Q1 2024 Revolution Medicines Inc Earnings Call
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Operator: Good day, and thank you for standing by. Welcome to the Revolution in Medicine's first quarter 2024 earnings conference call. At this time, all participants are in a listen-only mode.
Speaker Change: Good day and thank you for standing by welcome to the Revolution medicines first quarter 'twenty 'twenty four earnings conference call. At this time, all participants are in a listen only mode.
Operator: After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1-1 on your telephone. You will then hear an automated message advising that your hand is raised.
Operator: After the speaker's presentation, there will be a question and answer session.
To ask a question during the session you will need to press star one on your telephone you will then hear an automated message advising your hand is race.
Operator: To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Erin Graves, Senior Director of Corporate Communications and Investor Relations.
Operator: Withdraw your question. Please press star one again please.
Erin Graves: Please be advised that today's conference is being recorded I would now.
Erin Graves: I'd like to hand, the conference over to your first speaker today, Aaron grapes senior director of corporate Communications and Investor Relations. Please go ahead.
Erin Graves: Please go ahead. Thank you and welcome everyone to the first quarter 2024 earnings call. Joining me on today's call are Dr. Marc Goldsmith, Revolution Medicines Chairman and Chief Executive Officer, and Jack Anders, our Chief Financial Officer. Dr. Steve Kelsey, our President of R&D, will also join us for the Q&A portion of today's call. 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 Security Litigation Reform Act.
Aaron Grapes: Thank you and welcome everyone to the first quarter 2024 earnings call. Joining me on today's call are Dr. Mark Goldsmith Revolution, medicines, Chairman and Chief Executive Officer, and Jack Anders Our Chief Financial Officer, Dr. Steve <unk>, our president of R&D will also join us for the Q&A portion of today's call.
Aaron Grapes: As we begin I would like to note that our presentation will include statements regarding our 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.
Erin Graves: These statements are subject to a number of assumptions, risks, and uncertainty. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statement.
Erin Graves: These statements are subject to a number of assumptions risks and uncertainties.
Aaron Grapes: Actual results may differ materially from these statements and except as required by law. The company undertakes no obligation to revise or update any forward looking statements.
Erin Graves: I encourage you to review the legal disclaimer side 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 Medicine's Chairman and Chief Executive Officer. Mark. Thanks, Erin.
Erin Graves: I encourage you to review the legal disclaimer side of our corporate presentation or the earnings press release as well as all of the Companys filings with the SEC concerning these and other matters with that I will turn the call over to Dr. Goldsmith Revolution medicines, Chairman and Chief Executive Officer Mark.
Mark A. Goldsmith: It's good to be with you this afternoon and to provide an update on our first quarter 2024 earnings. On today's call, I'll provide a brief update on our company progress, and Jack Anders will provide highlights of our financial results before we open the line for questions. We began 2024 with ambitious goals for our pioneering rafts-on-inhibitor pipeline. We provided a roadmap outlining our three strategic priorities for the year, and anticipate a catalyst-rich second half of the year that has the potential to be transformative for revolution medicine.
Mark A. Goldsmith: Thanks, Erinn, it's going to be with you. This afternoon to provide an update on our first quarter 2024 earnings on today's call I'll provide a brief update on our company progress.
Speaker Change: Jack Anders who will provide highlights of our financial results before we open the line for questions.
Speaker Change: We began 2024 with ambitious goals for our pioneering rason inhibitor pipeline.
Speaker Change: We provided a roadmap outlining our three strategic priorities for the year and anticipate a catalyst rich second half of the year that has the potential to be transformative for revolution medicines.
Mark A. Goldsmith: Our highest priority in 2024 is to advance RMC6236 into its first pivotal monotherapy trials in major cancers driven by oncogenic RAS variants. In the second half of the year, we expect to share updated clinical data from the ongoing RMC6236 first-in-human study in each of the pancreatic ductal adenocarcinoma and non-small-cell lung cancer cohorts, including durability data.
Jack Anders: Our highest priority in 2024 is to advance RMC 63, six into its first pivotal monotherapy trials in major cancers, driven by an oncogenic rasp variance.
Jack Anders: In the second half of the year, we expect to share updated clinical data from the ongoing RMC 63, six first in human study from each of the pancreatic ductal adenocarcinoma and non small cell lung cancer cohorts, including durability data.
Mark A. Goldsmith: Elements of these data are part of the regulatory packages supporting engagement with the FDA to determine a go-forward dose and to obtain feedback on pivotal trial designs prior to initiating each of these studies. We are currently setting the operational foundation to enable initiating these global, randomized, controlled, registrational trials comparing RMC6236 monotherapy to standard of care treatments in the second half of this year. We anticipate that the first of these trials to launch will evaluate RMC6236 as second-line treatment for patients with advanced pancreatic cancer, and that we will disclose the updated clinical data supporting this trial near the study launch.
Jack Anders: Elements of these data are part of the regulatory packages supporting engagement with the FDA to determine our go forward dose and to obtain feedback on pivotal trial designs prior to initiating each of these studies.
Mark A. Goldsmith: Similarly, we expect that the second trial to launch will evaluate RMC6236 as second-line treatment for patients with advanced non-small cell lung cancer, and that we will disclose the updated clinical data supporting this trial near its launch. We believe that initiating these trials will represent an exciting step forward for RMC6236 on behalf of patients with these common RAS-mutated cancers, and these major steps will transition Revolution Medicines to an important new stage of company maturity.
Jack Anders: We are currently setting the operational foundation to enable initiating these global randomized controlled registrational trials, comparing RMC $63 six monotherapy to standard of care treatments in the second half of this year.
Mark A. Goldsmith: We anticipate that the first of these trials to launch we'll evaluate RMC 63, six as second line treatment for patients with advanced pancreatic cancer and that we will disclose the updated clinical data supporting this trial the study launch.
Jack Anders: Similarly, we expect that the second trial to launch we will evaluate RMC 63, 6% as second line treatment for patients with advanced non small cell lung cancer and that we will disclose the updated clinical data supporting this trial.
Jack Anders: It's launched.
Jack Anders: We believe that initiating these trials will represent an exciting step forward for RMC 63, six on behalf of patients with these common Ras mutated cancers. In these major steps will transition revolution medicines to an important new stage of company maturity.
Mark A. Goldsmith: Our second development priority is focused on expanding the reach of RMC6236 beyond G12X mutations into different RAS genotypes and tumor types. This work was amplified recently with an oral presentation at the AACR annual meeting and three original scientific publications in Nature and Cancer Discovery that describe the mechanistic foundations of this groundbreaking Grasson multiselective inhibitor and illustrate its compelling clinical potential.
Jack Anders: Our second development priority is focused on expanding the reach of RMC six to $3 six beyond <unk> mutations into different RASK genotypes and tumor types.
Jack Anders: This work was amplified recently with an oral presentation at the ACR annual meeting and three original scientific publications in nature in cancer discovery.
Jack Anders: Ascribe the mechanistic foundations of this groundbreaking grass on multi selective inhibitor.
Jack Anders: And illustrate its compelling clinical potential.
Mark A. Goldsmith: At the meeting, we also presented four clinical cases, which, while anecdotal, showed the potential for RMC6236 to drive deep anti-tumor responses at tolerated doses across a wide range of oncogenic RAS genotypes beyond KRAS G12X variants we had described previously, including the N-RAS isoform and oncogenic G13X and Q61RAS variants that drive cancers for R In further note, two of the patients described at the ACR, one with advanced pancreatic cancer and one with advanced melanoma, experienced complete responses on treatment with RMC6236, both having progressed through prior treatment. Although clearly complete responses to RMC 6036 are much less common than partial responses or the absence of an objective response by resist criteria.
Jack Anders: At the meeting we also presented core clinical cases, which while anecdotal showed the potential for RMC 66 to drive deep antitumor responses of tolerated doses across a wide range of oncogenic RASK genotypes beyond K Ras G 12 experience. We have described previously.
Jack Anders: Including the <unk> isoform.
Jack Anders: And oncogenic G 13, ex and <unk> 61 asked variance Ras variance that drive cancers, or Ras mediated drug resistance.
Mark A. Goldsmith: A further note two of the patients described at the ACR, one with advanced pancreatic cancer and one with advanced melanoma experienced complete responses on treatment with RMC $63 six both having progressed through prior treatment.
Jack Anders: Although clearly complete responses to RMC six or 306 are much less common than partial responses or absence of an objective response by resist criteria.
