Q1 2022 Revolution Medicines Inc Earnings Call

May 9, 2022

Good day. My name is Catherine and I'll be your conference facilitator today. Welcome to the Revolution Medicine's first quarter and 2022 earnings conference call.

Operator: Good day. My name is Catherine, and I'll be your conference facilitator today. Welcome to the Revolution Medicines Q1 2022 Earnings Conference Call. Today's call is being recorded. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will hold a Q&A session. To ask a question at that time, please press the star key followed by one on your touchtone telephone. If anyone has difficulty hearing the conference, please press star zero for operator assistance. I would now like to hand the conference over to David Arrington, Revolution Medicines SVP of Investor Relations and Corporate Affairs, for opening remarks. David, you may begin.

Good day my name is Catherine and I'll be your conference facilitator today welcome to the Revolution medicines first quarter and 2022 earnings conference call.

Today's call is being recorded. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will hold a Q&A session. To ask a question at that time, please press the star key followed by one on your touchtone telephone. If anyone has difficulty hearing the conference, please press star zero for operator assistance. I would now like to hand the conference over to David Errington, Revolution Medicines.

Today's call is being recorded at this time all participants are in a listen only mode. Following managements prepared remarks, we will hold a Q&A session to ask a question at that time. Please press the star key followed by one on your Touchtone telephone if anyone has difficulty hearing the conference. Please press star zero for <unk>.

Operator assistance I would now like to hand, the conference over to David Errington Revolution Medicine.

SVP of investor relations and corporate affairs for opening remarks. David, you may begin.

S V P of Investor Relations and corporate affairs for opening remarks, David you may begin.

David S. Arrington: Thank you, and welcome everyone to our Q1 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer, Dr. Steve Kelsey, the Company's President, Research and Development, and Jack Anders, our SVP of Finance and Principal Accounting Officer. Today, we will be referencing selected slides from our corporate presentation. The complete set is available for you to view and download on revmed.com. As we begin, I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act. These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements. Except as required by law, the company undertakes no obligation to revise any forward-looking statements.

David Arrington: Thank you, and welcome everyone to our Q1 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer, Dr. Steve Kelsey, the Company's President, Research and Development, and Jack Anders, our SVP of Finance and Principal Accounting Officer. Today, we will be referencing selected slides from our corporate presentation. The complete set is available for you to view and download on revmed.com. As we begin, I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act. These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements. Except as required by law, the company undertakes no obligation to revise any forward-looking statements.

Thank you and welcome everyone to our first quarter earnings call.

Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive

Joining me on today's call are Dr. Mark Goldsmith Revolution, medicines, Chairman and Chief Executive Officer, Dr. Steve Kelsey, the Companys President research and development.

Dr. Steve Kelsey, the company's president, research and develop...

and Jack Anders, our SVP of Finance and Principal Accounting Officer. Today we will be referencing...

And Jack Anders our SVP of finance and principal accounting officer.

Today, we will be referencing selected slides from our corporate presentation.

The complete set is available for you to view and download on RevMed.

The complete set is available for you to view and download on <unk> Dot com.

As we begin, I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward-looking statements with respect to our business.

As we begin I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business may constitute forward looking statements within the meaning of the private Securities Litigation Reform Act.

These statements are subject to a number of assumptions, risks, and uncertainties. cogon Thank you all!

These statements are subject to a number of assumptions risks and uncertainties.

Actual results may differ materially from these statements.

except as required by law, the company undertakes no obligation to revise any full

And except as required by law the company undertakes no obligation to revise any forward looking statements.

I encourage you to review the legal disclaimer slide of our corporate presentation or the earnings press release.

David S. Arrington: I encourage you to review the legal disclaimer slide of our corporate presentation or the earnings press release, as well as all of the company's filings with the SEC concerning these and other matters. With that, I will turn the call over to Dr. Mark Goldsmith, Chairman and Chief Executive Officer, Revolution Medicines, Inc.

David Arrington: I encourage you to review the legal disclaimer slide of our corporate presentation or the earnings press release, as well as all of the company's filings with the SEC concerning these and other matters. With that, I will turn the call over to Dr. Mark Goldsmith, Chairman and Chief Executive Officer, Revolution Medicines, Inc.

I encourage you to review the legal disclaimer slide of our corporate presentation or the earnings press release as well as all of the company's filings with the SEC concerning these and other matters.

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

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

Thanks, David. Good afternoon, everyone. Thank you all for joining us today. I'll start with a few top-line comments. We've made great progress in the first quarter. We continue to advance what we believe is the deepest portfolio of RAS-targeted therapeutics.

Mark A. Goldsmith: Thanks, David. Good afternoon, everyone. Thank you all for joining us today. I'll start with a few top-line comments. We've made great progress in Q1. We continue to advance what we believe is the deepest portfolio of RAS(ON)-targeted therapeutics in the field, led by our RAS(ON) inhibitors in development with significant opportunity for patient impact. Excessive RAS(ON) signaling drives some 30% of all human cancers. Today, I am very pleased to let you know that we have submitted the IND for RMC-6236, our RAS(ON) multi-selective inhibitor, and expect to dose the first patient in mid-2022. Preparation of the IND for RMC-6291, our KRAS G12C(ON) inhibitor, is also on track with our original guidance, and we expect to dose the first patient in H2 2022.

Mark Goldsmith: Thanks, David. Good afternoon, everyone. Thank you all for joining us today. I'll start with a few top-line comments. We've made great progress in Q1. We continue to advance what we believe is the deepest portfolio of RAS(ON)-targeted therapeutics in the field, led by our RAS(ON) inhibitors in development with significant opportunity for patient impact. Excessive RAS(ON) signaling drives some 30% of all human cancers. Today, I am very pleased to let you know that we have submitted the IND for RMC-6236, our RAS(ON) multi-selective inhibitor, and expect to dose the first patient in mid-2022. Preparation of the IND for RMC-6291, our KRAS G12C(ON) inhibitor, is also on track with our original guidance, and we expect to dose the first patient in H2 2022.

Thanks, David Good afternoon, everyone. Thank you all for joining us today.

I'll start with a few topline comments.

We've made great progress in the first quarter.

We continue to advance what we believe is the deepest portfolio of Ras targeted therapeutics in the field.

Led by our rasp inhibitors in development with significant opportunity for patient to impact access of Ras on signaling drives some 30% of all human cancers.

Today I am very pleased to let you know that we have submitted the IND for RMC6236, our RAS multi-ON inhibitor, and expect to dose the first patient in mid-2022.

Today I am very pleased to let you know that we have submitted the IND for RMC 63, six <unk>.

<unk> multi on inhibitor.

And expect to dose the first patient in mid 2022.

Preparation of the IND for RMC six to nine one R. K Ras <unk> inhibitor is also on track with our original guidance and we expect to dose the first patient in the second half of 2022.

Mark A. Goldsmith: These two RAS(ON) inhibitors approaching the clinic and an exciting pipeline behind them represent a wave of RAS(ON) inhibitor drug candidates that could address the majority of RAS-addicted cancers that lack effective targeted drugs. Concurrently, we continue clinical evaluation of the class-leading RAS companion inhibitors, RMC-4630 and RMC-5552, that are intended as combination agents with direct RAS inhibitors, including our own RAS(ON) inhibitors, to maximize patient benefit. Regarding our development stage compounds, we are transitioning our communication schedule. Going forward, we plan to focus milestones for development stage programs on clinical initiation rather than IND submissions. Investors should look to our postings on ClinicalTrials.gov for indications that an IND is open and that clinical investigation sites are being activated to enable study initiation. We also plan to communicate after we've begun dosing patients in each program. Slide 5.

Mark Goldsmith: These two RAS(ON) inhibitors approaching the clinic and an exciting pipeline behind them represent a wave of RAS(ON) inhibitor drug candidates that could address the majority of RAS-addicted cancers that lack effective targeted drugs. Concurrently, we continue clinical evaluation of the class-leading RAS companion inhibitors, RMC-4630 and RMC-5552, that are intended as combination agents with direct RAS inhibitors, including our own RAS(ON) inhibitors, to maximize patient benefit. Regarding our development stage compounds, we are transitioning our communication schedule. Going forward, we plan to focus milestones for development stage programs on clinical initiation rather than IND submissions. Investors should look to our postings on ClinicalTrials.gov for indications that an IND is open and that clinical investigation sites are being activated to enable study initiation. We also plan to communicate after we've begun dosing patients in each program. Slide 5.

These two RAS-on inhibitors approaching the clinic and an exciting pipeline behind them represent a wave of RAS-on inhibitor drug.

These two rason inhibitors approaching the clinic and an exciting pipeline behind them represent a wave of rason inhibitor drug candidates that could address the majority of Ras addicted cancers that lack effective targeted drugs.

address the majority of RAS-addicted cancers that lack effective targeted drugs. Concurrently, we continue clinical evaluation of the class-leading RAS companion inhibitors, RMC4630 and RMC480.

Concurrently we continue clinical evaluation of the class, leading Ras companion inhibitors, RMC for six REO and RMC $5 55 to.

That are intended as combination agents with direct rasp inhibitors, including our own rason inhibitors to maximize patient benefit.

Regarding our development stage compounds, we are transitioning our communication schedule

Regarding our development stage compounds, we are transitioning our communication schedule.

going forward, we plan to focus milestones for development stage programs on clinical

Going forward, we plan to focus milestones for development stage programs on clinical initiation rather than IND submissions.

Investors should look to our postings on clinicaltrials.gov for indications that an IND is open and that clinical investigations

Investors should look to our postings on clinical trials dot Gov for indications that an IND is open and that clinical investigation sites are being activated to enable study initiation.

We also plan to communicate after we've begun dosing patients in each program.

Slide five.

Revolution Medicines has a deep science-driven pipeline of targeted therapies for RAS-addicted cancers.

Mark A. Goldsmith: Revolution Medicines has a deep science-driven pipeline of targeted therapies for RAS-addicted cancers. We have four RAS-ON drug candidates that are supported by robust and growing datasets that have large clinical opportunities with the potential to serve patients with a wide range of RAS-addicted cancers. Further, we expect that our pipeline will continue to grow with highly distinctive new assets deriving from our RAS cancer innovation engine, which should expand our reach to other key oncogenic mutations on RAS proteins. Although RAS-addicted cancers are induced primarily by mutations that cause RAS-ON proteins to behave as cancer drivers, often these cancers are also supported and maintained by other cellular proteins we call RAS cooperating targets and pathways.

Mark Goldsmith: Revolution Medicines has a deep science-driven pipeline of targeted therapies for RAS-addicted cancers. We have four RAS-ON drug candidates that are supported by robust and growing datasets that have large clinical opportunities with the potential to serve patients with a wide range of RAS-addicted cancers. Further, we expect that our pipeline will continue to grow with highly distinctive new assets deriving from our RAS cancer innovation engine, which should expand our reach to other key oncogenic mutations on RAS proteins. Although RAS-addicted cancers are induced primarily by mutations that cause RAS-ON proteins to behave as cancer drivers, often these cancers are also supported and maintained by other cellular proteins we call RAS cooperating targets and pathways.

Evolution medicines have had deep science driven pipeline of targeted therapies for rasp addicted cancers, we have four Ras on drug candidates that are supported by robust and growing datasets that have large clinical opportunities with the potential to serve patients with a wide range of Ras addicted cancers.

that are supported by robust and growing data sets that have large clinical opportunities with the.

Further, we expect that our pipeline will continue to grow with highly distinctive new assets deriving from our RAS cancer innovation.

Further we expect that our pipeline will continue to grow with highly distinctive new assets deriving from our RASK cancer innovation engine.

Which should expand our reach to other key oncogenic mutations on Ras proteins.

Although RAS-addicted cancers are induced primarily by mutations that cause RAS-on proteins to behave as cancer drivers, often these cancers are also supported and maintained by other cellular proteins we call RAS-cooperating targets and pathways. We believe it is important, scientifically.

Although ras addicted cancers are induced primarily by mutations that cause Ras on proteins to behave as cancer drivers.

Often these cancers are also supported and maintained by other cellular proteins, we call RASK cooperating targets and pathways.

