the music's over, until we know all the answers, there's a dance to be danced. And so people are going to switch around and try different partners. And we've been doing that. We'll continue doing that. And I suspect everybody else will do that. That makes perfect sense in a rational approach to drug development.

We've always suggested that.

Everybody with dance with everybody else when it comes to these sorts of companion inhibitors.

Until the music's over until we know all the answers.

Advanced to the dance and so people are going to.

Mark Goldsmith: We've been doing that. We'll continue doing that. I suspect everybody will do that. That makes perfect sense in a rational approach to drug development.

Switched around private and partners.

Mark Goldsmith: We've been doing that. We'll continue doing that. I suspect everybody will do that. That makes perfect sense in a rational approach to drug development.

We've been doing that we will continue doing that.

And I suspect everybody will do that because that makes perfect sense in a rational approach.

Eliana Rachel Merle: Yeah, that makes a lot of sense to me. Well, thanks for your comments there, Marc.

Michael Schmidt: Yeah, that makes a lot of sense to me. Well, thanks for your comments there, Mark, and thanks for taking my question.

To drug development.

Yes that makes a lot of sense to me well. Thanks for all your comments that market.

Eliana Rachel Merle: Thank you for all your comments there, Marc, and thanks for taking my questions.

Mark Goldsmith: Thank you.

Taking my question.

Operator 2: Thank you. Our next question comes from the line of Jonathan Chang with SVB Leerink. Your line is open.

Mark Goldsmith: Thank you. Our next question comes from the line of Jonathan Chang with SVB Leerink. Your line is open.

Thank you.

Jonathan Chang: Our next question comes from the line of Jonathan Chang with SBB Lebrink. Your line is open.

Thank you.

Our next question comes from the line of Jonathan Chang with SBB Leerink. Your line is open.

Faisal Ali Khurshid: Hi guys, this is Faisal Khurshid on behalf of Jonathan Chang. Thanks for taking my question.

Faisal Rashid: Hi, guys. This is Faisal Rashid on for Jonathan Chang. Thanks for taking my question. For RMC-5845, the SOS1, just a clarification. Is this an asset that would be considered for, like, a potential out-licensing, or is this simply a delay in a potential IND filing? Then I guess a related question, are there any features of the molecule itself that kind of played into the decision, or was it just the other priorities? Thank you.

Hi, guys first because she had on for Jonathan Chang. Thanks for taking my question.

Faisal Ali Khurshid: For RMC5845, the SOS-1, just a clarification, is this an acid that would be considered for potential outlicensing? Or is this simply a delay in a potential IND filing? And then, I guess a related question, are there any features of the molecule itself that kind of played into the decision? Or was it just the other priorities?

Our RMC 50.845, the source one clarification is this an asset that would be considered for like a potential out licensing or is it simply a delay in a potential IND filing and then I guess the related question are there any features of the molecule itself that contemplated the decision or was it just the other priority.

Faisal Ali Khurshid: Thank you.

Faisal Ali Khurshid: Yeah, thanks for the question. I don't think that they're specific features of the molecule that are affecting that position.

<unk>.

Mark Goldsmith: Yeah. Thanks for your question. I don't think that there are specific features of the molecule that are affecting that decision. I think it's primarily a prioritization decision. You know, we're moving two compounds into the clinic next year. We already have two compounds in the clinic. We said that there's at least another one coming and several more behind that. You know, over the next 12 months, we've got our hands quite full. And RMC-6291 is entering a crowded space, and RMC-6236 is entering a very large space. So those are pretty big programs. And we just announced the 03 program, which is gonna be a significant commitment of resources. I think it's really more a timing question, and we will evaluate.

Mark Goldsmith: Yeah. Thanks for your question. I don't think that there are specific features of the molecule that are affecting that decision. I think it's primarily a prioritization decision. You know, we're moving 2 compounds into the clinic next year. We already have 2 compounds in the clinic. We said that there's at least another 1 coming and several more behind that. You know, over the next 12 months, we've got our hands quite full. RMC-6291 is entering a crowded space, and RMC-6236 is entering a very large space. Those are pretty big programs. We just announced the RMC-4630-03 program, which is gonna be a significant commitment of resources. I think it's really more a timing question, and we will evaluate.