Mark A. Goldsmith: Observation of Complete Responses in Lung, Pancreatic, and Melanoma Patients signifies the potential power of targeting RAS addiction with this compound and further motivates us to seek to expand the reach of RMC6236 into earlier lines of treatment. In some instances, we anticipate that first-line treatment with RMC6236 will be based on a combination approach. This year, we are studying several key combination regimens to determine feasibility and to define options for first-line registration trials with drug combinations.
Jack Anders: Observation of complete responses in lung pancreatic and melanoma patients signifies the potential power of targeting Ras addiction with this compound.
Mark A. Goldsmith: And further motivates us to seek to expand the reach of RMC $63 six into earlier lines of treatment.
Jack Anders: In some instances, we anticipate that first line treatment with RMC 63, 6% will be based on a combination approach. This year. We are studying several key combination regiments to determine feasibility and to define options for first line registration trials with drug combinations.
Mark A. Goldsmith: A high priority combination is the Rason inhibitor doublet of RMC6236 plus RMC6291, our RAS-on G12C mutant selective inhibitor in patients with RAS G12C solid tumors. A study of this doublet is ongoing, and we anticipate reporting initial clinical data for the combination of RMC6236 and 6291 in the second half of the year. A second combination study is evaluating RMC6236 plus pembrolizumab with or without chemotherapy in patients with advanced RAS-mutated non-small cell lung cancer.
Jack Anders: Our high priority combination is the rason inhibitor doublet of RMC 63, six plus RMC six to 91.
Jack Anders: Ras on <unk> mutant selective inhibitor in patients with Ras <unk> solid tumors.
Mark A. Goldsmith: Study. This doublet is ongoing and we anticipate reporting initial clinical data for the combination of RMC 63, 6% and $6 91 in the second half of the year.
Jack Anders: A second combination study is evaluating RMC $63, six plus <unk> with or without chemotherapy in patients with advanced Ras mutated non small cell lung cancer.
Mark A. Goldsmith: That Pembroke is part of most first-line standard of care regimens in this indication. We anticipate providing initial clinical data for this combination in the second half of the year. We're also happy to share today that we've initiated two new combination studies evaluating RMC6236 with current standard of care regimens in GI cancers. The first is evaluating RMC6236 in combination with standard of care chemotherapy and first-line treatment of patients with pancreatic cancer.
Jack Anders: Since Pembroke as part of most first line standard of care regimens in the syndication.
Jack Anders: <unk>, providing initial clinical data for this combination in the second half of the year.
Mark A. Goldsmith: And the second is evaluating RMC6236 with chemotherapy and first-line treatment for colorectal cancer. These two additional studies will provide us with important insights into potential first-line registrational paths as a crucial component of our development vision for RMC6236. Our third priority for the year is to qualify our first two RAS-on mutant selective inhibitors in the clinic. RMC6291, our G12C selective inhibitor, and RMC9805, our G12D selective inhibitor, for late stage development. While we continue first-in-human monotherapy studies for both of these compounds, we are initiating combination studies to explore opportunities in early-line treatment settings.
Jack Anders: We're also happy to share today that we have initiated two new combination studies evaluating RMC 63, 6% with current standard of care regimens and Gi cancers.
Mark A. Goldsmith: The first is evaluating RMC 63, six in combination with standard of care chemotherapy in first line treatment of patients with pancreatic cancer and.
Jack Anders: And the second is evaluating RMC $63 six with chemotherapy in first line treatment for colorectal cancer.
Jack Anders: Two additional studies will provide us with important insights into potential first line registrational path as a crucial component of our development vision for RMC $63 six.
Jack Anders: Our third priority for the year is to qualify our first two rason mute selective inhibitors in the clinic.
Mark A. Goldsmith: RMC 60, 91, our <unk> selective inhibitor and RMC 9805, our <unk> selective inhibitor for late stage development.
Mark A. Goldsmith: While we continue first in human monotherapy studies for both of these compounds. We are initiating combination studies to explore opportunities in early line treatment settings.
Mark A. Goldsmith: The first in human study evaluating RMC6291 has yielded encouraging initial clinical data in second-line monotherapy treatment of patients with KRASG12C non-small cell lung cancer, including those previously treated with an approved KRASG12C off-inhibitor, and in patients with KRAS G12C colorectal cancer who had not been previously treated with a Ras-off inhibitor. At AACR, we presented data from preclinical models in which the Rasson inhibitor doublet RMC6236 plus RMC6291 demonstrated significant improvement in response rates and durability relative to either monotherapy. These encouraging data reinforce our hypothesis that a RAS-on doublet combining a RAS-on multi-selective inhibitor with a RAS-on mutant-selective inhibitor may deliver meaningful benefit to patients with RAS mutant cancers.
Mark A. Goldsmith: The first in human study evaluating RMC 69, one has yielded encouraging initial clinical data in second line monotherapy treatment of patients with <unk> non small cell lung cancer, including those previously treated with an approved K recipe drops the off inhibitor.
Jack Anders: And in patients with K rescue 12, see colorectal cancer, who had not been previously treated with <unk> inhibitor.
Mark A. Goldsmith: At ACR, we presented data from preclinical models in which the rason inhibitor doublet RMC six to $3 six plus RMC 69, one demonstrated significant improvement in response rates and durability relative to either monotherapy <unk>.
Jack Anders: These encouraging data reinforce our hypothesis that rason doublet, combining a ras on multi selective inhibitor with a ras on mutant selective inhibitor.
Mark A. Goldsmith: They deliver meaningful benefit to patients with Ras mutant cancers as mentioned in initial clinical study of this combination is ongoing.
Mark A. Goldsmith: As mentioned, an initial clinical study of this combination is ongoing. A clinical study of the combination of RMC6291 with Pembrolizumab is also ongoing, and we anticipate disclosing initial data for RMC6291 with Pembrolizumab in the first half of 2025. We also anticipate evaluating the triplet regimen comprising the RAS-on inhibitor doublet, 6236 plus RMC 6291 with Pembrolizumab for patients with RAS-mutated non-small cell lung cancer in the first-line setting. If exploration of the triplet proves supportive, it could open the path to pursuing late-stage development of a chemotherapy-free, first-line treatment regimen for patients with RAS mutant non-small cell lung cancer. Regarding RMC9805, the first Grasson G12 deselective inhibitor.
Jack Anders: Our clinical study of the combination of RMC six to 91 with <unk> is also ongoing and we anticipate disclosing initial data for RMC 60, 91 with <unk> in the first half of 2025.
Jack Anders: We also anticipate evaluating the triplet regimen, comprising the rason inhibitor doublet arm C 63, six plus RMC 60, 91 with <unk> for patients with Ras mutated non small cell lung cancer in the first line setting.
Jack Anders: Exploration of the triplet proved supportive it could open the path to pursuing late stage development of a chemotherapy free first line treatment regimen for patients with Ras mutant non small cell lung cancer.
Jack Anders: Regarding RMC $90 five the first graph on June 12, the selective inhibitor.
Jack Anders: We presented preclinical data in the New Drugs on the Horizon session at AACR, showing that RMC9805 induced deep and durable regressions in preclinical models of several KRAS G12D tumor types. As disclosed earlier this year, oral bioavailability in patients has been confirmed, and we've cleared several dose levels with good tolerability and no dose-limiting toxicities reported thus far. We expect to share initial safety, tolerability, and anti-tumor activity data in the second half of 2020.
Jack Anders: We presented preclinical data and the new drugs on the horizon session at ACR.
Jack Anders: Showing that RMC Magneto five induced deep and durable regression in preclinical models of several K Ras <unk> tumor types.
Jack Anders: As disclosed earlier this year oral bioavailability and patients has been confirmed.
Jack Anders: And we've cleared several dose levels with good tolerability and no dose limiting toxicities reported thus far.
Jack Anders: We expect to share initial safety tolerability and anti tumor activity.
Jack Anders: Later in the second half of 2024.
Jack Anders: We are also planning for our second RAS-on-DOUBLET combination study evaluating RMC6236 plus RMC9805 in patients with advanced RAS G12D mutated cancers. We also anticipate using RMC 9805 in combination with other standard of care treatments for RAS G12D tumors. Overall, we continue pursuing our ambitious plans covering a rich set of potential opportunities toward the goal of maximizing the clinical impact of our RAS-on inhibitors in monotherapy and combination treatments for patients living with RAS-addicted cancers.
Jack Anders: We're also planning for our second Ras on Doublet combination study evaluating RMC 63, six plus pharmacy 92, five in patients with advanced Ras <unk> mutated cancers.
Jack Anders: We also anticipate setting RMC 92, five in combination with other standard of care treatments <unk> tumors.