Mark A. Goldsmith: We believe it is important scientifically to match our treatment strategies to this biological cooperativity by developing RAS companion inhibitors to suppress the cooperating proteins while deploying RAS-ON inhibitors to suppress the primary RAS drivers. Lastly, I note that in many instances, we expect drugs of these two types may be combined to deliver the greatest clinical benefit. In the next few minutes, I'll highlight examples of three specific themes that are important to our strategy. First, RAS-ON inhibitors demonstrate compelling monotherapy antitumor activity in diverse preclinical models of genetically defined RAS cancers. Second, RAS-ON inhibitors can be combined with RAS companion inhibitors to improve antitumor activity in preclinical models that are less sensitive to monotherapy. Third, RAS-ON inhibitors as monotherapies reverse the immune suppressive tumor microenvironment in RAS-driven cancer models and can unlock profound antitumor immunity when combined with immune system modulators such as PD-1 checkpoint inhibitors.

Mark Goldsmith: We believe it is important scientifically to match our treatment strategies to this biological cooperativity by developing RAS companion inhibitors to suppress the cooperating proteins while deploying RAS-ON inhibitors to suppress the primary RAS drivers. Lastly, I note that in many instances, we expect drugs of these two types may be combined to deliver the greatest clinical benefit. In the next few minutes, I'll highlight examples of three specific themes that are important to our strategy. First, RAS-ON inhibitors demonstrate compelling monotherapy antitumor activity in diverse preclinical models of genetically defined RAS cancers. Second, RAS-ON inhibitors can be combined with RAS companion inhibitors to improve antitumor activity in preclinical models that are less sensitive to monotherapy. Third, RAS-ON inhibitors as monotherapies reverse the immune suppressive tumor microenvironment in RAS-driven cancer models and can unlock profound antitumor immunity when combined with immune system modulators such as PD-1 checkpoint inhibitors.

We believe it is important scientifically to match our treatment strategies to this biological cooperativity baidu.

By developing Ras companion inhibitors to suppress the cooperating proteins, while deploying rason inhibitors to suppress the primary drivers.

Lastly, I note that in many instances, we expect drugs of these two types may be combined to deliver the greatest clinical benefit.

Lastly, I note that in many instances, we expect drugs at these two types may be combined to deliver the greatest clinical benefit.

And the next few minutes I'll highlight examples of three specific themes that are important to our strategy.

First, RAS-on inhibitors demonstrate compelling monotherapy anti-tumor activity.

First rason inhibitors demonstrate compelling monotherapy antitumor activity in diverse preclinical models of genetically defined Ras cancers.

Second, RAS-on inhibitors can be combined with RAS companion inhibitors to improve anti-tumor activity in preclinical models that are less sensitive to monotherapy. And third, RAS-on inhibitors as monotherapies reverse the immune suppressive tumor microenvironment in RAS-driven cancer models and can unlock profound anti-tumor immunity when combined with immune system modulators such as PD-1 checkpoint inhibitors. Now I'll turn to specific comments about our portfolio.

Second rason inhibitors can be combined with Ras companion inhibitors to improve antitumor activity in preclinical models that are less sensitive to monotherapy.

And third rason inhibitors as mono therapies reverse the immune suppressive tumor microenvironment, and Ras driven cancer models and can unlock profound antitumor immunity when combined with immune system modulators, such as PD, one checkpoint inhibitors.

Mark A. Goldsmith: Now I'll turn to specific comments about our portfolio progress. The first theme is RAS-ON inhibitors as highly active monotherapy agents preclinically. We have produced a large collection of tri-complex inhibitors targeting diverse oncogenic RAS variants through highly differentiated chemical and pharmacologic profiles. Slide 9. As a first example, RMC-6236 is a potent oral RAS-ON selective inhibitor with broad potential across cancers driven by a variety of RAS mutations. To date, it has been shown to be active in three histotypes, including pancreatic, colorectal, and non-small cell lung cancer models, across mutations, including KRAS G12D, KRAS G12V, and KRAS G12R, cancer drivers for which patients whose tumors bear these mutations lack targeted therapy options. Slide 12. We are on the path to clinical data now that the IND has been submitted.

Mark Goldsmith: Now I'll turn to specific comments about our portfolio progress. The first theme is RAS-ON inhibitors as highly active monotherapy agents preclinically. We have produced a large collection of tri-complex inhibitors targeting diverse oncogenic RAS variants through highly differentiated chemical and pharmacologic profiles. Slide 9. As a first example, RMC-6236 is a potent oral RAS-ON selective inhibitor with broad potential across cancers driven by a variety of RAS mutations. To date, it has been shown to be active in three histotypes, including pancreatic, colorectal, and non-small cell lung cancer models, across mutations, including KRAS G12D, KRAS G12V, and KRAS G12R, cancer drivers for which patients whose tumors bear these mutations lack targeted therapy options. Slide 12. We are on the path to clinical data now that the IND has been submitted.

Now I'll turn to specific comments about our portfolio progress.

The first theme is rason inhibitors is highly active monotherapy agents pre clinically we have produced a large collection of Tri complex inhibitors targeting diverse oncogenic Ras variance through highly differentiated chemical and pharmacologic profiles slide nine.

As a first example, RMC 63, six is a potent oral rason selective inhibitor with broad potential across cancers, driven by a variety of Ras mutations.

To date it.

It has been shown to be active in three <unk> types, including pancreatic colorectal and non small cell lung cancer models and.

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are. Cancer drivers for which patients whose tumors bear these mutations

Cancer drivers for which patients whose tumors bear these mutations lack targeted therapy options.

Slide 12.

We are on the path to clinical data now that the IND has been submitted we expect to announce dosing of the first patient in a monotherapy dose escalation study in mid 2022 and in 2023, we plan to provide evidence of first in class single agent activity for RMC 63 six.

Mark A. Goldsmith: We expect to announce dosing of the first patient in a monotherapy dose escalation study in mid-2022, and in 2023, we plan to provide evidence of first-in-class single agent activity for RMC-6236. I also note that RMC-6236 may also be deployed as a RAS companion inhibitor in combination with mutant-selective RAS(ON) inhibitors, something I will say a bit more about later. Slide 14. As another example, RMC-6291 is a potent oral selective covalent inhibitor of KRAS G12C(ON) with a differentiated preclinical profile designed to serve patients with cancers driven by the KRAS G12C mutation, including lung, colorectal, and pancreatic cancers.

Mark Goldsmith: We expect to announce dosing of the first patient in a monotherapy dose escalation study in mid-2022, and in 2023, we plan to provide evidence of first-in-class single agent activity for RMC-6236. I also note that RMC-6236 may also be deployed as a RAS companion inhibitor in combination with mutant-selective RAS(ON) inhibitors, something I will say a bit more about later. Slide 14. As another example, RMC-6291 is a potent oral selective covalent inhibitor of KRAS G12C(ON) with a differentiated preclinical profile designed to serve patients with cancers driven by the KRAS G12C mutation, including lung, colorectal, and pancreatic cancers.

I also note that RMC 63, six may also be deployed as a Ras companion inhibitor in combination with mutant selective rason inhibitors, something I will say a bit more about later.

Slide 14.

As another example, RMC 691 is a potent oral selective covalent inhibitor of K Ras <unk> 12 C. On.

With a differentiated preclinical profile designed to serve patients with cancers, driven by the <unk> mutation, including lung colorectal and pancreatic cancers.

Mark A. Goldsmith: RMC-6291 has demonstrated best-in-class potential for treating KRAS G12C-driven lung cancers, non-small cell lung cancers based on superior outcomes in a mouse clinical trial with KRAS G12C lung cancer models. Slide 17. Our IND preparation is on track for submission in H1 2022, and we anticipate RMC-6291 will be our second RAS(ON) inhibitor program to enter the clinic this year and expect to disclose preliminary evidence of superior activity over the first generation KRAS G12C OFF inhibitors in 2023. Slide 19. As a third example, RMC-9805 is an oral selective covalent inhibitor of KRAS G12D(ON), the primary tumor driver for more than 50,000 new patients annually in the United States, predominantly patients with colorectal, pancreatic, or non-small cell lung cancer.

Mark Goldsmith: RMC-6291 has demonstrated best-in-class potential for treating KRAS G12C-driven lung cancers, non-small cell lung cancers based on superior outcomes in a mouse clinical trial with KRAS G12C lung cancer models. Slide 17. Our IND preparation is on track for submission in H1 2022, and we anticipate RMC-6291 will be our second RAS(ON) inhibitor program to enter the clinic this year and expect to disclose preliminary evidence of superior activity over the first generation KRAS G12C OFF inhibitors in 2023. Slide 19. As a third example, RMC-9805 is an oral selective covalent inhibitor of KRAS G12D(ON), the primary tumor driver for more than 50,000 new patients annually in the United States, predominantly patients with colorectal, pancreatic, or non-small cell lung cancer.

691 has demonstrated best in class potential for treating <unk>, driven lung cancers, non small cell lung cancers based on superior outcomes in a mouse clinical trial.

With <unk> lung cancer models.

Slide 17.

The IND preparation is on track for submission in the first half of 2022, and we anticipate RMC 60, 91 will be our second rason inhibitor program to enter the clinic this year and expect to disclose preliminary evidence of superior activity over the first generation <unk> inhibitors in.

2023.

Slide 19 as a third example, RMC 985 is an oral selective covalent inhibitor of <unk> <unk> on the primary tumor driver for more than 50000, new patients annually in the United States predominantly patients with colorectal pancreatic and non small cell lung cancer.

Mark A. Goldsmith: RMC-9805 exhibits a highly differentiated profile, and we believe it is one of our most technically sophisticated RAS(ON) inhibitors to date. It uniquely engages the KRAS G12D cancer variant covalently through the oncogenic aspartic acid residue by taking advantage of a proprietary chemical warhead, a bespoke linker, and our tri-complex binding modality. These design elements deliver a highly distinctive preclinical profile that includes oral bioavailability and selective and irreversible inhibition of this important cancer target. When administered orally to mice then grafted with the KRAS G12D tumor, RMC-9805 achieves favorable plasma exposures and dramatically suppresses DUSP6 mRNA, a molecular biomarker of RAS pathway signaling, for over 24 hours due to its irreversible inactivation of the target. Slide 20.

Mark Goldsmith: RMC-9805 exhibits a highly differentiated profile, and we believe it is one of our most technically sophisticated RAS(ON) inhibitors to date. It uniquely engages the KRAS G12D cancer variant covalently through the oncogenic aspartic acid residue by taking advantage of a proprietary chemical warhead, a bespoke linker, and our tri-complex binding modality. These design elements deliver a highly distinctive preclinical profile that includes oral bioavailability and selective and irreversible inhibition of this important cancer target. When administered orally to mice then grafted with the KRAS G12D tumor, RMC-9805 achieves favorable plasma exposures and dramatically suppresses DUSP6 mRNA, a molecular biomarker of RAS pathway signaling, for over 24 hours due to its irreversible inactivation of the target. Slide 20.

RMC nine 805 exhibits a highly differentiated profile and we believe it is one of our most technically sophisticated rason inhibitors to date.

Uniquely engaged is the <unk> cancer variant covalently through the oncogenic aspartic acid residue by taking advantage of a proprietary chemical warhead spoke linker and our Tri complex binding modality.

These design elements deliver a highly distinctive preclinical profile that includes oral bioavailability and selective and irreversible inhibition of this important cancer target.

When administered orally to mice and grafted with the <unk> tumor.

985 achieved favorable plasma exposures dramatically suppresses desk six mrna.

Biomarker of Ras pathway signaling.

Over 24 hours due to it's irreversible inactivation of the target.

Mid 'twenty.

Mark A. Goldsmith: We believe RMC-9805 is the first-ever drug candidate described that can covalently modify an aspartic acid residue in a targeted protein, drives deep and durable antitumor responses in pancreatic and colorectal cancer models in vivo upon oral dosing, and it is well-tolerated. Slide 22. As a fourth example, RMC-8839 is an oral selective covalent inhibitor of KRAS G13C(ON). We believe it is the first compound to directly inhibit KRAS G13C, a target primarily for lung and select colorectal cancer patients who are currently not served by a targeted RAS inhibitor. Slide 24. Lastly, in our pipeline expansion programs, we continue leveraging our RAS innovation engine to identify additional orally bioavailable tri-complex RAS(ON) inhibitors to target RAS variants driving RAS addicted cancers that are unserved by current targeted drugs.