Thank you.

Yes, thanks for the question.

Faisal Ali Khurshid: I think it's primarily a prioritization decision. You know, we're moving two compounds into the clinic next year. We already have two compounds in the ground.

I don't think that there are specific.

Features of the molecule that are affecting that decision I think it's primarily a prioritization decision. We're moving two compounds into the clinic next year.

Faisal Ali Khurshid: We've said that there's at least another one coming and several more behind that. So, you know, over the next 12 months, we've got our hands quite full. And RMC6291 is entering a crowded space, and RMC6236 is entering a very large space.

We already have two compounds in the clinic.

We said that there is at least another one coming in several more behind us so.

Over the next 12 months, we got our hands quite fallen at RMB 69, one is entering a crowded space and RMC 63, six is entering a very large space. So those are those are pretty big program and we just announced the <unk> III program, which is going to be a significant.

Faisal Ali Khurshid: So those are pretty big programs, and we just announced the O3 program, which is going to be a significant commitment of resources. So I think it's really more a timing question, and we will evaluate, and we'll continue evaluating what's the right time for moving that forward. And if and when that's what we do, but I don't think I would anticipate any sort of out-licensing. I'm not sure why we would do that since we have an integrated approach to RAS-driven tumors, and having a good quality SOS-1 inhibitor is part of that approach.

The resources so.

I see.

It's really more more a timing question and we will evaluate it we'll continue evaluating what's the right timing for moving that forward and if and when that's what we'll do but I don't think I would anticipate any sort of out licensing.

Mark Goldsmith: We'll continue evaluating what's the right timing for moving that forward and if and when, that's what we'll do. But I don't think I would anticipate any sort of out licensing. I'm not sure why we would do that since we have an integrated approach to RAS-driven tumors and having a good quality SOS1 inhibitor is part of that approach. It's not on the point of the spear, but it's part of our overall integrated approach.

Mark Goldsmith: We'll continue evaluating what's the right timing for moving that forward and if and when, that's what we'll do. I don't think I would anticipate any sort of out licensing. I'm not sure why we would do that since we have an integrated approach to RAS-driven tumors and having a good quality SOS1 inhibitor is part of that approach. It's not on the point of the spear, but it's part of our overall integrated approach.

I'm not sure why we would do that since we have an integrated approach to Ras driven tumors and having a good quality source one inhibitors as part of that approach is not it's not on the point of the spear, but as part of our overall integrated approach.

Faisal Ali Khurshid: It's not on the point of the sphere, but it's part of our overall integrated approach. Got it. Thank you for taking the questions. Thank you. Our final question comes from the line of Eric Joseph with J.P. Morgan. Hey, good evening.

Faisal Rashid: Got it. Thank you for taking the question.

Got it thank you for taking the question.

Mark Goldsmith: Thank you.

Operator 2: Thank you. Our final question comes from the line of Eric Joseph with J.P. Morgan. Your line is open.

Mark Goldsmith: Thank you. Our final question comes from the line of Eric Joseph with JP Morgan. Your line is open.

Thank you.

Our final question comes from the line of Eric Joseph with Jpmorgan. Your line is open.

Eric William Joseph: Hi, good evening. Thanks for taking the time to ask the question. Just to follow up on the O3 study, I'm curious to get a... Maybe a bit of a sense of the strategic rationale to pursue lung cancer as opposed to perhaps colorectal cancer, given the sort of the relatively higher unmet need and the lack of objective responses there. I guess, was this decision based on anything that you've seen thus far in Code Break 101 and is, Combination potential and colorectal cancer is something that

Eric Joseph: Hi. Good evening. Thanks for taking the question. Just to follow up on the 03 study, I'm curious to get a, maybe a bit of a sense of the strategic rationale to pursue lung cancer as opposed to perhaps colorectal, given the sort of the relatively higher unmet need and the lack of objective responses there. I guess was this decision based on anything that you've seen thus far in CodeBreaK 101? And is combination potential in colorectal cancer something that might still be on the table?