Jack Anders: Overall, we continue pursuing our ambitious plans covering a rich set of potential opportunities toward the goal of maximizing the clinical impact of our rasp inhibitors in monotherapy and combination treatments for patients living with rasp addicted cancers.
Jack Anders: In the second half of the year, we anticipate launching our first registrational studies of RMC6236 for second-line treatment in two major RAS-driven cancers, qualifying potential paths forward for evaluating RMC6236 in first-line treatments for these tumors, and establishing potential opportunities for advancing our first two clinical RASOM mutant selective inhibitors. Now, I'll now turn to Jack Anders, our CFO, to provide a financial update
Jack Anders: In the second half of the year, we anticipate launching our first Registrational studies of RMC 63, six for second line treatment in two major Ras driven cancers.
Jack Anders: Qualifying potential paths forward for evaluating RMC six to $3 six and first line treatments for these tumors and establishing potential opportunities for advancing our first two clinical ramps on mutant selective inhibitors.
Jack Anders: Thank you, Mark. We ended the first quarter of 2024 with $1.7 billion in cash and investments. This compares to $1.85 billion at the end of 2023. The decrease in cash and investments for the quarter was primarily driven by a net loss, plus a $50.9 million decrease in accounts payable and accrued liability.
Jack Anders: I'll now turn to Jack Anders our CFO to provide a financial update.
Jack Anders: Thank you Mark.
Jack Anders: We ended the first quarter of 2024 with $1 7 billion in cash and investments.
Jack Anders: This compares to $1 85 billion at the end of 2023.
Jack Anders: The decrease in cash and investments for the quarter was primarily driven by net loss plus a $59 million decrease in accounts payable and accrued liabilities.
Jack Anders: Please note that we saw some lumpiness in the timing of the expenses and the related cash payments, which caused a one-time increase in accounts payable and accrued liabilities of $56.7 million during the fourth quarter of 2023. This normalized by the end of the first quarter of 2024, resulting in anticipated cash payments and a corresponding decrease in accounts payable and accrued liabilities. Turning to expenses. R&D expenses for the first quarter of 2024 were $118.0 million, compared to $68.9 million for the first quarter of 2023.
Jack Anders: Please note that we saw some lumpiness in the timing of the expenses and the related cash payments, which caused a one time increase in accounts payable and accrued liabilities of $56 7 million during the fourth quarter of 2023.
Jack Anders: This normalized by the end of the first quarter of 2024, resulting in anticipated cash payments and a corresponding decrease in accounts payable and accrued liabilities.
Jack Anders: The increase in R&D expenses was primarily due to clinical trial expenses and related manufacturing expenses for our first wave of Rason inhibitors, as well as an increase in Personnel-Related Expenses Related to Additional Headcount and an increase in stock-based compensation. GNA expenses for the first quarter of 2024 were $22.8 million compared to $13.2 million for the first quarter of 2023. The increase in GNA expenses was primarily due to an increase in personnel-related expenses related to additional heads and an increase in stock-based compensation. The net loss for the first quarter of 2024 was $116.0 million, or $0.70 per share.
Jack Anders: Turning to expenses.
Jack Anders: R&D expenses for the first quarter of 2024 were 118.0 million compared to $68 9 million for the first quarter of 2023.
Jack Anders: The increase in R&D expenses was primarily due to clinical trial expenses and related manufacturing expenses for our first wave of rasp inhibitors as well as an increase in personnel related expenses related to additional head count.
Jack Anders: And an increase in stock based compensation.
Jack Anders: G&A expenses for the first quarter of 2024, or $22 8 million compared to $13 2 million for the first quarter of 2023.
Jack Anders: The increase in G&A expenses was primarily due to an increase in personnel related expenses related to additional head count and an increase in stock based compensation.
Jack Anders: Net loss for the first quarter of 2024 was 116.0 million.
Jack Anders: Or <unk> 70 per share.
Mark A. Goldsmith: We are reiterating our 2024 financial guidance and expect the projected full year 2024 gap net loss to be between $480 million and $520 million, which includes estimated non-cash stock-based compensation expense of between $70 million and $80 million. And with that, I'll turn the call back over to Mark. Thank you, Jack. Revolution Medicines is off to a strong start for the year. We are well capitalized and remain focused on delivering key data and actions to advance RMC6236 into its first registrational trials while qualifying the range of potential opportunities, extending the reach of our RAS-on inhibitors into earlier lines of treatment for patients living with RAS-induced cancer.
Jack Anders: We are reiterating our 2024 financial guidance and expect projected full year 2024, GAAP net loss to be between $480 million and $520 million, which.
Jack Anders: Which includes estimated noncash stock based compensation expense.
Mark: Between $70 million and $80 million.
Jack Anders: And with that I'll turn the call back over to Mark.
Mark A. Goldsmith: Thank you Jack.
Mark A. Goldsmith: Revolution medicines is off to a strong start for the year, we are well capitalized and remain focused on delivering key data and actions to advance our RMC 63, 6% into its first registrational trials, while qualifying the range of potential opportunities extending the reach of our rason inhibitors into earlier lines of treatment for patients.
Jack Anders: Living with Ras cancers.
Mark A. Goldsmith: Our work in progress would not be possible without the support of our patients, clinical investigators, scientific and business collaborators, advisors, and shareholders, and the tireless efforts of RevMed employees on behalf of patients. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session. Thank you. At this time, we will conduct a question and answer session. As a reminder, to ask a question, you will need to press star 11 on your telephone and wait for your name to be announced.
Jack Anders: Our work in progress would not be possible without the support of our patients clinical investigators scientific and business collaborators advisers and shareholders and the tireless efforts of <unk> employees on behalf of patients. This.
Speaker Change: This concludes our prepared remarks for today and I'll now turn the call over to the operator for the Q&A session.
Operator: To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. Our first question comes from Marc Frahm with TD Cowen. Please go ahead.
Speaker Change: Thank you at this time, we will conduct a question and answer session. As a reminder to ask a question you will need to press star one on your telephone and wait for your name to be announced to withdraw. Your question. Please press star one again, please standby, while we compile the Q&A roster.
Speaker Change: Our first question comes from Mark <unk> with TD Cowen. Please go ahead.
Marc Alan Frahm: Hi, thanks for taking my questions. Maybe on pancreatic cancer for 6236. I guess, what questions are you still looking to find answers to to finalize that design for the second line? Is it just regulatory feedback that you need, or is there still clinical data that you're looking to gather to know kind of exactly what you want to ask regulators? And then, you know, thinking forward to the first line, just, is it really dependent upon combinations? Because that seems to be how you're talking about it, or might monotherapy also ultimately get developed in the first? Thanks, Marc.
Mark A. Goldsmith: Hi, Thanks for taking my questions maybe.
Mark A. Goldsmith: Maybe on pancreatic cancer for 63, 6%.
Mark A. Goldsmith: Quick questions are you still looking to find answers too.
Mark A. Goldsmith: To finalize that design for the second line Gist regulatory feedback that you need or is there still clinical data that youre looking to gather to know kind of exactly what you want to ask regulators and then thinking forward to first line.
Mark A. Goldsmith: Just is it really dependent upon combinations because it seems to be how you are talking about it or.
Marc Alan Frahm: Mike Monotherapy also ultimately get developed in the first one.
Mark A. Goldsmith: Appreciate your questions. To the first question of time, what's driving the timing for the pancreatic cancer study, it basically is the same as the issues we've identified before. We need to come to agreement with the FDA on a dose and as well as on the trial design. So I think, you know, those are our first half-year events. We're in May.
Speaker Change: Thanks, Mark I appreciate your questions. So the first question of timing, what's driving the timing for the pancreatic cancer study. It basically is the same as the issues. We've identified before we need to come to agreement with the FDA.
Speaker Change: On a dose.
Mark A. Goldsmith: And.
Mark A. Goldsmith: As well as on the trial design, so I think.
Mark A. Goldsmith: Those are first half of the year events.
Speaker Change: We're in May.
Mark A. Goldsmith: So we're still in the first half of the year, and we'll get those done. And then, in the second half of the year, we'll likely move forward and provide the data that we said we would provide. On the question about the first-line study, I think you asked whether we would wait for the results of the second-line monotherapy pivotal trial before initiating the first line or not. It seems like you're very focused on the kind of combinations in that opening up the first line opportunity.
Speaker Change: So we're still in the first half of the year and we'll get those done and then in the second half of the year will will likely move forward and provide the data that we have said we would provide.
Speaker Change: On the question about the first line study.
Mark A. Goldsmith: Thank you asked whether.
Speaker Change: We would wait for the results of the second line monotherapy pivotal trial before initiating the first of all I don't know.