Mark Goldsmith: We believe RMC-9805 is the first-ever drug candidate described that can covalently modify an aspartic acid residue in a targeted protein, drives deep and durable antitumor responses in pancreatic and colorectal cancer models in vivo upon oral dosing, and it is well-tolerated. Slide 22. As a fourth example, RMC-8839 is an oral selective covalent inhibitor of KRAS G13C(ON). We believe it is the first compound to directly inhibit KRAS G13C, a target primarily for lung and select colorectal cancer patients who are currently not served by a targeted RAS inhibitor. Slide 24. Lastly, in our pipeline expansion programs, we continue leveraging our RAS innovation engine to identify additional orally bioavailable tri-complex RAS(ON) inhibitors to target RAS variants driving RAS addicted cancers that are unserved by current targeted drugs.

We believe RMC nine 805 is the first ever drug candidate described that can covalently modifying aspartic acid residue in a targeted protein.

<unk> deep and durable antitumor responses in pancreatic and Colo colorectal cancer models in vivo upon oral dosing and it is well tolerated.

Slide 22 as a fourth example, RMC 83 nine is an oral selective covalent inhibitor of <unk> on.

We believe it is the first compound to directly inhibit <unk> target primarily for long and select colorectal cancer patients who are currently not served by a targeted Ras inhibitor.

Slide 24.

Lastly, in our pipeline expansion programs, we continue leveraging our Ras innovation engine to identify additional orally bio available try complex rason inhibitors target Ras variants driving RASK.

<unk> cancers that are unserved by current targeted drugs.

Mark A. Goldsmith: As illustrated on this slide, our tri-complex inhibitors bind to RAS(ON) proteins at a site that provides the opportunity for direct chemical interaction with amino acids at each of the three well-recognized mutational hotspots affecting residues G12, G13, or Q61. This binding geometry is leveraged in each of our programs to design compounds that are selective in engaging mutant amino acids at these positions that are responsible for most RAS-addicted cancers. Today, I'll share compelling initial data about RMC-0708, a representative mutant-selective non-covalent inhibitor of KRAS Q61H(ON) that was shown for the first time at the recent AACR annual meeting.

Mark Goldsmith: As illustrated on this slide, our tri-complex inhibitors bind to RAS(ON) proteins at a site that provides the opportunity for direct chemical interaction with amino acids at each of the three well-recognized mutational hotspots affecting residues G12, G13, or Q61. This binding geometry is leveraged in each of our programs to design compounds that are selective in engaging mutant amino acids at these positions that are responsible for most RAS-addicted cancers. Today, I'll share compelling initial data about RMC-0708, a representative mutant-selective non-covalent inhibitor of KRAS Q61H(ON) that was shown for the first time at the recent AACR annual meeting.

As illustrated on this slide our Tri complex inhibitors bind to Ras on proteins at a site that provides the opportunity for direct chemical interaction with amino acids at each of the three well recognized mutational hotspots affecting residues <unk> 12, <unk> 13, or <unk> 61.

This binding geometry is leveraged in each of our programs to design compounds that are selective in engaging mutant amino acids. At these positions that are responsible for most ras addicted cancers.

Today I'll share compelling initial data about <unk> three <unk>.

Representative mutant selective non covalent inhibitor of <unk>, 61% <unk> on that were shown for the first time at the recent ACR annual meeting RM.

Mark A. Goldsmith: RMC-0708 shows nanomolar activity in cells driven by the KRAS Q61H variant, is selective for KRAS Q61H over wild type RAS, and drives deep regressions in a KRAS Q61H xenograft model of lung cancer. To our knowledge, this is the first-ever example of a targeted RAS inhibitor directed to an oncogenic RAS variant at the Q61 mutation hotspot. This compound not only represents proof of principle for selective targeting of codon 61 by tri-complex inhibitors but also demonstrates that this modality can be leveraged to develop highly mutant-selective inhibitors even when covalent bonding is not possible. Slide 26.

Mark Goldsmith: RMC-0708 shows nanomolar activity in cells driven by the KRAS Q61H variant, is selective for KRAS Q61H over wild type RAS, and drives deep regressions in a KRAS Q61H xenograft model of lung cancer. To our knowledge, this is the first-ever example of a targeted RAS inhibitor directed to an oncogenic RAS variant at the Q61 mutation hotspot. This compound not only represents proof of principle for selective targeting of codon 61 by tri-complex inhibitors but also demonstrates that this modality can be leveraged to develop highly mutant-selective inhibitors even when covalent bonding is not possible. Slide 26.

<unk> hundred three shows an animal or activity in sales driven by the <unk> 61 H variance.

Is selective for K rescue 61, H O for wild type Ras and drives deep regressions and at <unk>.

<unk> hundred 61, H xenograft model of lung cancer.

To our knowledge. This is the first ever example of a targeted RAF inhibitor directed to an oncogenic Ras variant at the Q 61 mutation hotspot.

This compound not only represents proof of principle for selective targeting of code on 61 by try complex inhibitors, but also demonstrates that this modality can be leveraged to develop highly mutant selective inhibitors.

When covalent bonding is not possible.

Slide 26.

Mark A. Goldsmith: The second theme and parallel approach that I'll talk about today is that our RAS companion inhibitors in development may be combined with RAS(ON) inhibitors to improve antitumor activity in preclinical models that are less sensitive to monotherapy. These RAS companion inhibitors are targeted drugs that suppress cooperating targets and pathways known to work in coordination with RAS cancer drivers to sustain RAS-addicted cancers, and in some instances, confer drug resistance. We believe that combining best-in-class RAS(ON) inhibitors with best-in-class RAS companion inhibitors offers the greatest chance of pathway suppression and durability of response to deliver the best clinical outcomes. Ultimately, the optimal RAS(ON) and companion inhibitor strategy will likely be disease-specific. I will highlight here two clinical stage assets that support combination treatment approaches. Slide 28.

Mark Goldsmith: The second theme and parallel approach that I'll talk about today is that our RAS companion inhibitors in development may be combined with RAS(ON) inhibitors to improve antitumor activity in preclinical models that are less sensitive to monotherapy. These RAS companion inhibitors are targeted drugs that suppress cooperating targets and pathways known to work in coordination with RAS cancer drivers to sustain RAS-addicted cancers, and in some instances, confer drug resistance. We believe that combining best-in-class RAS(ON) inhibitors with best-in-class RAS companion inhibitors offers the greatest chance of pathway suppression and durability of response to deliver the best clinical outcomes. Ultimately, the optimal RAS(ON) and companion inhibitor strategy will likely be disease-specific. I will highlight here two clinical stage assets that support combination treatment approaches. Slide 28.

The second theme and parallel approach that I'll talk about today is that our RASK companion inhibitors in development may be combined with <unk> inhibitors to improve antitumor activity in preclinical models that are less sensitive to mono therapy.

These Ras companion inhibitors are targeted drugs that suppress cooperating targets and pathways known to work in coordination with Ras cancer drivers to sustain raster to cancers and in some instances conferred drug resistance.

We believe that combining best in class Rason inhibitors with best in class Ras Companion inhibitors offers the greatest chance of pathway suppression and durability of response to deliver the best clinical outcomes.

Similarly, the optimal Ras on companion inhibitor strategy will likely be disease specific.

I will highlight here two clinical stage assets that support combination treatment approaches.

Slide 28.

Mark A. Goldsmith: First, RMC-4630 is a potent oral small molecule that is designed to selectively inhibit the activity of SHP2, an upstream cellular protein that plays a central role in modulating cell survival and growth by facilitating RAS pathway signaling. Amgen continues its initial evaluation of dosing RMC-4630 in combination with sotorasib in second-line treatment of various KRAS G12C tumors in the US CodeBreaK 101-C study, and recently announced it has submitted initial data from this study to a medical congress for late summer. Revolution Medicines' clinical study, called RMC-4630-03, is progressing and continues to enroll.

Mark Goldsmith: First, RMC-4630 is a potent oral small molecule that is designed to selectively inhibit the activity of SHP2, an upstream cellular protein that plays a central role in modulating cell survival and growth by facilitating RAS pathway signaling. Amgen continues its initial evaluation of dosing RMC-4630 in combination with sotorasib in second-line treatment of various KRAS G12C tumors in the US CodeBreaK 101-C study, and recently announced it has submitted initial data from this study to a medical congress for late summer. Revolution Medicines' clinical study, called RMC-4630-03, is progressing and continues to enroll.

First RMC for six <unk> is a potent oral small molecule.

That is designed to selectively inhibits the activity of ship to an upstream cellular protein that plays a central role in modulating cell survival and growth by facilitating Ras pathway signaling.

Amgen continues its initial evaluation of dosing RMC for <unk> in combination with <unk> in second line treatment of various <unk> <unk> tumors in the U S code break 101 C study and recently announced that is submitted initial data from this study to a medical Congress for late summer.

Revolution medicines clinical study called RMC 463, or three is progressing and continues to enroll.

Mark A. Goldsmith: This is a global phase 2 study of RMC-4630 in combination with sotorasib in patients with advanced non-small cell lung cancer with a KRAS G12C mutation who have failed prior standard therapy and who have not been previously treated with a RAS(ON) inhibitor. We are on track to enroll the study fully this year and have sufficient data by the end of the year to share some of the high level findings. Slide 29. Second, RMC-6236, the exciting RAS(ON) multi-on inhibitor I described earlier, is notable within our broad RAS(ON) inhibitor portfolio because it, in particular, has the potential to be deployed as a RAS(ON) companion inhibitor as well as a primary cancer driver targeted agent.

Mark Goldsmith: This is a global phase 2 study of RMC-4630 in combination with sotorasib in patients with advanced non-small cell lung cancer with a KRAS G12C mutation who have failed prior standard therapy and who have not been previously treated with a RAS(ON) inhibitor. We are on track to enroll the study fully this year and have sufficient data by the end of the year to share some of the high level findings. Slide 29. Second, RMC-6236, the exciting RAS(ON) multi-on inhibitor I described earlier, is notable within our broad RAS(ON) inhibitor portfolio because it, in particular, has the potential to be deployed as a RAS(ON) companion inhibitor as well as a primary cancer driver targeted agent.

This is a global phase II study of RMC for <unk> in combination with <unk> in patients with advanced non small cell lung cancer with a <unk> mutation, who have failed prior standard therapy, and who have not been previously treated with <unk> inhibitor with a <unk> inhibitor.

We are on track to enroll the study fully this year and have sufficient data by the end of the year to share some of the high level findings.

Slide 29.

Second RMC 63, six the exciting RASK multi on inhibitor I described earlier is notable within our broad rason inhibitor portfolio because it in particular has the potential to be deployed as a Ras companion inhibitor as well as a primary cancer drive that drive our targeted agents.

Mark A. Goldsmith: In some clinical contexts, patients may gain maximal clinical benefit from the broad activity of this RAS(ON) multi-selective inhibitor in combination with the deep and sustained target coverage provided by a mutant-selective RAS(ON) inhibitor such as RMC-6291. Slide 30. At the AACR meeting, we reported that RMC-6236 in combination with RMC-6291 demonstrated enhanced antitumor activity in KRAS G12C non-small cell lung cancer and colorectal cancer models that are relatively resistant to single agent treatments. An example shown on this slide, CRC-022 is one such KRAS G12C colorectal cancer model in which either the G12C(ON) inhibitor RMC-6291 or the RAS(ON) multi-selective inhibitor RMC-6236 as a single agent slows tumor growth but fails to induce tumor regressions. In contrast, combining these two agents converts the impact into significant tumor regression. Slide 32.

Mark Goldsmith: In some clinical contexts, patients may gain maximal clinical benefit from the broad activity of this RAS(ON) multi-selective inhibitor in combination with the deep and sustained target coverage provided by a mutant-selective RAS(ON) inhibitor such as RMC-6291. Slide 30. At the AACR meeting, we reported that RMC-6236 in combination with RMC-6291 demonstrated enhanced antitumor activity in KRAS G12C non-small cell lung cancer and colorectal cancer models that are relatively resistant to single agent treatments. An example shown on this slide, CRC-022 is one such KRAS G12C colorectal cancer model in which either the G12C(ON) inhibitor RMC-6291 or the RAS(ON) multi-selective inhibitor RMC-6236 as a single agent slows tumor growth but fails to induce tumor regressions. In contrast, combining these two agents converts the impact into significant tumor regression. Slide 32.