Eric Joseph: Hi. Good evening. Thanks for taking the question. Just to follow up on the RMC-4630-03 study, I'm curious to get maybe a bit of a sense of the strategic rationale to pursue lung cancer as opposed to perhaps colorectal, given the relatively higher unmet need and the lack of objective responses there. I guess was this decision based on anything that you've seen thus far in CodeBreaK 101? And is combination potential in colorectal cancer something that might still be on the table?

Hi, good evening and thanks for taking the question.

Just a follow up on the <unk> III study.

Curious to get a <unk>.

Can be a bit of a sense of the strategic rationale to pursue lung cancer as opposed to perhaps colorectal given the.

The relatively higher unmet need and the lack of objective responses there.

I guess was this decision basically anything that you've seen thus far in co break 101, and as combination potential in colorectal cancer or something that might still be on the table.

Eric William Joseph: Thanks for your question. I think Steve's got some comments to make on that. Yeah, let's start with the Kellogg hats for a bit.

Mark Goldsmith: Thanks for your question. I think Steve's got some comments to make on that.

Thanks for your question.

I think he's got some comments to make on that.

Steve Kelsey: Yeah, let's start with the colon cancer bit first. Absolutely, it's on the table. The reason for focusing on non-small cell lung cancer, I think, is really twofold. One is, we were swayed to some extent by the data that was partly presented at AACR and then published in the New England Journal of Medicine about the mechanisms by which tumors escape from KRAS G12C off inhibitors. I think if you look at that data, the potential for a SHP2 inhibitor to intervene meaningfully in the effect of a KRAS G12C off inhibitor or at least augment the effect of emerging resistance is potentially greater in non-small cell lung cancer.

Steve Kelsey: Yeah, let's start with the colon cancer bit first. Absolutely, it's on the table. The reason for focusing on non-small cell lung cancer, I think, is really twofold. One is, we were swayed to some extent by the data that was part presented at AACR and then published in the New England Journal of Medicine about the mechanisms by which tumors escape from KRAS G12C off inhibitors. I think if you look at that data, the potential for a SHP2 inhibitor to intervene meaningfully in the effect of a KRAS G12C off inhibitor or at least augment the effect of aggregating resistance is potentially greater in non-small cell lung cancer.

Yes, let's start with let's start with the catalog.

Yes.

Stephen M. Kelsey: Absolutely, it's on the table. The reason for focusing on non-smoking...

Absolutely on the table.

The.

The reason for focusing on non small cell lung cancer.

Stephen M. Kelsey: and also lung cancer, I think it is really twofold.

Stephen M. Kelsey: One is that we were swayed.

<unk> is is really twofold. One is we were a sleigh.

Stephen M. Kelsey: to some extent by

To some extent.

unknown: [inaudible]

So that was presented.

unknown: New England Journal of Medicine about mechanisms by which tumors escape from KRS-G12C off-inhibitors. I think if you look at that data, the potential for a shift to it is...

Presented at ACR event calculation in the New Orleans.

Some of the mechanisms by which choose to escape from <unk> often and this is I think if you look at that data.

The potential for a shift to inhibit HD meaningfully in the and the effects of it.

Stephen M. Kelsey: to be meaningfully involved in the effect.

unknown: [inaudible]

unknown: It makes it easier to detect the difference if you're living above it, but it's still the same, that's it.

<unk> inhibitors are already sold and we in fact to navigate the system.

Stephen M. Kelsey: Clearly, we wanted to focus our attention on a single disease and make sure we got the right answer, but it absolutely doesn't say anything negative about the potential for 4-6-3-0 and colon cancer, and I think there's every expectation that at some point in the future, we will be doing that combination as well. And if I could add to that, Eric, the COCHRATE-101c study continues, and it is an exploratory study looking at multiple histotypes, so we're going to continue to get information out of that.

Steve Kelsey: Secondly, we know the objective response rate to single agent cetuximab is a little bit higher, and that actually, oddly enough, in a if you're comparing makes it easier to detect a difference if you're dealing with double versus a single. So I think there's a very good reason. But thirdly, we wanted to focus our attention on a single disease and make sure we got the right answer. But absolutely doesn't say anything negative about the potential for RMC-4630 in colon cancer. And I think, there’s every expectation that at some point in the future, we will be doing that combination as well.