Speaker Change: Okay great.
Speaker Change: It seems like your focus very focused on kind of combinations and that opening up. The first line opportunity is that is that really the main path forward in first line in your mind or is monotherapy also on the table for firstly.
Mark A. Goldsmith: Is that really the main path forward in first line in your mind, or is monotherapy also on the table for first line? Yeah, I don't think we know yet. I think, as we've said before, we want to qualify what the options are. We know what the option would be for monotherapy; it would be monotherapy. But we don't know what the options are for chemotherapy, so we need to evaluate that from a safety point of view. So that's why doing that exploratory work is very important.
Speaker Change: Yes, I don't think we know yet I think as we've said before we want to quantify what the options are we know what the option would be for monotherapy would be mono therapy, but.
Speaker Change: We don't know what the options are for chemotherapy, we need to evaluate that from a safety point of view so.
Speaker Change: That's why doing that exploratory work is very important and once we know that we'll be able to decide what kind of trial was supposed to appropriate is it a two arm trial is a three arm trial are we evaluating both of those paths or just one or just one of them compared to standard of care, we don't know yet.
Mark A. Goldsmith: And once we know that, we'll be able to decide what kind of trial is most appropriate. Is it a two-arm trial, is it a three-arm trial? Are we evaluating both of those paths or just one of them compared to standard of care? We don't know yet.
Speaker Change: Okay. Thank you.
Speaker Change: Thank you one moment for our next question.
Mark A. Goldsmith: Okay, thank you. Thank you. One moment for our next question. Our next question comes from Michael Schmidt with Guggenheim Securities. Please go ahead. Hey guys, thanks for taking my questions. On, RMC6236.
Speaker Change: Our next question comes from Michael Schmidt with Guggenheim Securities. Please go ahead.
Michael Werner Schmidt: Hey, guys. Thanks for taking my questions.
Michael Werner Schmidt: On.
Michael Werner Schmidt: I think we've recently seen the announcement from Bristol at the Crystal 12, where the trial met its primary endpoint in a second-line lung cancer setting, and we'll probably get a few additional. Phase III readouts from other KRAS G12C inhibitors in the coming year or so. And yeah, I was just wondering how that potentially increased the use down the road for those. 12c inhibitors might impact. Your study or perhaps enrollment, you know; do you think it might be biased in any way away from K-12? patients in your study, in your planned study, and or how it may affect your trial design at all.... Yeah, hi, Michael.
Michael Werner Schmidt: Our M C 63 six.
Michael Werner Schmidt: I think we've recently seen the announcement from Bristol at the Crystal 12 trial met its primary endpoint in the second line lung cancer, setting and probably get a few additional.
Michael Werner Schmidt: Phase III readouts.
Michael Werner Schmidt: From other <unk> inhibitors.
Michael Werner Schmidt: Coming.
Speaker Change: So yes, I was just wondering how that.
Speaker Change: Potentially increased use down the road of those.
Speaker Change: <unk> inhibitors might impact.
Speaker Change: Your study or perhaps enrollment do you think it might be biased in any ways away from <unk>.
Speaker Change: Patients in your study in your planned study.
Speaker Change: <unk> made affect your trial design at all.
Michael Werner Schmidt: Yes.
Mark A. Goldsmith: Thanks for your question. I think it depends on what indication you're talking about. In pancreatic cancer, it won't have any impact at all because G12C represents such a small subpopulation. And I don't know that they're even seeking approval in that indication, but it wouldn't make much difference. And then in lung cancer, obviously, roughly 12% of non-small cell lung cancer is KRS-G12C, and another 13% are other KRAS G12 mutations, and then there's another 5% or so beyond that that are other mutations. So that is a significant population.
Speaker Change: Yeah, Hi, Michael Thanks for your question.
Speaker Change: I think it depends on what indications youre talking about in pancreatic cancer. It won't have any impact at all because chelsea represent such a small subpopulation in I don't know that they are even seeking approval in that indication, but it wouldnt make much difference.
Speaker Change: And then in lung cancer obviously.
Mark A. Goldsmith: Roughly well.
Speaker Change: <unk> percent.
Speaker Change: <unk> cell lung cancer is curious to 12 <unk> in another.
Speaker Change: 13% of our other K Ras <unk> mutations and then theres, another 5% or so beyond that there are other mutations.
Mark A. Goldsmith: It's already a crowded space from patients' perspective. They have access to two approved drugs today. They might have access to two approved drugs tomorrow, and then maybe a few more that will come after that, potentially; we don't know for sure. So patients do have options today, and it's very credible for them to consider one of the approved drugs instead of entering a registration trial. I think we'll try to deal with that in some form in the design of the trial.
Speaker Change: So that is a significant population it's already a crowded space from patient perspective, they have access to two approved drugs today, they might have access to two approved drugs.
Speaker Change: Tomorrow, and then maybe a few more that will come after that potentially we don't know for sure.
Speaker Change: So patients do have options today, and it's very credible for them to consider one of the approved drugs instead of entering.
Speaker Change: Our registration trial I think we all try to deal with that.
Speaker Change: In some form in the design of the trial.
Mark A. Goldsmith: But ultimately, to the extent that G12C patients are eligible for that population, we'll get what we'll get. And I don't think it will necessarily affect the overall outcome, because we do expect that RMC6236 would be active on G12C just as it's active on the others, although we've not reported any clinical data on that. But preclinically, that's the case.
Mark A. Goldsmith: But ultimately yes.
Mark A. Goldsmith: To the extent that <unk> patients are eligible for that population will get what we'll get.
Speaker Change: And I.
Speaker Change: I don't think it will necessarily.
Speaker Change: The overall outcome, because we do expect that RMC six to $3 six would be active on GE 12, just as effective on the others. Although we've not reported any clinical data on that but pre clinically.
Speaker Change: The case, so we will get what we get.
Mark A. Goldsmith: So we'll get what we get. Obviously, the most important thing here is offering potential treatment for patients without G12C, the patients that have non-G12C mutations. That's really the main driver for proceeding. But we're interested in G12C, and we'll get them if we can get them.
Mark A. Goldsmith: Obviously, the most important thing here is offering a potential treatment for patients without gene <unk> see the patients that have non <unk> mutations that's really the main driver for proceeding.
Mark A. Goldsmith: But we're interested in <unk> and we'll get them if we can go.
Operator: That makes sense. And then a specific question about your press release. I think you're guiding to presenting initial data from the 6236 Pembrolizumab combination in the second half, and I think I was just wondering, is that specifically in first-line lung cancer patients, or is that in late-stage patients? Yeah, thanks for the question. We're just handing the microphone over to Steve.
Speaker Change: That makes sense and then specific question on your press release I think.
Speaker Change: You're guiding to presenting initial data from the <unk> 36, <unk> <unk> combination in the second half.
Steve: And I think I was just wondering is that specifically in first line lung cancer patients or is that in late stage patients.
Steve: Yeah. Thanks for the question, we're just adding a microphone over to Sandeep.
Stephen M. Kelsey: There we go. I'll deal with the question. The study evolves. The initial safety, even though first-line patients are not precluded from the study, most of the initial safety data will probably not be in the first line space, to be completely honest with you.
Sandeep: I'll deal with it.
Sandeep: The question.
Steve: The study evolves.
Sandeep: The initial safety, even though first line patients are not precluded from the study most of the initial safety data will.
Sandeep: Probably not be in the first line space to be completely honest with you, but as the safety emerges then the study will increasingly start to focus on the first line patients.
Stephen M. Kelsey: But as safety emerges, then the study will increasingly start to focus on the first line patients. How that reads into what we will actually report or disclose at any given time and at any given forum, I think is subject to some further discussion when we get closer to the event. If your question is largely about how enabling will the data be for moving the program forwards.
Stephen M. Kelsey: How that reads into what we will surely report just close at any given time and at any given forum. I think is is subject to some sort of the discussion when we get closer to the.
Sandeep: Events.
Sandeep: If your question is largely about how enabling will the.
Stephen M. Kelsey: I think that from our perspective, it's likely to be extremely, It's like extremely compelling and conclusive in that, largely because the most important question we're asking there is a safety question. It's not really an efficacy-driven uh proof of concept at this stage; it's more of a can you combine with pembrolizumab full stop, and I don't think that the number of prior therapies or even really the disease of interest is going to determine that. Having said that, obviously, for obvious reasons, the actual combinations are largely restricted to patients with lung cancer. Okay, super helpful. Thanks so much.
Sandeep: Dates would be for moving the program forward I think from our perspective, it's likely to be extremely.
Sandeep: It's like I say extremely compelling inconclusive in that respect.