And some clinical context patients may gain maximal clinical benefit from the broad activity of this rash multi <unk> inhibitor in combination with the deep and sustained target coverage provided by a mutant selective <unk> inhibitor, such as RMC 69, one.

Slide 30 at the ACR meeting, we reported that RMC 63, six in combination with RMC 69, one demonstrated enhanced antitumor activity and K Ras <unk> 12, <unk> non small cell lung cancer and colorectal cancer cancer models.

That are relatively resistant to single agent treatments in.

An example shown on this slide CRC <unk> is one such <unk> 12, see colorectal cancer model in which either the <unk> on inhibitor RMC 69, one for the RASK multi on inhibitor RMC 63, 6% as a single agent.

Slows tumor growth, but fails to induce.

Tumor regressions.

In contrast, combining these two agents convert the impact into significant tumor regression.

Slide 32.

Mark A. Goldsmith: Lastly, RMC-5552 continues to advance. This drug candidate is a potent first-in-class bi-steric mTORC1-selective inhibitor designed to suppress phosphorylation and inactivation of 4EBP1 for cancers with hyperactive mTORC1 signaling, including certain RAS-addicted cancers. We aim to combine RMC-5552 with RAS(ON) inhibitors in patients with cancers harboring RAS and mTOR pathway co-mutations. We are making progress in our ongoing phase 1/1b clinical trial evaluating RMC-5552 as a monotherapy and are now focused on dose optimization in preparation for combinations with RAS(ON) inhibitors. Slide 11. Our third theme is unlocking the antitumor immune response by targeting RAS cancer drivers within tumors.

Mark Goldsmith: Lastly, RMC-5552 continues to advance. This drug candidate is a potent first-in-class bi-steric mTORC1-selective inhibitor designed to suppress phosphorylation and inactivation of 4EBP1 for cancers with hyperactive mTORC1 signaling, including certain RAS-addicted cancers. We aim to combine RMC-5552 with RAS(ON) inhibitors in patients with cancers harboring RAS and mTOR pathway co-mutations. We are making progress in our ongoing phase 1/1b clinical trial evaluating RMC-5552 as a monotherapy and are now focused on dose optimization in preparation for combinations with RAS(ON) inhibitors. Slide 11. Our third theme is unlocking the antitumor immune response by targeting RAS cancer drivers within tumors.

Lastly, RMC 55, two continues to advance this drug candidate is a potent first in class <unk>, Eric <unk>, one selective inhibitor.

Designed to suppress phosphorylated <unk> and inactivation of for Edp, one for cancers with hyperactive <unk>, one signaling, including certain Ras addicted cancers.

We aim to combine RMC $5 55 to with Ras on inhibitors in patients with cancers, harboring Ras and <unk> pathway mutations.

We are making progress in our ongoing phase <unk> clinical trial.

<unk> RMC $5 55 to as a model therapy and are now focused on dose optimization and preparation for accommodations with rason inhibitors.

Slide 11.

Our third theme is unlocking the anti tumor immune response by targeting Ras cancer drivers within tumors.

Mark A. Goldsmith: We have seen examples, multiple examples in which RAS(ON) inhibitors as monotherapies reverse the immunosuppressive tumor microenvironment in RAS-driven cancer models and can unlock profound antitumor immunity when combined with immune system modulators such as PD-1 checkpoint inhibitors. In particular, both RMC-6236 and RMC-6291 alone can favorably transform the immune microenvironment in RAS tumors and are highly additive with a checkpoint inhibitor. RMC-6236 favorably transforms the tumor immune microenvironment by modulating both the adaptive and innate immune cells infiltrating these RAS-addicted tumors. These changes significantly increase the sensitivity of such tumors to immune checkpoint inhibitors. Hence, the combination of RMC-6236 with a checkpoint inhibitor causes profound, durable, and even complete antitumor responses in some preclinical models in mice with intact immune systems. Slide 16.

Mark Goldsmith: We have seen examples, multiple examples in which RAS(ON) inhibitors as monotherapies reverse the immunosuppressive tumor microenvironment in RAS-driven cancer models and can unlock profound antitumor immunity when combined with immune system modulators such as PD-1 checkpoint inhibitors. In particular, both RMC-6236 and RMC-6291 alone can favorably transform the immune microenvironment in RAS tumors and are highly additive with a checkpoint inhibitor. RMC-6236 favorably transforms the tumor immune microenvironment by modulating both the adaptive and innate immune cells infiltrating these RAS-addicted tumors. These changes significantly increase the sensitivity of such tumors to immune checkpoint inhibitors. Hence, the combination of RMC-6236 with a checkpoint inhibitor causes profound, durable, and even complete antitumor responses in some preclinical models in mice with intact immune systems. Slide 16.

We've seen examples multiple examples in which rason inhibitors as mono therapies reverse the immune suppressive tumor microenvironment, and Ras driven cancer models and can unlock profound antitumor immunity when combined with immune system modulators, such as PD, one checkpoint inhibitors.

In particular, both RMC 63, six and RMC six to 91 alone.

Phone can favorably transform the immune microenvironment in RASK tumors.

And are highly additive with the checkpoint inhibitor.

RMC 63, six favorably transforms the tumor immune microenvironment by modulating, both the adaptive and innate immune cells infiltrating these rats addicted tumors.

These changes significantly increase the sensitivity of such tumors to immune checkpoint inhibitors, hence the combination of RMC six to $3 six with a checkpoint inhibitor causes profound durable and even complete antitumor responses in some preclinical models in mice with intact immune systems.

Slide 16.

Mark A. Goldsmith: RMC-6291 is able to modulate the immune microenvironment via tumor intrinsic effects that prime cancer cells for antitumor immunity in the presence of a checkpoint inhibitor. Here we show this combination is also able to drive complete responses in an immunogenic model of KRAS G12C cancer. In summary, these prepared comments have provided an update on our portfolio across three core themes that are important to our strategy. First, RAS(ON) inhibitors demonstrate compelling monotherapy antitumor activity in diverse preclinical models of genetically defined RAS cancers. Second, RAS(ON) inhibitors can be combined with RAS companion inhibitors to improve antitumor activity in preclinical models that are less sensitive to monotherapy. Third, RAS(ON) inhibitors as monotherapies reverse the immune suppressive tumor microenvironment in RAS-driven cancer models and can unlock profound antitumor immunity when combined with immune system modulators such as PD-1 checkpoint inhibitors.

Mark Goldsmith: RMC-6291 is able to modulate the immune microenvironment via tumor intrinsic effects that prime cancer cells for antitumor immunity in the presence of a checkpoint inhibitor. Here we show this combination is also able to drive complete responses in an immunogenic model of KRAS G12C cancer. In summary, these prepared comments have provided an update on our portfolio across three core themes that are important to our strategy. First, RAS(ON) inhibitors demonstrate compelling monotherapy antitumor activity in diverse preclinical models of genetically defined RAS cancers. Second, RAS(ON) inhibitors can be combined with RAS companion inhibitors to improve antitumor activity in preclinical models that are less sensitive to monotherapy. Third, RAS(ON) inhibitors as monotherapies reverse the immune suppressive tumor microenvironment in RAS-driven cancer models and can unlock profound antitumor immunity when combined with immune system modulators such as PD-1 checkpoint inhibitors.

RMC 69, one is able to modulate the immune microenvironment via tumor intrinsic effects.

Cancer cells for antitumor immunity in the presence of a checkpoint inhibitor.

Here. We show. This combination is also able to drive complete responses.

Genic model of <unk> cancer.

In summary, these prepared comments have provided an update on our portfolio across three core themes that are important to our strategy.

First rason inhibitors demonstrate compelling monotherapy antitumor activity and diverse preclinical models of genetically defined Ras cancers.

Ras on inhibitors can be combined with Ras companion inhibitors to improve antitumor activity in preclinical models that are less sensitive to mono therapy.

Mark A. Goldsmith: These concepts, in conjunction with preclinical data sets behind each of the development-stage assets in our R&D portfolio, underlie our belief that we may be able to serve significant unmet clinical needs for patients with a wide range of RAS-addicted cancers. I'll now turn to Jack Anders, our Senior Vice President of Finance, to report on our financial condition. Jack?

Mark Goldsmith: These concepts, in conjunction with preclinical data sets behind each of the development-stage assets in our R&D portfolio, underlie our belief that we may be able to serve significant unmet clinical needs for patients with a wide range of RAS-addicted cancers. I'll now turn to Jack Anders, our Senior Vice President of Finance, to report on our financial condition. Jack?

These concepts in conjunction with preclinical datasets behind each of the development stage assets in our R&D portfolio.

Underlie our belief that we may be able to serve significant unmet clinical needs for patients with a wide range of rasp addicted cancers.

I'll now turn to Jack Anders our senior Vice President of Finance to report on our financial condition Jack.

Jack Anders: Thank you, Mark. The details of our financial results are in our press release, so I'll focus on a few highlights as shown on slide 36. We ended the quarter with $519 million in cash and investments. Revenue from our collaboration agreement with Sanofi was $7.6 million in Q1 2022. The decrease in revenue from the prior year period was due to lower development cost reimbursement from Sanofi. Total operating expenses for Q1 2022 were $65.5 million and increased by 38% over the prior year period. The increase in operating expenses was largely due to R&D expenses associated with our preclinical portfolio and increased headcount. Net loss for Q1 2022 was $57.6 million or $0.78 per share.

Thank you Mark.

The details of our financial results are in our press release, So I'll focus on a few highlights as shown on slide 36.

We ended the quarter with $519 million in cash and investments.

Revenue from our collaboration agreement with Sanofi was $7 6 million in the first quarter of 2022.

The decrease in revenue from the prior year period was due to lower development cost reimbursements from Sanofi.

Total operating expenses for the first quarter of 2022 were $65 5 million and increased by 38% over the prior year period.

The increase in operating expenses was largely due to R&D expenses associated with our preclinical portfolio and increased head count.

Net loss for the first quarter of 2022, with $57 6 million or <unk> 78 per share.

Jack Anders: Our financial guidance for 2022 remains unchanged, and we continue to expect full year GAAP net loss to be between $260 and $290 million, which includes estimated non-cash stock-based compensation expense of between $35 and $40 million. With that, I'll now turn the call back over to Mark.

Our financial guidance for 2022 remains unchanged.

And we continue to expect full year GAAP net loss to be between 260 and $290 million.

Which includes estimated noncash.

Stock based compensation expense.

<unk> $35 million to $40 million.

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

Mark A. Goldsmith: I'm proud of the continued, excellent execution by our R&D team with support by our broader organization and many partners and collaborators. We expect to have two RAS(ON) inhibitors in the clinic this year and to advance two additional RAS(ON) programs subsequently. We're pursuing an exciting multi-part approach aiming to outsmart RAS-driven cancers, including both RAS(ON) inhibitors and RAS companion inhibitors. We believe that Revolution Medicines is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients, whose participation in our clinical studies is deeply appreciated. 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: I'm proud of the continued, excellent execution by our R&D team with support by our broader organization and many partners and collaborators. We expect to have two RAS(ON) inhibitors in the clinic this year and to advance two additional RAS(ON) programs subsequently. We're pursuing an exciting multi-part approach aiming to outsmart RAS-driven cancers, including both RAS(ON) inhibitors and RAS companion inhibitors. We believe that Revolution Medicines is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients, whose participation in our clinical studies is deeply appreciated. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session. Operator?

I am proud of the continued excellent execution by our R&D team with support by our broader organization and many partners and collaborators. We expect to have two rason inhibitors in the clinic this year and to advance two additional Ras on programs subsequently.

Assuming an exciting multi part approach aiming to outsmart, Ras driven cancers, including both rason inhibitors in Ras companion inhibitors.

We believe that Revolution medicines is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients.

Whose participation in our clinical studies is deeply appreciated.

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: Thank you. As a reminder, if you would like to ask a question, press the star then the one key on your touchtone telephone. Our first question comes from Marc Frahm with Cowen. Your line is open.

Thank you as a reminder, if you would like to ask a question press. The Star then the one key on your Touchtone telephone.

Our first question comes from Marc Frahm with Cowen Your line is open.