Steve Kelsey: Secondly, we know the objective response rate to single agent cetuximab is a little bit higher, and that actually, oddly enough, if you're comparing makes it easier to detect a difference if you're dealing with double versus a single. I think there's a very good reason. Thirdly, we wanted to focus our attention on a single disease and make sure we got the right answer. Absolutely doesn't say anything negative about the potential for RMC-4630 in colon cancer. I think there's every expectation that at some point in the future, we will be doing that combination as well.

Type C grades are in non small cell lung cancer. Secondly, we know the objective response rate simulations with <unk> is a little bit higher.

And that actually oddly enough.

Comparing mix makes it easiest types different Europe.

With all of those things so I think thats a very good reason.

Thirdly, we wanted to focus our attention on a single disease make sure we've got the right answer.

Absolutely absolutely doesn't say anything negative about the potential for horses kind of I'll pass here I think.

There's every expectation that at some point.

In the future, we will be doing a combination of all that.

Mark Goldsmith: Yeah, if I could add to that, Eric, the CodeBreaK 101c study continues, and it is an exploratory study looking at multiple histotypes, so we're gonna continue to get information out of that. I'd also highlight that in the formal part of the presentation, we did show an example of colorectal cancer tumor line that was relatively unresponsive or had low response to RMC-6291 alone, but when combined with the SHP2 inhibitor, actually developed quite deep regressions. I think we're still quite committed to other things as well. At this point, you sort of break off of the broad multi-tumor approach and start delving down one at a time. The first approval for Lumakras, of course, is in non-small cell lung cancer.

Mark Goldsmith: Yeah, if I could add to that, Eric, the CodeBreaK 101C study continues, and it is an exploratory study looking at multiple histotypes, so we're gonna continue to get information out of that. I'd also highlight that in the formal part of the presentation, we did show an example of colorectal cancer tumor line that was relatively unresponsive or had low response to RMC-6291 alone, but when combined with the SHP2 inhibitor, actually developed quite deep regressions. I think we're still quite committed to other things as well. At this point, you sort of break off of the broad multi-tumor approach and start delving down one at a time. The first approval for Lumakras, of course, is in non-small cell lung cancer.

Stephen M. Kelsey: I'd also highlight that in the formal part of the presentation, we did show an example of a colorectal cancer tumor line that was relatively unresponsive or had a low response to RMC6291 alone but, when combined with the SHIPA inhibitor, actually developed quite deep regressions. And so I think we're still quite committed to other things as well, but at this point, we sort of break off from the broad, multi-tumor approach and start delving down one at a time.

I could add to that Eric.

One of our C study continues and it is an exploratory study is looking at multiple tissue types that we're going to continue to get information out of that.

Highlight.

Highlight that in the formal part of the presentation. We did show. An example of colorectal cancers tumor ly that was relatively unresponsive or had low response to obviously 69 was alone, but when combined with the ship inhibitor actually develop.

Quite deep.

And so I think we're still quite committed other things as well but.

At this point do you sort of break off with a broad multi tumor approach and start delving down one at a time in the first approval for <unk>, perhaps the courses in.

Stephen M. Kelsey: And the first approval for LUMOCRAS, of course, is in non-soul cell lung cancer, so if we're looking for a place where we can make a difference and build on improved treatment regimens, that would be the place to start. But by no means, as Steve said, are we excluding other opportunities.

Mark Goldsmith: If we're looking for a place where we can make a difference and build on an improved treatment regimen, that would be the place to start. By no means, as Steve said, are we excluding other opportunities.

Wholesale lung cancer. So if we're looking for a place where we can make a difference and.

This build on improved treatment regimen that would be the place to start.

By no means as Steve said, our we excluding other opportunities.

Eric Joseph: Okay. Okay, great. And with respect to the RAS(ON) portfolio, it looks like you're deciding between two targets, and naming a third development candidate between RAS G12D and G13C. Just kind of curious to get a sense of your thinking and what remains in deciding between sort of which you nominate here. I guess, how far apart are these compounds, I guess, in their preclinical development? Should we be thinking about multiple development candidates coming to the fore being named over the next year or so?