Sandeep: Largely because the most important question. We're asking there is a safety question correct, it's not really an efficacy driven.
Stephen M. Kelsey: Proof of concept at this stage, it's more of a can you combine with <unk> full stop and I don't think that the.
Stephen M. Kelsey: <unk>.
Sandeep: The <unk>.
Sandeep: A number of prior therapies or even really the disease of interest is going to determine that having said that obviously for obvious reasons. The actual combinations are.
Sandeep: Largely restricted to patients with lung cancer.
Speaker Change: Okay Super helpful. Thanks, so much.
Sandeep: Yes.
Speaker Change: Thank you one moment for our next question.
Sandeep: Okay.
Operator: Thank you. One moment for our next question. Our next question comes from Eric Joseph with J.P. Morgan. Please go ahead. Great. Good evening.
Sandeep: Our next question comes from Eric Joseph with JP Morgan. Please go ahead.
Eric William Joseph: Great Good evening.
Eric William Joseph: Actually, just really wanted to pick up on the last point you made there, Steve, appreciating sort of what you're looking for, what you're looking for, really focusing on establishing safety with Pembroke Plus RMC 6236. I wonder whether in your regulatory interactions over your planned second-line trials in non-small cell lung cancer, you've had the opportunity to discuss first-line development. We've seen that Merck has gone straight into front-line with their G12C inhibitor plus Pembroke on about 25 patients' worth of data. I wonder whether you might have similar optionality to pursue a front-line trial and perhaps pivot from the second-line strategy earlier than expected. Okay. Thank you. Bye.
Eric William Joseph: Actually just really wanted to pick up on the last point you made there Steve.
Eric William Joseph: And appreciating sort of what Youre looking forward what you are looking for.
Eric William Joseph: Really focusing on establishing safety with the Pembroke class arm C $63 six I wonder.
Eric William Joseph: Weather.
Eric William Joseph: Your regulatory interactions over your.
Eric William Joseph: Planned second line trials in non small cell lung cancer, you have had the opportunity to discuss.
Eric William Joseph: First line.
Eric William Joseph: Development, we've seen that.
Eric William Joseph: Merck has gone straight into frontline with their <unk> inhibitor plus <unk>. Unlike 25 patients worth of data I Wonder whether you might have similar optionality too.
Eric William Joseph: Pursue.
Eric William Joseph: Frontline trial.
Eric William Joseph: Perhaps pivot from the second one strategy.
Eric William Joseph: Earlier than expected.
Sandeep: Okay.
Stephen M. Kelsey: Let's let's distill three questions. So firstly, what what we are not firstly we're not in a position to report out on our regulatory interactions with regards to 6236 either in pancreatic cancer or non-stroke cell lung cancer and I think we've deliberately guided to second half of the year with regards to that because we really need to be able to report something that is definitive rather than speculative secondly, Does the emerging data or will the emerging data on the combination of RMC6036 with Pembro enable a first-line strategy?
Speaker Change: There's still three questions. So firstly.
Speaker Change: What what we are not firstly, we're not in a position to report on our regulatory interactions with regards to $63 six either in pancreatic cancer non small cell lung cancer I think we deliberately guided to second half of the year with regards to that because we really need to be able to report something that is definitive.
Speaker Change: Rather than speculative secondly.
Stephen M. Kelsey: Does the.
Sandeep: Emerging data.
Sandeep: Will the emerging data on the combination of RMC $63 six with <unk> enable a first line strategy absolutely. That's what the study is designed to enable them.
Stephen M. Kelsey: Absolutely. That's what the study is designed to enable, and we've deliberately focused on. We've said several times that accelerating what is clearly an active drug into earlier lines of therapy where we expect the clinical benefit to be even more impactful is a very high priority for the company. The third question, which I think was implicit in your question, is whether or not if we were accelerating into first-line lung cancer, whether we would do a second-line lung cancer study. Right now, we have no reason to deviate from the plan that we have communicated.
Stephen M. Kelsey: Deliberately focused we've said several times that accelerate seeing what is clearly an active drug into earlier lines of therapy, where we expect the trend will benefit to be even more impactful is a very high priority for the company.
Stephen M. Kelsey: Third question Marcia think was implicit in your question is whether or not if we.
Sandeep: We're accelerating into first line lung cancer, whether we would do a second line lung cancer study right now we have no reason to deviate from the plan that we have communicated.
Stephen M. Kelsey: And if at any point in the future, we do deviate from that plan, no doubt we'll communicate that and the reasons for doing so. But right now, we are committed to a second-line, single-agent, non-small-cell lung cancer study for RMC6236. And at the same time, in parallel, we're trying to enable not just first-line metastatic, first-line advanced disease, but treatment for non-small-cell lung cancer in even earlier lines of therapy as well. All very clear. I appreciate it. Yeah, go ahead, Mark. Yeah, I was just gonna add one little line of color to that.
Sandeep: And if at any point in the future. We do deviate from that plan note that we will communicate that and the reasons for doing so but right. Now we are committed to a second line single agent in non small cell lung cancer study for RMC 63, six and at the same time in parallel we're trying to enable not just first line metastatic.
Mark: First line advanced disease, but even treatment in non small cell lung cancer, and even earlier lines of therapy as well.
Mark: I appreciate it Yeah go ahead Mike.
Mark A. Goldsmith: I mean, bear in mind that for another G12C inhibitor coming into play, they do face quite a bit of competition for G12C patients on second line, so it's quite crowded there. For RMC6236, more than half of the patients that we'd be targeting don't have a G12C inhibitor option available to them. So I think the dynamics aren't exactly the same for a G12C inhibitor coming into play versus a 6236.
Mike: Yes, I was just going to add one little line of color to that I mean bear in mind that for for another <unk> inhibitor coming in play they do face.
Mike: A bit of competition for <unk> C patients in second line, so that it's quite crowded there.
Mike: RMC 63 six.
Mike: More than half of the patients that we'd be targeting.
Mark A. Goldsmith: Don't have a <unk> inhibitor option available to them so.
Mike: I think the dynamics aren't exactly the same for <unk> inhibitor coming into play versus $6 three six but with that said as Steve pointed out we have a current plan. The plan changes, we'll disclose those plans change but.
Mark A. Goldsmith: But with that said, as Steve pointed out, we have a current plan. If the plan changes, we'll disclose when the plans change, but that is our current plan. Okay. Should we expect any of the combination data with 6236?
Mike: That's our that is our current belief.
Mike: Okay.
Mike: Okay.
Mike: Should we expect.
Mike: If the.
Mark A. Goldsmith: Combination data was 63 six.
Mike: Yes.
Eric William Joseph: whether it's PEMBRO or other regimens to be paired with either of the data updates with monotherapy and pancreatic and then lung cancer, the second half. I don't know the answer to that, to be honest. I mean, as we pointed out, there are scientific meetings that we'd like to present at if we have an opportunity. There are corporate presentations that we can present at our leisure, when we have the data and we are ready to say something, and how those all line up and how we sort of, I would just say, I think our goal here is to be really crystal clear about what we're trying to enable in the second half of the year.
Mark A. Goldsmith: Whether it's with <unk> or.
Eric William Joseph: Other regimens to be paired with.
Mike: Neither of the data updates with the mono therapy in pancreatic and lung cancer in the second half.
Eric William Joseph: I don't know the answer to that to be honest I mean, as we pointed out there is there are scientific meetings that we'd like to present that if we have an opportunity there corporate presentations that we can present sort of.
Mike: At our at our leisure when the opportunity when we have the data and we are ready to say something and how those all lineup and how are we sort of.
Mike: Divvy up and allocate the data to different things.
Eric William Joseph: I don't know the answer to that yet.
Mike: I would just say I think our goal here is to be really crystal clear about what we're trying to enable.
Mike: In the second half of the year.
Eric William Joseph: And that is the number one priority, those second-line studies that we've just talked about, and those don't really require any other information than the monotherapy data. And then everything else is there to help guide our future studies, which are You know, primarily first-line studies or studies and other indications, et cetera. So I think of them conceptually as being really different baskets, but that doesn't mean we might not. Bundle them together in some context; I don't.
Mike: And that is number one priority go second line studies that we've just talked about and those don't really require any other information and this has been a monotherapy.
Mike: Data.
Mike: And then everything else is there to help guide our future studies, which are.
Mike: Primarily first line studies or studies in other indications et cetera.
Eric William Joseph: No.
Mike: Think of them conceptually as being really different baskets, but that doesn't mean, we might not be.
Mike: Bundle them together in some context I don't really know.