Marc Frahm: Thanks for taking my questions, and congrats on all the progress and starting to get the INDs filed. Maybe just starting with RMC-6236 and RMC-6291, Mark, if you could describe just kind of what you've submitted, in terms of starting dose and, you know, how close is that to what you think might be the active range if the preclinical modeling on exposures is correct. You know, within RMC-6236, how might that dose differ kind of based on the underlying RAS alteration?

Thanks for taking my questions and congrats on all the progress and getting starting to get the IND filed.

Maybe just starting with 63, 6% and 60 91.

Mark if you could describe it.

What you've submitted.

In terms of starting dose and how close is that to what you think might be the active range.

Preclinical modeling on exposures is correct.

Within 63, six how might that dose differ based on the underlying Ras alteration.

Mark A. Goldsmith: Hi, Mark. Thanks for your questions. You know, I think with regard to the specifics of starting dose, I don't think that's something that we'll be disclosing today. I will say for RMC-6236, obviously, given that it is a RAS multi inhibitor and we know at some point it will have effects on normal tissues, we certainly are starting on the lower end to make sure that we creep up on the optimal dosing. Beyond that, I don't really have anything more specific to say today. With regard to whether the dosing will differ across different mutants, maybe I can ask Steve Kelsey, our president of R&D, to comment on that question.

Mark Goldsmith: Hi, Mark. Thanks for your questions. You know, I think with regard to the specifics of starting dose, I don't think that's something that we'll be disclosing today. I will say for RMC-6236, obviously, given that it is a RAS multi inhibitor and we know at some point it will have effects on normal tissues, we certainly are starting on the lower end to make sure that we creep up on the optimal dosing. Beyond that, I don't really have anything more specific to say today. With regard to whether the dosing will differ across different mutants, maybe I can ask Steve Kelsey, our president of R&D, to comment on that question.

Hi, Mark Thanks for your questions.

I think with regard to the specifics so starting dose I don't think thats something.

We'll be disclosing today.

I will say pharmacy 63 six.

And given that it is a vast multi inhibitor.

And so at some point it will have effects on normal tissues. We certainly are starting on lower end to make sure that we pick up on the optimal.

Dosing, but beyond that I don't know.

More specific to say today with regard to.

Whether the dosing will differ across different.

Maybe I can ask Steve healthy our president of R&D.

On that question.

Steve Kelsey: I think it's highly unlikely, and that's certainly not the intent. I don't think there's any, at this stage, any rationale or preclinical justification for believing that the dosing schedule would be different for any given histotype or any given genotype, particularly as a single agent. I think where the dosing of RMC-6236 may alter going down the track is if it's given in combination with something, then that might require some form of adjustment either to the dose or schedule or both. But as a single agent inhibitor of RAS(ON) mutations, I don't think so. I think that we're going to explore the optimum dosing schedule for mutant RAS, and that will be it.

Thank you.

Sorry about that I think it's highly unlikely.

No.

We intend.

Is that at this stage any.

Shallow hole preclinical justification for Felicia.

Can you just confirm it isn't just a typo.

And again genotype cyclicality.

I think.

What doses at RMC 63 six.

Very helpful.

Subtract <unk> <unk> combination.

Mike caused some suggestions to the cloud.

Thank you.

As a single agent.

So the vast mutations.

Thanks.

Turning to explore the optimal dosing schedule for <unk>.

Last but not yet.

Marc Frahm: Okay, thanks. Just brought up combos and, you know, that's obviously part of the longer-term strategy here. I guess what do you need to see to start opening up those combos? Is it just safety at reasonable exposures and go straight into combos? Do you wanna see clinical activity? Do you wanna see recommended Phase 2 dose and schedule for these agents? Just when do you open up that part of the program?

Okay. Thanks, and then just brought up combo thing, that's obviously part of the longer term strategy here I guess.

What do you need to see to start opening up those.

<unk> is it just safety at reasonable exposures and go straight into combos do you want to see clinical activity do you want to see recommended phase II dosing schedule for these agents just when do you open up that that part of the program.

Mark A. Goldsmith: Mark, is that specifically regarding RMC-6236 and using it as a combination agent, or are you asking about a mutant-selective inhibitor like RMC-6291, and when you would begin adding a RAS companion inhibitor to it?

Mark Goldsmith: Mark, is that specifically regarding RMC-6236 and using it as a combination agent, or are you asking about a mutant-selective inhibitor like RMC-6291, and when you would begin adding a RAS companion inhibitor to it?

And Mark is that specifically regarding RMC 66, and using it as a combination agent why are you asking about.

Immune suppressive behavior like RMC 69, one.

Just add again, adding a ras companion.

Yes.

Marc Frahm: Either. You can answer either of them.

Hi.

If either of them.

Mark A. Goldsmith: Okay.

Mark Goldsmith: Okay.

Okay.

Steve Kelsey: Right now, the strategy for RMC-6291 is to really start combinations as soon as we possibly can, and the minimum amount of information we need is preliminary tolerability data. We also need to make sure that we've got the schedule right. It's not immediately obvious that a once daily schedule is right for any given RAS inhibitor, as I think has been illustrated admirably in the debate between sotorasib and adagrasib. We need to make sure that we know the PK, and we need to make sure that our schedule is right. Then I think we can start combinations with RMC-6291. Combining it with RMC-6236 is pretty high on the agenda right now, given what we know about the mechanisms of escape from adagrasib and sotorasib.

Yes.

Right now.

So is the strategy for Cc 91.

All combinations as soon as we possibly can.

And on the line to the information we need.

Is some we need preliminary Tolerability study you also need to make sure that we thought was scheduled runs.

Install.

It's not immediately obvious for walnuts schedules right for any given last one with the whole thing.

As seen in the <unk>.

They did absolutely into the.

Given the fact that we need to make sure we know the PPA and we need to make sure that our schedule is.

Right and then I think we can start combinations.

Nine one combined with RMB 63, six is pretty high on the agenda.

What we know about the mechanisms of the state.

Steve Kelsey: That partly answers your question about RMC-6236 combinations as well. With regards to using RMC-6236 as a RAS mutant inhibitor in combinations with that. That may not be quite as early on in the program with regards to other inhibitors. I think firstly, when we're looking at combining with other agents that have some form of single agent toxicity profile themselves, we need to understand a little bit more about the toxicity profile of RMC-6236 before we start combinations. That may take a little bit longer, but I don't see any real barrier to starting combinations of RMC-6236 with the mutant-selective RAS inhibitor RMC-6291 as soon as we possibly can.

Jason This is Paul.

Partly answers your question about RMB 63 seats combinations as well.

With regards to using RMC 63, six as a rash.

So in combination with that.

That may not be.

Quite early on in the program with regards to other inhibitors.

Firstly, when we're looking at.

Combining with other agents that have some form of single agent toxicity profile themselves, we need to understand a little bit more about the toxicity profile.

So combinations.

So that may take a little bit longer, but I don't see any.

Real barriers starting from combinations of RMB six two to six with them since.

Since last fall.

One one as soon as we possibly can.

Marc Frahm: Okay, thanks. Very helpful.

Great. Thanks very helpful.

Mark A. Goldsmith: Mark, if I could add a conceptual, sort of another layer on it that would match up with Steve's comments. Obviously RMC-6291's entering a more crowded space where there are multiple other KRAS G12C inhibitors, and we've indicated that our goal is to differentiate it from those others. It makes sense for us early in that program to begin including the best combination agents that make the most sense to us based on preclinical work and mechanistic understanding. In contrast, RMC-6236 of course is being tested in complete white space in diseases for which there are no targeted therapies available, no RAS-directed targeted therapies for sure. There, we're looking to figure out what's the optimal use of RMC-6236 and what's the best kind of antitumor activity we can obtain.

Mark Goldsmith: Mark, if I could add a conceptual, sort of another layer on it that would match up with Steve's comments. Obviously RMC-6291's entering a more crowded space where there are multiple other KRAS G12C inhibitors, and we've indicated that our goal is to differentiate it from those others. It makes sense for us early in that program to begin including the best combination agents that make the most sense to us based on preclinical work and mechanistic understanding. In contrast, RMC-6236 of course is being tested in complete white space in diseases for which there are no targeted therapies available, no RAS-directed targeted therapies for sure. There, we're looking to figure out what's the optimal use of RMC-6236 and what's the best kind of antitumor activity we can obtain.

At a conceptual sort.

Nothing wrong with that.

With these comments.

Obviously, obviously 69, one is entering a more crowded space.

There are multiple other hey, RFC closely inhibitors, and we indicated that our goal is to differentiate it from most others and so it makes sense for us early in that program to begin including the best combination agents that make the most sense to us based on preclinical work mechanistic understanding.

Contracts RMC 63, six of course is being tested in complete white space.

Diseases for which there are no targeted therapies.

<unk>, the last direct and targeted therapies for sure and so there we're looking to figure out what's the optimal use of honestly 63, six and what's the best kind of activity we can.

Mark A. Goldsmith: Maybe a related concept obviously is that RMC-6236 is sort of a RAS companion inhibitor built into a RAS direct inhibitor. It has the ability not only to target the mutant driver, let's say KRAS G12D or G12E or G12R, but also other companion signaling activities that can support those primary drivers. It's a multi-component in one. The urgency around getting into combinations with it is not nearly as high.

And maybe a related concept, obviously is that pharmacy 63, yes.

Mark Goldsmith: Maybe a related concept obviously is that RMC-6236 is sort of a RAS companion inhibitor built into a RAS direct inhibitor. It has the ability not only to target the mutant driver, let's say KRAS G12D or G12E or G12R, but also other companion signaling activities that can support those primary drivers. It's a multi-component in one. The urgency around getting into combinations with it is not nearly as high.

It's sort of a SaaS companion inhibitor built into our vast directly into their it has the ability not only to target the driver, let's say congrats jacoby of <unk> 12.

And <unk>, but also other companion signalling activities.

That can support those primary drivers and so it's.

Multi component one so the urgency around getting the combinations with <unk>.

It's not as high.

Marc Frahm: Okay, thank you.

Okay. Thank you.

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

Thank you. Our next question comes from Michael Smith with Guggenheim. Your line is open.

Michael Schmidt: Hey, guys. Thanks for taking my questions. Maybe just a couple of questions, maybe sort of following up on the comments from just now. I guess on RMC-6291, you know, in terms of the longer-term development strategy and the regulatory path, do you view it as a monotherapy player? And if so, I guess would that need to be in a sotorasib refractory patient population? Or is it mainly viewed as a combination strategy that would, you know, sort of differentiate the drug from others?

Hey, guys. Thanks for taking my questions, maybe just a couple of ones maybe sort of following up on that comment from just now I guess on 69 one.

In terms of the longer term development strategy and regulatory path.

Is there do you view it as a mono therapy player and if so I guess would that need to be in a.

Total Ras Ed.

<unk> III patient population or is it mainly viewed as a combination strategy that what sort of differentiate.

Derived from others.

Mark A. Goldsmith: I think Steve and I probably both have some things to say about that. Why don't we start with the expert, Steve?

Mark Goldsmith: I think Steve and I probably both have some things to say about that. Why don't we start with the expert, Steve?

Thanks, Steven I, probably got to have some things to say about that so we start with the extra week.

Okay.

Steve Kelsey: Yeah, I think that, you know, the approval of sotorasib has basically divided the non-small cell lung cancer space into patients who get treated before sotorasib and patients who get treated in that second-line space, and then people who get salvage after it's failed. I think that's the most easy conceptual way of thinking about it. I'm deliberately using non-small cell lung cancer as the, probably the best example to answer your bigger question. There is an opportunity essentially to use RMC-6291 as a single agent in the salvage space. It's not our primary strategy for RMC-6291, but there are some mechanistic bases for believing that it would work there in some patients that do fail on sotorasib.

Yes, let's try to I think.

So for US this is basically divided into non small cell lung cancer.

Okay.

Et cetera.

And the second line space and I'm thinking I guess.

<unk> offers the same I think.

Most easy conceptual way of.

Thinking about it.

Deliberately used in non small cell lung cancer is probably the best example.

Hey, good question so.

If we don't get there is an opportunity essentially to us honestly.

As a single agent in salvage space, it's not our it's.

No.

Yes.

Our primary strategy to 69 one.

There are some mechanistic so you've seen stability.

Sure.

And some patients who fail on sort of asset.