Eric Joseph: Okay. Okay, great. With respect to the RAS(ON) portfolio, it looks like you're deciding between two targets, and naming a third development candidate between RAS G12D and G13C. Just kind of curious to get a sense of your thinking and what went into deciding between sort of which you nominate here. I guess, how far apart are these compounds, I guess, in their preclinical development? Should we be thinking about multiple development candidates coming to the fore being named over the next year or so?

Okay, Okay great.

And with respect to the Ras on portfolio it looks like you're deciding between two.

Stephen M. Kelsey: Okay, okay, great. And with respect to the Rasmun portfolio, it looks like you're deciding between two targets, in naming a third development candidate between G12D and G13C. Curious to get a sense of your thinking, that remains in deciding between sort of which you you nominate here and I guess how far apart are these compounds I guess in their preclinical development? Should we be thinking about multiple development candidates coming to the fore or being named over the next year or so? Yeah.

<unk> targets.

A third development candidate between sorry.

<unk> see.

Just kind of.

Curious to get a sense of your thinking.

That remains in deciding between sort of which you nominate here and I guess, how far apart are these compounds I guess in there.

Preclinical development should be thinking about multiple development candidates coming through before being named over the next year or so.

Mark Goldsmith: Yeah. I wouldn't read too much into that. That's the question of sort of the complex strategic decision about which one to move forward. We basically have a bunch of teams competing with each other to put forth the best package when they've got the package together. When they've got a package, we'll look at it and consider whether to approve moving forward with it. It's not as if we ask one team to slow down and another team to speed up. I mean, everybody's moving as fast as they can. We also didn't explicitly say that we'll be choosing between G12D or G13C for this decision. We just said those are two that we've disclosed that are in late lead optimization, and we expect to select a next development candidate coming up.

Yes.

I wouldn't read too much into that.

The question is sort of the.

Complex strategic decision about which lets move forward, we basically have a bunch of teams competing with each other to put forth. The best package limit that the package together and when they've got a package to look at and consider whether to approve moving forward with it. So it's not as if we asked lumpy to slowdown and other pieces.

Eric William Joseph: We also didn't explicitly say that we'll be choosing between G-12B or G-13B for this decision. We just said those are two that we've disclosed that are in late lead optimization, and we expect to select a next development candidate coming up. In principle, there could be other options on the table, too. So I wouldn't read too much into whatever comes out of that. And we'll move things forward as quickly as we can.

Everybody is moving as fast as they can.

We also didn't explicitly say that will be choosing between 12 year <unk>.

Four.

This decision. We just said those are two that we've disclosed that are in lead optimization that we expect to select a development candidate coming up but.

First of all it could be other options on the table too.

So I wouldn't read I wouldn't read too much into the whatever comes out of that and we're moving forward as quickly as we can.

I'm, just saying that the only it doesn't at some point thereafter, not too far after the other one I'm sure we'll get names in each of these programs are moving along well as our unnamed target programs.

That are continuing to work their way through.

Eric Joseph: Okay. All right. I'll try not to overinterpret, I guess, from the slides going forward. Thanks. Thanks for taking the questions.

Okay, Alright, alright.

unknown: Okay. All right. All right. [inaudible]

Try not to over interpret I guess going forward. Thanks, Thanks for taking my questions.

Mark Goldsmith: Yeah. All right.

unknown: Thank you.

Operator 2: Thank you. As there are no more questions in the queue, I will turn the call back over to Dr. Goldsmith for his closing remarks.

Mark Goldsmith: Thank you. As there are no more questions in the queue, I will turn the call back over to Dr. Goldsmith for his closing remarks.

Alright.

Mark A. Goldsmith: As there are no more questions in the queue, I will turn the call back over to Dr. Goldsmith for his closing remarks. Thank you, Operator, and thank you to our analysts who just participated in the Q&A and to everyone for participating today and for your continued support of Revolution Medicine.

Thank you.

As there are no more questions in the queue I will turn the call back over to Dr. Goldsmith for his closing remarks.

Mark Goldsmith: Thank you, operator, and thank you to our analysts who just participated in the Q&A and to everyone for participating today and for your continued support of Revolution Medicines.

Thank you operator, and thank you to our analyst just participated in the Q&A and to everyone for participating today and for your continued support of our bullishness.

Operator: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Operator 2: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Mark Goldsmith: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation you may now disconnect.

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