Operator: Okay, great, very helpful. Thanks for taking the questions. Yeah, thank you. Thank you. One moment for our next question. Our next question comes from Jonathan Chang with Lyrinc Partners. Please go ahead. Hi guys.
Speaker Change: Okay, great very helpful. Thanks for taking the questions.
Jonathan Chang: Yes. Thank you.
Speaker Change: Thank you one moment for our next question.
Operator: Our next question comes from Jonathan Chang with Leerink Partners. Please go ahead.
Jonathan Chang: Hi, guys. Thanks for taking my questions.
Jonathan Chang: Thanks for taking my questions. Two questions. First, for the initial RMC6236 combination data with your mutant-selective inhibitors, can you discuss what you're hoping to see that would give you confidence for further development of these combinations? And second, how are you thinking about potential business development opportunities, given the breadth of the company's efforts? Jonathan, thanks for joining us. Thanks for your question. 6236 plus 6291.
Jonathan Chang: Two questions first for the initial RMC <unk> combination data with their mutant selective inhibitors.
Jonathan Chang: Can you discuss what you are hoping to see that would give you confidence for further development of these combinations.
Jonathan Chang: Second question, how are you thinking about potential business development opportunities given the breadth of the company's efforts. Thank you.
Speaker Change: Hey, Jonathan Thanks for joining us thanks for your question.
Mark A. Goldsmith: Well, the first question, of course, is also a safety question, just like always, not that we have any particular concerns, but we do need to establish that. And then the second one is an activity question. And, In a perfect world, we'd identify situations where response rates or some other indicator of anti-tumor activity is low for monotherapy and where we'd look to see something from the combination that differentiates that. Obviously, much harder to do if you're talking about... Let's say, G12C, second-line lung cancer. You would have to run a pretty large phase 2 trial if you were trying to establish, you So that's the conceptual framework; if we can find opportunities to sort of qualitatively differentiate them as opposed to looking for a difference of X percent in response rate, Um, with regard to business development.
Speaker Change: $636 691, well. The first question of course is also a safety question just like always not that we have any particular concern, but we do need to establish that and then the second one is an activity question and.
Speaker Change:
Mark A. Goldsmith: In a perfect world, we'd identify situations, where response rates or some other indicator of anti tumor activity.
Mark A. Goldsmith: LOE for monotherapy and what we'd look to see something from the combination that that differs.
Mark A. Goldsmith: <unk> that obviously much harder to do if you are talking about.
Mark A. Goldsmith: Let's say.
Mark A. Goldsmith: <unk> second line lung cancer you'd have to run a pretty large phase III trial. If you were trying to establish superiority of of an ore are for example.
Mark A. Goldsmith: And so I don't think thats likely that we would be doing something like that so that's the conceptual framework. If we can find opportunities to sort of qualitative qualitatively differentiate them as opposed to looking for a difference of X percent and response rate I think that would be more meaningful to us.
Mark A. Goldsmith: Okay.
Mark A. Goldsmith: Yes.
Mark A. Goldsmith: With regard to business development.
Mark A. Goldsmith: I think our posture on this is really very much the same as it's been for quite a while now, which is that we have an integrated, Portfolio, and Rich Portfolio of Rasson Inhibitors, three of which are already in the clinic. That, in and of itself, is highly differentiated in the field today. And there may be interactions among these three, and we have a whole stack of compounds behind those that can be brought into the clinic targeting different mutant selective profiles. Therefore, it is hard to tease apart different parts of the portfolio for partnering purposes. It's not impossible, but it's just harder to do it.
Speaker Change: I think our posture and this is really very much the same as it's been for quite a while now which is that we have an integrated.
Mark A. Goldsmith: Portfolio and rich portfolio of Ras on inhibitors, three of which are already in the clinic that in of itself is highly differentiated in the field today.
Speaker Change: And there may be interactions among these three.
Mark A. Goldsmith: And we have a whole stack of.
Mark A. Goldsmith: Of compounds behind those that can be brought into the clinic targeting different mutant selective profiles.
Speaker Change: Therefore.
Mark A. Goldsmith: It is hard to tease apart.
Mark A. Goldsmith: Different parts of the portfolio for partnering purposes, it's not impossible, but it's just harder to do it.
Mark A. Goldsmith: That's one comment. The second is that we're pretty committed, deeply committed to U.S. operations, extending into the commercialization of these compounds, and at this point, we don't really see a need to have a partner help us do that in the U.S., if anything, that complicates things. And potentially, if the partnership is around any slice of the portfolio, it might create strategic misalignment between the partners' interests and ours. So I think in the U.S., our intention is to commercialize on our own. The exact inverse of that is true outside the U.S., where we have no intention in the foreseeable future of commercializing ourselves, and therefore, we would expect a partner or multiple partners to be a part of that.
Speaker Change: That's one comment.
Mark A. Goldsmith: The second is that we're pretty committed.
Mark A. Goldsmith: Deeply committed to U S operations.
Mark A. Goldsmith: Extending into the commercialization of these compounds and at this point don't really see a need to have a partner help us do that in the U S.
Mark A. Goldsmith: That complicates things.
Mark A. Goldsmith: And potentially if the partnership is around any slice of the portfolio it might create strategic misalignment between the partner's interest in ours. So I think in the U S. Our intention is to commercialize on our own.
Speaker Change: The exact inverse of that is true outside the U S, where we have no intention.
Speaker Change: In the foreseeable future of commercializing ourselves.
Mark A. Goldsmith: And therefore would expect a partner or multiple partners to be up.
Mark A. Goldsmith: Part of that and again the question dividing the portfolio and potentially creating mis strategic misalignment versus unifying the portfolio and having everybody.
Mark A. Goldsmith: And again, the question of dividing the portfolio and potentially creating strategic misalignment versus unifying the portfolio and having everybody on roughly the same page is going to be a factor in sorting all of this out. So, I think when you take all of that together, I think it's reasonable to expect a Partner for Marketing Outside the U.S. and Potentially Development, that involves a footprint outside the U.S. as well. But inside the U.S., I think we can manage the commercialization on our own once we've built that capability, acknowledging that we don't have that capability today, but we are very much already investing in it and expect to be able to feel the competitive sales force at the right time.
Mark A. Goldsmith: On roughly the same page.
Mark A. Goldsmith: Going to be a factor and sorting all of this out so I think when you take all of that put together I think it's reasonable to expect that we would have one potentially more than one but one.
Mark A. Goldsmith: Partner for marketing outside the U S and potentially development that involves.
Mark A. Goldsmith: Our footprint outside the U S as well.
Mark A. Goldsmith: The U S. I think we can manage.
Mark Goldsmith: Commercialization on our own once we built that capability technology that we don't have that capability today, but we are very much.
Mark A. Goldsmith: Already investing in it and expect to be.
Mark A. Goldsmith: To be able to feel the competitive salesforce at the right time.
Operator: God, that's helpful. Thanks for taking my questions. Thank you. One moment for our next question. Our next question comes from Ellie Merle with UBS. Please go ahead. Hey guys, thanks so much for taking the question. It's just a high-level strategy one.
Speaker Change: Got it that's helpful. Thanks for taking my questions.
Operator: Sure.
Eliana Rachel Merle: Thank you one moment for our next question.
Operator: Our next question comes from Ellie Merle with UBS. Please go ahead.
Eliana Rachel Merle: How are you thinking about which indication you would next start a pivotal study in, and how are you thinking about prioritization around moving into another tumor type relative to moving into a combination, say, in front line lung? Hi, thanks for joining us. And thanks for the question. Yeah, very straightforward.
Eliana Rachel Merle: Hey, guys. Thanks, so much for taking my question just a high level strategy one.
Speaker Change: How are you thinking about which indications next startup pivotal study and how are you thinking about prioritization around.
Speaker Change: Moving into another chemo type relative Q living in Q, a combination in front line lung.
Mark A. Goldsmith: Our top priority is going to be to move into first-line indications in the disease areas that we've identified, pancreatic cancer and lung cancer. Because we have the most traction there, we have the most data there, we're moving forward in second line. And so it is our immediate priority behind those first two pivotal trials and second line is to get this compound into first-line settings. And there's a lot of opportunity across first-line settings for pancreatic and lung. That's not necessarily just one trial for each, because there are a lot of subsets of early-stage disease. So there's quite a lot to do there.
Speaker Change: Hi, Thanks for joining us and thanks for the question, yes, very straightforward our top priority is going to be to move into first line.
Mark A. Goldsmith: Indications in the disease areas that we've identified pancreatic cancer and lung cancer, because we have the most traction there we have the most data there.
Mark A. Goldsmith: Moving forward in second line and so.