Steve Kelsey: Having said that, probably the best way of approaching those patients is with some sort of combination that involves a KRAS G12C inhibitor, and we would obviously prefer that G12C inhibitor to be RMC-6291 in combination with something else that's suppressing the known escape mutations, of which I think RMC-6236 is probably a good candidate. The most obvious place where you could develop RMC-6291 as a single agent is if it's demonstrably superior to sotorasib in the patients who are currently getting sotorasib. I think that's an obvious opportunity for us.

Having said that well, but I believe the best way to approach those patients is with some sort of combination that involves.

Okay.

We prefer the pizza.

In combination with something else is suppressing the Netherlands state mutations of which I think 300.

Probably in.

Canada.

The most obvious place where you could well not one as a single agent is it is demonstrably superior so they're actually than the in the patients.

What kind of getting there, but I think that that's an obvious opportunity for us.

Steve Kelsey: If the data we've seen in the preclinical, what we call mouse clinical trial, if you like, plays out in the clinic, then there is obviously a huge opportunity there to get RMC-6291 approved as a single agent. It still doesn't mean it's the best treatment for patients. I think we still believe that the best treatment for patients is gonna be combining RMC-6291 with some form of companion inhibitor, whether that's RMC-4630 or RMC-6236 or RMC-5552 or something else. We just don't know right now.

So we've seen in the preclinical what.

What we call <unk> clinical trial.

And to some extent.

And there is obviously a huge opportunity to get <unk>.

To improve our presence as a single agent.

As a maintenance treatment.

Treatments to patients. So I think we still believe that the best treatment patients who is going to be combining six one with some form of companion, whether that's 43.

<unk> six <unk>.

Something else, we just don't know right now.

Steve Kelsey: I think where there's really probably not so much of an opportunity for a single agent RMC-6291 is in that first-line space where you're going up against chemotherapy plus pembrolizumab, and that's a pretty tough ask, to be honest with you, for any single agent, not the least, a single agent KRAS G12C inhibitor. That's probably an obligate combination play, I think, and probably an obligate combination play in combination with a checkpoint inhibitor, which going back to the previous caller's question, is a very high priority combination for us to test.

Well, there's really probably not so much of an opportunity for a single agency. Non one is in that first line, it's a place where you've done enough events chemotherapy plus <unk>.

<unk> talked all along in Sweden for any single region.

Not in the lease.

AC module cost in 14, so thats, probably an all present combination side.

I think probably a combination study in combination with <unk>.

Checkpoint inhibitors.

Back to the previous.

<unk> question is.

A very high priority for us to plan.

Michael Schmidt: Right. That makes sense. You know, on 6236, I guess, you know, so you're, you know, positioning it as a combination drug to some degree with something like 6291. I guess my question is, you know, what percent of... what percentage of patients that are treated with a G12C selective inhibitor would, I guess, benefit from the multi inhibitor addition? You know, if you think about resistance mechanisms and how that combination, you know, compare to something like a SHP2 inhibitor combination, for example?

Alright that makes sense.

162.

I guess so.

Your.

Positioning it as a combination.

To some degree with Lyft something like $6 91, and then I guess my question is.

What percentage what percentage of patients that are treated with a.

<unk> selective inhibitor, what would I guess benefit from that the multi inhibitor edition.

About resistance mechanisms.

How would that combination.

You know compare to something like <unk> two inhibitor combination for example.

Mark A. Goldsmith: Okay. Well, there are a lot of layers to that. Michael, good comment questions. Maybe go back to something Steve said. I just want to emphasize that the preclinical data with RMC-6291 suggests that it alone is superior in a head-to-head comparison with a KRAS G12C off inhibitor in lung cancer models carrying KRAS G12C. That is part of our hypothesis going into the clinic, that that's what we'll see as well in the clinic. Whether that translates into a registration path or not, Steve got into some of the nuances in second line versus first line. But that, Steve, I think, said something that's really worth emphasizing.

Mark Goldsmith: Okay. Well, there are a lot of layers to that. Michael, good comment questions. Maybe go back to something Steve said. I just want to emphasize that the preclinical data with RMC-6291 suggests that it alone is superior in a head-to-head comparison with a KRAS G12C off inhibitor in lung cancer models carrying KRAS G12C. That is part of our hypothesis going into the clinic, that that's what we'll see as well in the clinic. Whether that translates into a registration path or not, Steve got into some of the nuances in second line versus first line. But that, Steve, I think, said something that's really worth emphasizing.

Okay, well there are a lot of layers to that.

Michael Good question.

Questions.

Can you go back to something you said I just want to emphasize that.

The preclinical data.

<unk> suggested alone is superior in the head to head comparison.

Lets say theoretically hopefully off inhibitor Ian.

In lung cancer model, they're actually closely so that's all.

That is part of our hypothesis going into play because.

Thats, what we will see as well in the clinic.

And whether that translates into a registration pathway not so you got into some of the nuances and second one versus first line.

Steve I think you said something that's really worth emphasizing that is not the same thing as saying that that's necessarily the best way and most durable way.

Mark A. Goldsmith: That's not the same thing as saying that that's necessarily the best way and most durable way to treat a patient. We know that RAS pathway-driven cancers are extremely resilient. As you know, we've said this now for several years. It's really important to address those resiliency pathways, those pathways of persistence, and ultimately those will require combinations. The answer isn't cleanly, yes, we're only interested in monotherapy or no, we're only interested in combinations. It's both. We first have to see a bit about its monotherapy profile in the clinic, and then we'll begin pursuing the combinations. The combinations may differ depending on context, as you just asked. The question that I think you asked and I haven't addressed is RMC-6236 a better RAS companion than RMC-4630 or SHP2 inhibitor?

Mark Goldsmith: That's not the same thing as saying that that's necessarily the best way and most durable way to treat a patient. We know that RAS pathway-driven cancers are extremely resilient. As you know, we've said this now for several years. It's really important to address those resiliency pathways, those pathways of persistence, and ultimately those will require combinations. The answer isn't cleanly, yes, we're only interested in monotherapy or no, we're only interested in combinations. It's both. We first have to see a bit about its monotherapy profile in the clinic, and then we'll begin pursuing the combinations. The combinations may differ depending on context, as you just asked. The question that I think you asked and I haven't addressed is RMC-6236 a better RAS companion than RMC-4630 or SHP2 inhibitor?

We are patient and we know that rats.

Halfway driven cancers are extremely resilient.

And as you know we've said this now for several years, it's really important to address the resiliency pathways.

Pathways of persistence.

Ultimately those will require a combination so the answer is it cleanly.

We're only interested in monotherapy.

No. We're only interested in the combination is both and we first start to see a bit about monotherapy profile in the clinic and then will begin pursuing the combination.

Nations may differ depending on the context as you just asked.

Yes.

The question.

I think you asked and I Havent addresses is honestly 60, 360, <unk> better Raskin Canyon.

Then pharmacy for <unk>, we shipped two inhibitor.

Mark A. Goldsmith: I wanna say something about that, and then I wanna ask Steve to comment on it. Something I wanna say first is we think of RMC-6236 first as an inhibitor of a driver of cancers that are not currently served by KRAS G12C inhibitors. Our first goal is to get it into the clinic and see what it does in monotherapy for KRAS G12V, KRAS G12D, KRAS G12R, et cetera. We're still excited about that. We did introduce this second idea that has occurred to a number of people, including us, that there may be benefit in adding it to regimens that are anchored in a RAS mutant selective inhibitor like RMC-6291. We think that's a parallel path to pursue. These really aren't competing with each other. They're the two somewhat independent hypotheses.

Yes.

Mark Goldsmith: I wanna say something about that, and then I wanna ask Steve to comment on it. Something I wanna say first is we think of RMC-6236 first as an inhibitor of a driver of cancers that are not currently served by KRAS G12C inhibitors. Our first goal is to get it into the clinic and see what it does in monotherapy for KRAS G12V, KRAS G12D, KRAS G12R, et cetera. We're still excited about that. We did introduce this second idea that has occurred to a number of people, including us, that there may be benefit in adding it to regimens that are anchored in a RAS mutant selective inhibitor like RMC-6291. We think that's a parallel path to pursue. These really aren't competing with each other. They're the two somewhat independent hypotheses.

I want to say something about that and then I want to ask Keith to comment on is that something I want to say first is.

We think of RMC 63, six first.

As an inhibitor of the driver of cancers that are not currently serve Nike closely inhibitors. So our first goal again in the clinic and see what it does in monotherapy for <unk> 12, or so and we're still excited about that but we did introduce the second idea.

That is according to a number of people, including us that there may be benefit in adding it to regimens that are.

Anchor in a Ras mutant selected in their lifetime.

And we think that's a parallel path to pursue these really arent competing with each other there too.

Some of them kind of hypothesis.

Mark A. Goldsmith: With that in mind, then that's sort of teeing up for Dr. Kelsey to comment on RMC-6236 versus RMC-4630 as a companion agent.

Mark Goldsmith: With that in mind, then that's sort of teeing up for Dr. Kelsey to comment on RMC-6236 versus RMC-4630 as a companion agent.

So with that in mind that for US. It's also just comment on pharmacy 66 versus RMC four six.

Companion.

Steve Kelsey: I think the answer, the honest answer to your question, is that right now we don't know. There's very good biological rationale and preclinical data to support the use of either of them as a companion for a RAS mutant selective inhibitor that inhibits KRAS G12C. I think we are not going to get any further down that road by doing more preclinical studies. I think this is gonna be something that has to be tested in the clinic, and we will, and we will see in due course which one of them is most appropriate in which circumstance. Don't forget, there are at least three populations of patients with KRAS G12C mutations that are significant, that occur with significant frequency to create an unmet medical need.

Okay.

So it would be all installed.

Right now we don't know.

Sure.

There's very good biological rationale and preclinical data.

You survive with them as a companion for.

Rasp inhibitor.

Davidson.

Okay. That's helpful.

<unk>.

And I think we knock that down any further than that.

Doing more preclinical studies I think this is going to be something has to be tested.

And we will see in due course with one of them is most appropriate.

And which circumstance that thereof.

There are at least three populations of patients with <unk>.

Hey, Ross G towards seeing mutations that are significant.

Significant frequency too great.

And then medical need.

Steve Kelsey: I mean, the patients with lung cancer, colon cancer, and then other, which includes pancreatic cancer. The answer may be different for each of those three groups. If you go back to my sort of lung cancer division again, I mean, the answer may be different depending on whether you're looking at first line, second line, or third line, and whether the patient has or hasn't previously had the KRAS G12C inhibitors. I think we're just gonna have to do the clinical experiment and figure it out. We, you know, we're privileged to have the wealth of companion inhibitors that we have, and hopefully we will figure out how best to use them for the treatment of any given group or hopefully an individual patient.

Patients with lung cancer colon cancer, and then other which includes <unk>.

And may be different for each of those three groups.

If you go back to <unk>, So a long time, so division again.

So may be different depending on whether you're looking at first line second line third line and whether the patient has or hasnt seem to do.

Do you still see also inhibitor. So I think we're just going to have to say that sounds good.

Thank you Eric.

We're privileged to have the world.

A companion inhibitors.

And hopefully we will figure out how best to use them for.

Treatment plenty, given Grupo Hudson individual pricing.

Mark A. Goldsmith: I'm sure we've simplified that for you, Michael, now.

Mark Goldsmith: I'm sure we've simplified that for you, Michael, now.

Im sure we simplify that for you Michael.

Michael Schmidt: Yeah, thanks. Too many drugs, I guess. Thanks for the question.

Yes. Thanks.

Congrats I guess, thanks for the question.

Operator: Thank you. Our next question comes from Chris Santone with Goldman Sachs. Your line is open.

Thank you. Our next question comes from Christopher <unk> with Goldman Sachs. Your line is open.

Chris Santone: Thank you. Good evening, and thanks for taking the question. Wanted to talk a little bit more about RMC-4630. We have a couple datasets coming up, H2. The two studies were kind of set up because of limitations in the CodeBreaK study in terms of being able to come up with a strong answer for what we can see with SHP2 inhibition in lung cancer. I was wondering what you hope we should all learn with the Amgen update towards the late summer, and how might that augment the plans for the next step with RMC-4630?

Chris Zap: Thank you. Good evening, and thanks for taking the question. Wanted to talk a little bit more about RMC-4630. We have a couple datasets coming up, H2. The two studies were kind of set up because of limitations in the CodeBreaK study in terms of being able to come up with a strong answer for what we can see with SHP2 inhibition in lung cancer. I was wondering what you hope we should all learn with the Amgen update towards the late summer, and how might that augment the plans for the next step with RMC-4630?

Thank you good morning.

Good evening and thanks for taking the question.

I wanted to talk a little bit more about 46% or do you have a couple of datasets coming out.

Second half of the year.

Okay.

Two studies, we're kind of set up because of limitations in the code break study in terms of being able to cope with the strong answer for.

What we can see with ship two inhibition in lung cancer.

So I was wondering what do you hope we should we should all learn with the Amgen update.

Towards the late summer and how might that augment the plans for the next step with 46 30.

Chris Santone: Would the next steps kind of become clear with that data and combining that with what you'll show from the O3 study later this year? Or will the next kind of stage of development become clear more next year after the second update? Thanks.

Chris Zap: Would the next steps kind of become clear with that data and combining that with what you'll show from the O3 study later this year? Or will the next kind of stage of development become clear more next year after the second update? Thanks.

The next step is going to become clear with that data and combining that with.

Youll show from the <unk> III study later, this year or where the next kind of stage of development become clear more next year. After the second update thanks.

Mark A. Goldsmith: Hi, CJ. Thanks for your question. Yeah, I think with regard to anticipating what Amgen will or will not show this summer, we can't really comment on that, of course. They're the sponsor of the study, and they'll present what they present. I think it'd be easier to discuss that after they've presented something; we can discuss what the implications of that would be. With regard to the first part of your question, though, which is relating the CodeBreaK study to the O3 study, they really are complementary, and to some degree overlapping. Amgen had a head start with the CodeBreaK study.

Mark Goldsmith: Hi, CJ. Thanks for your question. Yeah, I think with regard to anticipating what Amgen will or will not show this summer, we can't really comment on that, of course. They're the sponsor of the study, and they'll present what they present. I think it'd be easier to discuss that after they've presented something; we can discuss what the implications of that would be. With regard to the first part of your question, though, which is relating the CodeBreaK study to the O3 study, they really are complementary, and to some degree overlapping. Amgen had a head start with the CodeBreaK study.

Hi, P. J. Thanks for your question.

Yes.

I think with regard to anticipating what Amgen will or will not show. This summer we can't really comment on that.

Of course, there are the sponsor of the study.

The present, what they present, so I think it would be easier to discuss that.

After they presented something we can discuss what the implications of that would be.

With regard to the first part of your question, though which is.

Relating the perfect study to the <unk> study they really are complementary.

And to some degree overlapping.

Amgen had a head start with the cobalt study we expect collaboration.

Mark A. Goldsmith: We entered that collaboration, you know, a few years ago, and they've had an opportunity to really learn a lot about dosing, tolerability, and safety, and then to expose patients with various histotypes to RMC-4630 and look for antitumor activity. They'll report about those things when they do. We've built on that by creating a dedicated single histotype study, the lung cancer, non-small cell lung cancer study, and used the opportunity in a dedicated study to create boundaries for several different cohorts within that, as you know, specifically to help us understand the sensitivity of those tumors with only a KRAS G12C mutation driver and not concurrent mutations elsewhere, versus those that carry co-mutations in RAS and RAS-related signaling.

Mark Goldsmith: We entered that collaboration, you know, a few years ago, and they've had an opportunity to really learn a lot about dosing, tolerability, and safety, and then to expose patients with various histotypes to RMC-4630 and look for antitumor activity. They'll report about those things when they do. We've built on that by creating a dedicated single histotype study, the lung cancer, non-small cell lung cancer study, and used the opportunity in a dedicated study to create boundaries for several different cohorts within that, as you know, specifically to help us understand the sensitivity of those tumors with only a KRAS G12C mutation driver and not concurrent mutations elsewhere, versus those that carry co-mutations in RAS and RAS-related signaling.

A few years ago, and they've had an opportunity to.

<unk> really learned a lot about dosing colored.

Tolerability and safety.

Then to expose patients with very assisted types.

Two RMC for <unk> and look for anti tumor activity report.

About those things.

When they do.

We've built on that by creating a dedicated single type study.

Cancer, non small cell lung cancer study.

The opportunity in a dedicated study.

To create.

Boundaries for several different cohorts within that as you know.

Specifically to help us understand.

The sensitivity of those tumors.

With.

Only at KFC, So we'll see.

Patient driver and not concurrent mutations elsewhere.

Versus those that carry <unk> mutations in Ras and Ras related signaling because we do know from the experience of the last couple of years now something we didn't know at the beginning of all this which is that at least for the <unk> inhibitors areas. There are some factors that can create.

Mark A. Goldsmith: Because we do know from the experience of the last couple of years now, something we didn't know at the beginning of all this, which is that at least for the KRAS G12C ON inhibitors, there are some factors that can create differential sensitivity. We needed to build that in, and this was an opportunity to do it since it was not preemptively built into the CodeBreaK study. As to how we'll use the results of these two studies, we'll look at them both in deciding what to do going forward. Our aim is to learn enough that we can design a compelling, credible phase 3 study, and we'll take information from either of those sources or both of those sources to help us make those decisions.

Mark Goldsmith: Because we do know from the experience of the last couple of years now, something we didn't know at the beginning of all this, which is that at least for the KRAS G12C ON inhibitors, there are some factors that can create differential sensitivity. We needed to build that in, and this was an opportunity to do it since it was not preemptively built into the CodeBreaK study. As to how we'll use the results of these two studies, we'll look at them both in deciding what to do going forward. Our aim is to learn enough that we can design a compelling, credible phase 3 study, and we'll take information from either of those sources or both of those sources to help us make those decisions.

Differential sensitivity and so we needed to build that in and this is an opportunity to do it since it does not preemptively built into the study.

And then as to how we will use the results of these two studies will look at them both.

And deciding what to do.

Going forward our aim.

Is to learn enough that we can design.

A compelling credible phase III study.

And we will take information from either of those sources of both of those sources.

Us.

A decision.

Chris Santone: Great. Thank you.

Chris Zap: Great. Thank you.

Thank you.

Operator: Our next question comes from Eric Joseph with J.P. Morgan. Your line is open.

Our next question comes from Eric Joseph with Jpmorgan. Your line is open.

[Analyst] (J.P. Morgan): This is Sean for Eric Joseph. Thanks for taking our question and, you know, congrats on the progress. So just coming back to the RMC-6236. We're wondering how we should be thinking about the patient demographics eligible for the phase 1 study, you know, by tumor or mutational backgrounds and histology and, you know, and perhaps PD-1 status. How broadly are you looking at the potential activity and pharmacodynamics in the phase 1 study, you know, on top of safety and PK? Thanks.

Oh, Hi, this is Sean.

[Analyst] (JPMorgan): This is Sean for Eric Joseph. Thanks for taking our question and, you know, congrats on the progress. So just coming back to the RMC-6236. We're wondering how we should be thinking about the patient demographics eligible for the phase 1 study, you know, by tumor or mutational backgrounds and histology and, you know, and perhaps PD-1 status. How broadly are you looking at the potential activity and pharmacodynamics in the phase 1 study, you know, on top of safety and PK? Thanks.

Eric Joseph Thanks for taking my question and congrats on the progress.

So just coming back to the rap alteon.

Thanks to series six.

Im wondering how we should be thinking about the patient demographics eligible for the phase one study by tomorrow mutational backgrounds and physiology.

Perhaps PD one status and how broadly are you looking at potential activity and pharmacodynamics in the phase one study on comparable safety and PK.

Thanks.

Mark A. Goldsmith: Thanks very much for your question. It's got a few layers to it. I think Dr. Kelsey can address how we're approaching bringing RMC-6236 into the clinic initially. What mechanisms we're using to be able to learn as much as possible, as quickly as possible about it.

Mark Goldsmith: Thanks very much for your question. It's got a few layers to it. I think Dr. Kelsey can address how we're approaching bringing RMC-6236 into the clinic initially. What mechanisms we're using to be able to learn as much as possible, as quickly as possible about it.

Thanks very much for your question, it's got a few layers to it I think Dr. Kelsey address.

The address how we are approaching bringing 66 into the clinic initially and what mechanisms, we're using to be able to.

Learn as much as possible as quickly as possible.

Steve Kelsey: Yes. The protocol really allows for any patient with advanced cancer who would be eligible for a phase I trial, who also has a mutation in KRAS at the KRAS G12 position. We expect the vast majority of those patients in the first instance, purely because of the, you know, the demographic distribution of those mutations, the majority are gonna have non-small cell lung cancer, pancreatic cancer or colorectal cancer. I think that's just the truth. These will be patients that by necessity, you know, by ethical necessity, have failed, you know, available therapies that are approved and available to them in the geographic location in which they reside.

Yes.

The protocol.

Full.

So.

We'll be eligible for.

A phase one trial, who also has a mutation in <unk>.

SG 12 position.

We expect the vast majority of those patients in their faces.

It tells us.

The distribution of those mutations the majority is going to have non small cell lung cancer.

So all correctly, so I think that's just.

That's just the truth at least will be patients by necessity by acetyl necessity.

<unk>.

Second of all therapies that are approved and available to them in the geographic.

The location in which they resolved so.

Steve Kelsey: I don't think there's anything terribly unusual about the patient population in the early stages of the program. Then of course, you know, as we start to see signals, it'll become a lot easier to refine the program or even open it up to other patients that were not included in the initial stages of the development. As we go, you know, that could include patients with other mutations that are not at the G12 position. It could include focusing on specific histotypes, or it could include of course, combinations as well, as we've already discussed.

I don't think there's anything terribly unusual.

Patient population.

The early stages of.

Of the program.

Yes.

Then of course as we start to see what we see as we start to see signals that it's become a lot easier to refine the program or even open it up to other patients.

While not included in the initial stages of the <unk>.

As we have done that will and that could include patients with other mutations.

<unk> positioned it could fit.

Putting include focusing on specific this is Todd.

Or it could.

<unk> combinations as well as we've already discussed.

Steve Kelsey: I hope, you know, we are very keen to give you the impression that within the initial stages of development of this compound, a lot of the general principles of oncology drug development will be brought to bear. That's partly because we want it like that, and it's partly because of the constraints that are placed upon us by, you know, testing a novel agent.

Yes.

We are very keen to give you the impression.

The initial stages of development of this compound.

A lot of the general principles loan calls you've got government will be when we grow up.

Partly because we want to buy that and that's partly because of the constraints.

The pharma side.

Type testing and diligence.

Yeah.

Mark A. Goldsmith: If I could add a couple of things that relate to disclosures we've made in the past. You know, as Steve said, there presumably are three major histotypes that will be represented simply because epidemiologically, those are the tumors that are largely represented. We focused on G12 mutations, what we've called for convenience, G12X, where X is any one of several different amino acid substitutions. Really only because in our mouse clinical trial, while we saw sensitivity across many different genotypes, we just saw greater sensitivity in those G12 X mutant-driven cancers. That's not to say that we're not interested in the other ones. It's just that we're elevating those as early as possible to try to help us get the signals as early as possible.

Mark Goldsmith: If I could add a couple of things that relate to disclosures we've made in the past. You know, as Steve said, there presumably are three major histotypes that will be represented simply because epidemiologically, those are the tumors that are largely represented. We focused on G12 mutations, what we've called for convenience, G12X, where X is any one of several different amino acid substitutions. Really only because in our mouse clinical trial, while we saw sensitivity across many different genotypes, we just saw greater sensitivity in those G12 X mutant-driven cancers. That's not to say that we're not interested in the other ones. It's just that we're elevating those as early as possible to try to help us get the signals as early as possible.

And if I could ask a couple of things that relate to the disclosures we've made in the past.

He said they are principally a free major hits the types that will be represented simply because that could be logically those consumers that are.

Largely represented we focused on <unk>.

<unk> mutations what we call for convenience <unk> X, where X is one of any one of the settlement.

Subscriptions.

Really only because in our mouse clinical trial.

While we thought asset sensitivity across many different genotypes, we just saw greater sensitivity and those June 12.

<unk> driven cancers, that's not to say that we're not interested in the other ones. Its just that were elevating those.

Is it really possible to try to help us get the signals as early as possible.