Speaker Change: It is.
Mark A. Goldsmith: Our immediate priority behind those first two pivotal trials in second line is too.
Mark A. Goldsmith: Get these get this compound into into first line settings, and Theres a lot of opportunity across first line settings for pancreatic and lung.
Mark A. Goldsmith: Not necessarily just one trial for each there are a lot of sub steps of early stage disease. So there's quite a lot to do there behind that would be other indications going beyond.
Mark A. Goldsmith: Behind that would be other indications going beyond lung and pancreatic cancer, and as you saw from the ACR, we certainly have evidence of activity in multiple tumor types and multiple genotypes beyond the core that we had studied previously. So we feel like there's a great opportunity, but we definitely prioritize these in the way that you alluded to and that I described.
Mark A. Goldsmith: Our other tumor types going beyond lung and pancreatic cancer and as you saw from the ACR. We certainly have evidence of activity in multiple tumor types and multiple genotypes beyond beyond the core that we have said previously so we feel like there's a great opportunity, but we definitely prioritize these and the way that you that you alluded to in that.
Mark A. Goldsmith: Right.
Speaker Change: Thank you.
Speaker Change: Okay, one moment for our next question.
Mark A. Goldsmith: Okay.
Operator: Thank you. One moment for our next question. Our next question comes from Ami Fadia with Needham & Company. Please go ahead. Hi, this is Poonam for Ami.
Mark A. Goldsmith: Our next question comes from Amit <unk> with Needham <unk> Company. Please go ahead.
Poonam: Hi, This is point on for Amit. Thank you for taking our question.
Ami Fadia: Thank you for taking our question. So my first question is, at AACR, you presented patient cases where two patients had dose reduction. So just wondering, based on the mechanism of action and preclinical profile, do you anticipate the safety profile for 6236 to be different based on the mutational profile? And the second question is, but given the competitive space in non-small cell lung cancer, what would you need to see in terms of clinical profile from the triple therapy to move forward with development?
Poonam: So my first question is on ACI, you presented patient cases.
Ami Fadia: Two patients had dose reductions.
Ami Fadia: Just wondering based on the mechanism action and peaking petrol file do you anticipate the safety profile for <unk> to be different based on the mutational profile.
Ami Fadia: And the second question is that given the competitive space in non small cell lung cancer, what do you need to see in terms of clinical profile from the triple therapy to move forward with development.
Ami Fadia: Yeah.
Ami Fadia: Okay, well, on the first question, maybe I could just sort of put that in context, and then if Dr. Lin wants to add anything, he can. We did show a couple of cases with dose reductions. I don't think one should take those as representative of the percentage of patients across hundreds of patients receiving the compound. Those cases were picked to illustrate certain mechanistic points about the activity of the compound against different genotypes and tumor types, which they did very successfully, including showing examples of complete response. They weren't particularly picked to show a safety or tolerability profile.
Speaker Change: Okay, well on the first question, maybe I could just sort of put that in context, and then if Dr. Lynn Webster add anything he can.
Ami Fadia: We did show a couple of cases with dose reductions I don't think one should take those as representative of the percentage of patients across hundreds of patients receiving compound.
Ami Fadia: Those were those cases, where picture illustrates certain mechanistic points about the activity of the compound against different genotypes in tumor types, which which they did very successfully including showing examples of complete responses.
Wei Lin: They weren't particularly pick to show safety or Tolerability profile that really comes from a much larger kind of aggregate dataset and if anything we might have leaned towards showing more examples of tolerability or side effects just to illustrate that.
Mark A. Goldsmith: That really comes from a much larger kind of aggregate data set. And if anything, we might have leaned towards showing more examples of tolerability or side effects just to illustrate that. The compound does carry some side effects. I mean, that's for sure, into Wei Lin's space, but even in those cases where there were dose reductions, the doses were still quite substantial, and their responses were persistent, and they were sustained.
Mark A. Goldsmith: The compound does carry some side effects I mean thats for sure.
Mark A. Goldsmith: Sure not sure of any drug that doesn't and even though the profile for the compound has been quite attractive and people have seen that and commented on it.
Mark A. Goldsmith: That doesn't mean that there are no side effects associated with it and so we want to be just very clear, especially when we're picking out a few examples are particularly interesting responses to make sure that people are saying that there can be side effects that cost with dose reductions and the last point I'd make and maybe this quite transitioned over to into two wavelengths space, but.
Mark A. Goldsmith: Even in those cases, where there were dose reductions.
Mark A. Goldsmith: The doses, we're still quite substantial.
Mark A. Goldsmith: And their responses persistent that they were sustained and so those dose reductions really didn't seem to have.
Mark A. Goldsmith: And so those dose reductions really didn't seem to have much impact. I think you answered that well. This trained me well.
Mark A. Goldsmith: Much impact so.
Speaker Change: Why is there anything you'd like to add to that.
Speaker Change: Thank you you answered comfortably yeah fully agree.
Mark A. Goldsmith: He's trained me well.
Mark A. Goldsmith: Okay.
Operator: Okay, thank you. So I guess the second question is, just wanted to understand what you would need to see from the clinical profile of the triple therapy 62916236 of PEMDRO to move forward with clinical development. Yeah, well, I think there are two different parts. What does 6291 plus 6236 look like?
Speaker Change: Okay. Thank you so I guess the second question.
Operator: Wanted to understand like what do you need to see on the conventional side of the triple therapy six to nine months extra teeth Anjelica move forward, it's critical that that group.
Operator: Sure.
Mark A. Goldsmith: And I think an earlier question asked what would give us, you know, confidence about the activity, and that really comes from those two targeted agents. So that's a separate question. And then for safety, we'd have to be confident that we could combine those three agents together to be able to move forward into a registrational study. Don't think it's likely that the triplet would have a great deal of efficacy data that [inaudible] Yeah, I agree.
Operator: Yes, well I think there are two different parts. One is 6% to 91, 6% to $3 six look look like and I think an earlier question asked what would give us.
Mark A. Goldsmith: Confidence about the activity in that.
Mark A. Goldsmith: It's really comes from those two targeted agent. So that's a separate question.
Mark A. Goldsmith: And then for.
Mark A. Goldsmith: Safety, we'd have to be confident that we can combine those three agents together.
Mark A. Goldsmith: To be able to move forward into.
Mark A. Goldsmith: A registrational study.
Mark A. Goldsmith: I.
Mark A. Goldsmith: I don't think it's likely that the triplet we would have.
Mark A. Goldsmith: A great deal of efficacy data that would draw.
Mark A. Goldsmith: <unk>, specifically, but again, maybe he wants to comment on that.
Speaker Change: Yeah, I agree I think.
Mark A. Goldsmith: I think we were initially wanting to establish the combinability of each of the components, a doublet, and then the stack with safety of all three. I think if each of the doublet components within the triplet is combinable, then we feel pretty confident this triplet will be combinable.
Wei Lin: I think on the efficacy side, without putting any numbers in, I think you can appreciate what the benchmark is really. Now the hemo alone typically gives a 30 to 40% response rate. In common with Pembroke, they have about a 50% response.
Wei Lin: So far, I think the amount of data we've presented, each of our monotherapies, whether it be 6291 or 6296, is about 40% in non-therapy. So if we're able to combine the two, we're optimistic that we'll have an agent that'll be superior.
Operator: Thank you. Thank you. Thank you. It should actually produce a fairly promising trip.
Mark A. Goldsmith: And I should just clarify, the person who was just speaking is Dr. Wei Lin, our chief medical officer, who we didn't introduce earlier, but he's joined us, so you get the benefit of his input. Thank you so much. Thank you. One moment for our next question. Our next question comes from Alec Stranahan with Bank of America. Please go ahead. Hey guys, thanks for taking our questions. Just two for me.
Alec Warren Stranahan: Maybe first on your RAS inhibitor doublets. I thought it's interesting that you're combining G12C or G12D specific inhibition with your multi-RAS as they will likely have some target overlap. I guess maybe could you talk about your thought process here?
Stephen M. Kelsey: Is this primarily driven by thoughts around mechanisms of resistance, or maybe something else like optimizing the therapeutic window? Dr. Kelsey is chomping at the bit to answer that question. The original concept, biologically, goes back to the observations that were made by multiple researchers looking at mechanisms by which tumors escape from mutant-selective RAS inhibitors, particularly the G12C offshoots, and demonstrating that there are really two major mechanisms, both of which involve upregulation or circumnavigation of the mutant RAS so that signaling through the RAS pathway can continue.
Stephen M. Kelsey: But logically it goes back to the observations that were made.