Mark A. Goldsmith: Once we see those signals, we have the opportunity, as Steve alluded to, either to broaden the criteria to bring in other genotypes and/or to focus further on places where we're seeing a signal, or both. We may do both broadening and focusing at the same time. The last comment I wanna make is to remind you that there is a backfill recruitment mechanism for filling the slots as we approach that allows us, as we're dose escalating, to expand in many below MTD expansions, so that we can increase the data sets. In those settings, in that context, we'll not only get more experience as we're dose escalating, but we also have the opportunity to sample diverse genotypes. A lot going on there.

Mark Goldsmith: Once we see those signals, we have the opportunity, as Steve alluded to, either to broaden the criteria to bring in other genotypes and/or to focus further on places where we're seeing a signal, or both. We may do both broadening and focusing at the same time. The last comment I wanna make is to remind you that there is a backfill recruitment mechanism for filling the slots as we approach that allows us, as we're dose escalating, to expand in many below MTD expansions, so that we can increase the data sets. In those settings, in that context, we'll not only get more experience as we're dose escalating, but we also have the opportunity to sample diverse genotypes. A lot going on there.

Once we see those signals, we have the opportunity as Steve alluded to.

Neither to broaden the criteria to bring in other genotypes and or.

To focus further on places, where we're seeing the signal where both we may do both broadening and focusing at the same time.

And the last comment I want to make is to remind you that there is a backfill.

Recruitment mechanism.

We're filling the slot approach that allows us as we're dose escalating to expand for many.

And many below MTV expansions, so that we can increase the datasets in those settings.

That context will not only get more.

As we're dose escalating, but we also have the opportunity to.

Yes.

Sample diverse diverse phenotypes so.

Mark A. Goldsmith: At the end of the day, we'd like to first demonstrate that it's a safe and useful, you know, agent. Second, identify who's most likely to benefit from it so we can further study them.

Mark Goldsmith: At the end of the day, we'd like to first demonstrate that it's a safe and useful, you know, agent. Second, identify who's most likely to benefit from it so we can further study them.

What's going on there, but at the end of the day, we would like to first demonstrate that it's safe and useful.

Sure.

Agents and second identify who's most likely to benefit from it. So we can further study.

Steve Kelsey: Yeah. Just to wrap up your question about, specifically about biomarkers, I think what we've tried to imply is that the majority of the focus, the biomarker-based focus of the program, is on patient selection. Also obviously we'll be monitoring things like circulating tumor DNA to look at mechanisms of escape. There's not a huge amount of effort going into looking at pharmacodynamic markers of drug activity or hitting the target. Because the vast majority of the preclinical data that we've generated with RMC-6236 suggests that if you hit the target, then the tumor will shrink. We're gonna be using...

Yes, and just to wrap up with a question specifically about pharma.

What we've tried to imply.

Yes.

Majority of the focus the biomarker based focus of the program is on patient selection.

And also obviously, we'll be monitoring things like simply been choosy NIH looked at mechanisms of escape.

Huge amount of effort going into looking at.

Pharmacodynamic markers of drug activity hitting solve because the vast majority of the preclinical data that we've generated with $63 six suggests.

The talk of it than the tumor will shrink.

We're using.

Steve Kelsey: I know that sounds a bit trite, but the reality is that we don't see an awful lot of value in figuring out whether or not we're inhibiting the RAS pathway with RMC-6236, because if we do it effectively, then we expect to see the tumor shrink. So the PD marker of choice is the efficacy marker of choice, which is the CT scanner. But that doesn't mean we haven't put a huge amount of energy and resource into looking at genomic basis of a priori sensitivity and the genomic basis of potential escape.

The other side of electronics.

The reality is that we don't see an awful lot of value in and figuring out whether I'm all in.

Liberty in the rack.

Powerfully with $63 six because if we could effectively then we expect to see the change so the PD marker choices the efficacy markers such as the <unk>.

But that doesn't mean, we haven't put a huge amount of energy and resource into.

Looking at genomic places.

Sensitivity in the genome replaces essentially.

Chris Santone: Great. Thanks for the comprehensive answer, and that's really helpful. Thanks.

Chris Zap: Great. Thanks for the comprehensive answer, and that's really helpful. Thanks.

Great Thanks for that.

Hence our friends right that's really helpful. Thanks.

Mark A. Goldsmith: Thank you. Our next question comes from Jonathan Chang with SVB Securities. Your line is open.

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

Thank you. Our next question comes from Jonathan Chang with SBB Securities. Your line is open.

[Analyst] (SVB Securities): Everyone, thanks for taking the questions. This is Faisal on for Jonathan. Wanted to ask about RMC-5552. We saw the title in the ASCO program. Wanted to see if you could help set expectations for that data update and what we might see relative to what you disclosed in January.

Hi, everyone. Thank you for taking the question just this vessel encore Jonathan I wanted to ask about RMC five clarify two we saw the title on the ESCO program I wanted to see if you could help set expectations for that data update in what we might see relative to what you disclosed in January .

Mark A. Goldsmith: Thanks for your question. I think Steve can comment on that.

Mark Goldsmith: Thanks for your question. I think Steve can comment on that.

Thanks for your question I think Steve can comment on that.

Steve Kelsey: We don't have a formal update on the RMC-5552 program as of yet. We've dosed 14 patients across 5 dose levels. We're still doing dose optimization to some extent, because we really do feel that we need to get the dose right for this at least the single agent expansion and then obviously at some point in combination with our RAS(ON) portfolio. All we can tell you is essentially what we previously reported, which is, you know, we clearly have an active drug at the dose of 6 milligrams weekly. It may be possible to dose it at a dose that's slightly higher than that, but certainly not as high as 12 milligrams weekly. The toxicity is mainly on target toxicity. In fact, almost exclusively on target toxicity.

We don't have a full update on the RMC.

Program.

As of yet.

We've dosed 14 patients across dose levels.

We're still doing it does help to monetization.

Some expense because we really didn't feel that we need to get the dose right for this.

At least.

Single agent expansion and then obviously at some point in combination with our rock solid.

Portfolio.

All we can tell you is essentially what we what we previously reported which is we clearly have an active drug at the dose of six milligrams weekly.

Possible to dose at a dose of slightly higher than that but certainly not as high as 12.

Milligrams weekly and the toxicity is mainly on pause it helps us in fact almost exclusively on target toxicity. So.

Steve Kelsey: You know, we're feeling pretty good about RMC-5552, and we almost certainly will have a further update for you at some point, but we don't have a huge amount of additional data to report right now.

Yes.

We're feeling pretty good about the five to.

Almost certainly will have a further update for you at some point.

We don't have a huge amount of additional data to report right now.

[Analyst] (SVB Securities): Great. Thanks for that. Slightly different question. Can you remind us what we know about potential CNS activity of the RAS(ON) inhibitors?

Great. Thanks for that and then.

It's slightly different question can you remind us what we know about potential CNS activity of the RAF inhibitors.

Mark A. Goldsmith: Yeah. We don't know a lot about it. It hasn't been a major area of focus. We do know that these compounds in general are beyond rule of five molecules, so they're rather large. The starting chemistry that we started with isn't intrinsically expected to deliver compounds that can cross the blood-brain barrier into tumor metastases. We haven't studied it extensively. Our focus right now is on systemic disease, where we feel both within the G12C space and the other mutant space, we still have a long way to go before we can declare victory in terms of systemic disease. We do acknowledge that CNS disease can be very important in some of these histotypes.

Mark Goldsmith: Yeah. We don't know a lot about it. It hasn't been a major area of focus. We do know that these compounds in general are beyond rule of five molecules, so they're rather large. The starting chemistry that we started with isn't intrinsically expected to deliver compounds that can cross the blood-brain barrier into tumor metastases. We haven't studied it extensively. Our focus right now is on systemic disease, where we feel both within the G12C space and the other mutant space, we still have a long way to go before we can declare victory in terms of systemic disease. We do acknowledge that CNS disease can be very important in some of these histotypes.

Yes, we don't know a lot about it hasnt been a major area of focus we do know that.

These compounds in general or beyond we'll have five molecules. So they are rather large.

Let's start with the chemistry that we started with isn't intrinsically.

Expected to deliver compounds that can cross the.

Great barrier into the tumor.

And metastases, but we havent studied it extensively our focus.

Now is on systemic disease, where we feel both within the <unk> space and other space.

Space, we still have a long way to go before we can declare victory.

In terms of systemic disease, but we do acknowledge that CNS diseases can be very important in some of these dissipates.

[Analyst] (SVB Securities): Got it. Thank you for taking our questions.

Got it thank you for taking our questions.

Mark A. Goldsmith: Thank you.

Mark Goldsmith: Thank you.

Thank you.

Operator: Thank you. Our final question comes from Benjamin Burnett with Stifel. Your line is open.

Thank you. Our final question comes from Ben Burnett with Stifel. Your line is open.

Yes.

Dane Leone: Yeah, good afternoon. This is Dane Leone on for Ben. Thanks for taking our questions. Novartis had a presentation at AACR, showing a response rate in lung cancer patients that was relatively in line with what we've seen for Lumakras and adagrasib. Can you talk about some of the preclinical metrics, maybe a bit beyond the mouse model data you've shown that suggest RMC-6291 will be improved relative to this mid-40s response rate we're seeing in lung cancer patients, once it reaches the clinic? Thanks.

Yes. Good afternoon. This is Neil Carnahan on for Ben Thanks for taking our questions.

Novartis has had a presentation at ACR showing a response rate in lung cancer patients.

Relatively in line with what we've seen for <unk> and <unk>.

Can you talk about some of the preclinical metrics.

Maybe a bit beyond the mouse model data you've shown that suggest 691 will be improved relative to this mid forties.

The response rate, we're seeing in lung cancer patients.

Once it reaches the clinic thanks.

Mark A. Goldsmith: Thanks for your question. Not sure I totally understand. I think you asked, do we have more preclinical data other than in mouse xenograft models? That's really the only setting in which we can do those sorts of studies. We primarily have looked at response rates in our public disclosures from those kinds of studies, but we also looked beyond. We provided data beyond response rates. We talked about both depth of inhibition of tumors and durability, and we reported that we've seen positive impact across all three of those parameters. While I think response rate is certainly something, you know, we can't avoid looking at, and it's the sort of simplest thing to start with, that's really not the whole game, and it's not necessarily the singular end game for showing clinical superiority.

Mark Goldsmith: Thanks for your question. Not sure I totally understand. I think you asked, do we have more preclinical data other than in mouse xenograft models? That's really the only setting in which we can do those sorts of studies. We primarily have looked at response rates in our public disclosures from those kinds of studies, but we also looked beyond. We provided data beyond response rates. We talked about both depth of inhibition of tumors and durability, and we reported that we've seen positive impact across all three of those parameters. While I think response rate is certainly something, you know, we can't avoid looking at, and it's the sort of simplest thing to start with, that's really not the whole game, and it's not necessarily the singular end game for showing clinical superiority.

Thanks for your question.

Not sure I totally understand I think you asked do we have more preclinical data other than in mouse xenograft models.

And that's really the only setting in which we can do those sorts of studies.

We primarily have looked at response rates.

Public disclosures from those kinds of studies, but we also look beyond.

We provided data beyond.

Response rates, we've talked about both depth of inhibition.

Of tumors and durability.

And we reported that we've seen.

Absent of impact across all three of those parameters.

So while I think response rate is certainly something.

We cannot avoid looking at it as sort of the simplest thing to start with that's really not the.

A whole game.

Not necessarily the singular and gained for showing a clinical superiority.

Dane Leone: Great. That answers it. Thank you.

Great.

That answers it thank you.

Thank you.

Mark A. Goldsmith: Thank you.

Mark Goldsmith: Thank you.

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

Thank you.

As there are no more questions in the queue I'll turn the call back over to Dr. Goldsmith for closing remarks.

Mark A. Goldsmith: Thank you, operator, and thank you to everyone for participating today and for your continued support of Revolution Medicines.

Mark Goldsmith: Thank you, operator, and thank you to everyone for participating today and for your continued support of Revolution Medicines.

Thank you operator, and thank you to everyone for participating today and for your continued support of evolution medicines.

Operator: This concludes today's conference call. Thank you for participating. You may now disconnect. Everyone, have a great day.

This concludes today's conference call. Thank you for participating you may now disconnect everyone have a great day.

[music].

Okay.

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