Stephen M. Kelsey: By multiple researchers looking at mechanisms by which tumors escape for mutant selective Ras inhibitors, particularly the <unk> inhibitors.
Stephen M. Kelsey: And demonstrating that there are really two major mechanisms both of which involve.
Stephen M. Kelsey: Up regulation also come navigation of the mutant Ras signaling through the Ras pathway can continue.
Stephen M. Kelsey: And we felt very strongly that if that is the main mechanism by which tumors are escaping from our mutant-selective RAS-on inhibitors, then a really good solution to that, potentially, would be our RAS multi-inhibitor because it does a number of things. Firstly, it stops signaling through the emergence of other mutations other than the original oncogenic mutation.
Stephen M. Kelsey: And we felt very strongly that if that is the main mechanism by which tumors or estate thing from our mutant selective <unk> inhibitors.
Stephen M. Kelsey: And then a really good solutions about potentially would be a ras multi inhibitor because it does a number of things firstly it stops signaling through the emergence of other mutations other than the one the original oncogenic mutation and we've seen <unk> mutant tumors.
Stephen M. Kelsey: And we've seen G12C mutant tumors escape by acquiring clones with G12D, G12R, and other mutations, all of which are amenable to inhibition with 6236. And secondly, we've seen tumors escape by upregulation of wild-type RAS, again, which is amenable to inhibition with RNC6236. Therefore, we could prevent tumor escape and therefore significantly prolong progression-free survival and potentially overall There are some empiric observations, which were exemplified by our recent presentation at AACR, that in fact, you may also be able to increase the depth of response and potentially the frequency of response as well by having the combination versus the single agent. And it may be that certain tumors that just don't respond very well to either agent when given as a single agent respond extremely well to the combination.
Speaker Change: Kate by.
Stephen M. Kelsey: Acquiring clones with G talk D. G 12 are another mutations all of which are amenable to inhibition was $63 six and secondly, we've seen tumor escape by Upregulation of Wild type Ras again, but which is amenable to inhibition with RMC $63 six so the original concept.
Stephen M. Kelsey: Was that we could prevent tumor escape and therefore significantly prolonged progression free survival and potentially overall survival. If we were to combine the mutant selective inhibitor with the with the RASK Melty inhibits are not.
Speaker Change: Awesome and pair it helps patients.
Stephen M. Kelsey: We're exemplified by our recent presentation of ICR.
Stephen M. Kelsey: That in fact, you may also be able to increase the depth of response and potentially the frequency of response as well by having the combination versus the single agent and it may be that certain tumors that just don't respond very well to either agent given as a single agent respond extremely well.
Stephen M. Kelsey: All too so the combination so it turns out that that.
Stephen M. Kelsey: So it turns out that there may be even more reasons for giving those combinations than invoked from the pre-clinical data and early emergent data on solar acid and atomic acid, but it all points in the same direction. Okay, great. Thanks, Steve. That's very clear. And then maybe one more, if I may, just on the second half updates for 6.2.3.6.
Speaker Change: That may be.
Stephen M. Kelsey: That may be even more reasons for giving those combinations than we had originally.
Stephen M. Kelsey: Invoked from the preclinical data.
Stephen M. Kelsey: Urgent data on solar asset without a grass, it, but but but at all points in the same direction.
Speaker Change: Okay, great. Thanks, Steve that's very clear and then.
Speaker Change: Maybe one more if I may just on the second half updates for 63, six sorry, if I missed this but just to be clear do you think data will be mature enough to provide an early look at PFS. As I think you mentioned previously this is one of the gating factors for moving into late stage studies, particularly for P. DAC or its duration of disease control, maybe still the best surrogate to look at.
Mark A. Goldsmith: Sorry if I missed this, but just to be clear, do you think data will be mature enough to provide an early look at PFS? Since I think you mentioned previously this is one of the gating factors for moving into late-stage studies, particularly for PDAC, or is duration of disease control maybe still the best surrogate to look at here? Thanks. Yes, I mean, I think we do expect durability to be part of those presentations before launching those trials.
Mark A. Goldsmith: Thanks.
Mark A. Goldsmith: Yeah.
Mark A. Goldsmith: Yes, I mean, I think we do expect to our ability to be part of those presentations for launching those trials you know.
Mark A. Goldsmith: You know, in the past, we've shown DCR data that actually was quite strong. And so I think we already know the answer to it from a DCR point of view, but the PFS is really going to be an important component of those others.
Mark A. Goldsmith: In the past, we've shown PCR data that actually were quite strong.
Mark A. Goldsmith: And so I think we already know the answer to it from a D C. Our point of view, but the PFS is really going to be.
Mark A. Goldsmith: An important component of those updates.
Operator: Great, thank you. Thank you. One moment for our next question. Our next question comes from Laura Prendergast with Raymond James. Please go ahead. Hey guys, congrats on the exciting progress you guys have made this year.
Speaker Change: Great. Thank you.
Laura Anne Prendergast: Thank you one moment for our next question.
Operator: Our next question comes from Laura Prendergast with Raymond James. Please go ahead.
Laura Anne Prendergast: Hey, guys. Congrats on the progress you guys made this year.
Laura Anne Prendergast: You know, as you think about the phase 3 design in non-small cell lung cancer, you know, thinking as I think about how the Code Break 200 study unfolded, where the FDA had suggested they use overall survival as an endpoint, and then, you know, we saw what happened there. Do you, do you expect, do you think there's any chance that the FDA might require you to use an overall survival endpoint versus a PFS endpoint? And how you think maybe the CRYSTAL-12 readout will relate to that.
Laura Anne Prendergast: Thinking about the phase III design in non small cell lung cancer.
Laura Anne Prendergast: Think about how.
Laura Anne Prendergast: How that could make it 130, and Holidayed, where the FDA had suggested they use overall survival as an endpoint and then you know.
Laura Anne Prendergast: We thought what happened there do you are you.
Laura Anne Prendergast: Do you expect do you think there's any sense what the FDA might require you. He was an overall survival end point versus a PFS endpoint and how you think maybe the crystal 12 readout will really into that.
Wei Lin: I'm relieved to call on Dr. Lin to answer that question. I think the, with regard to, I think if you've had a cancer, I think over-survival is probably expected to be required. With regard to non-small cell lung cancer, I think the FDA's position is less clear at this point. I think at multiple meetings, the message they've since given out is if the PFS improvement is clinically meaningful, obviously, they would never give a precise benchmark, but if it's following their criteria of being clinically meaningful, I think that they would consider granting full approval based on PFS alone, knowing that the number of viable therapies in lung cancer is very different than pancreatic cancer.
Jonathan Chang: I'm relieved to call on Dr. Lindsey answer that question.
Wei Lin: Hum.
Wei Lin: Hum.
Speaker Change: I think the.
Wei Lin: With regard to I think.
Wei Lin: That a cancer over survival was probably expected to be required with regard to non small cell lung cancer I think con.
Wei Lin: The I think the FTE positions less clear at this point I think.
Wei Lin: At multiple meetings I think the message.
Wei Lin: Hence, giving out as if the PFS improvement is company meaningful obviously.
Wei Lin: We never give a precise benchmark, but if its falcon their criteria of being clinically meaningful deal with <unk>.
Wei Lin: Granted full approval based on PFS alone.
Wei Lin: The only debt number.
Wei Lin: Number available therapy in lung cancer, it's very different than pancreatic cancer and so obviously, if you do deliver overall survival and that's one that's.
Operator: And so, obviously, if you do deliver overall survival, then that will definitely clear the bar. I think the Adagraf-Sibbs... We would be probably be very informative in that regard, on FDA's position on the requirement for overall survival in hospitals. Great, thank you very much. And then just regarding the expansion cohorts of vast genotype and tumor type, is that data set still expected for the second quarter or third quarter of this year? No, we think we've really already ticked the box for that milestone.
Operator: Definitely create a bar I think.
Operator: On the <unk> done.
Operator: We would be it would probably be very informative.
Operator: On that regard on fda's position on about the requirement of overall survival in non small cell lung cancer.
Operator: Great. Thank you very much and then just regarding the expansion cohorts of SaaS Genotyping tumor type is that data is that still expected for the second quarter or third quarter of this year.
Operator: Yeah.
Operator: No we think we've we've really already.
Operator: Check the box for that milestone the intestinal list and provided an initial a preliminary look at that which we did at the ACR with the cases that are that way.
Stephen M. Kelsey: The intention was to provide an initial or preliminary look at this, which we did at the AACR with the cases that Wei presented. And again, it was really primarily to make a mechanistic point that now there are multiple isoforms of RAS across mutations at different mutations even within G12 and different mutations outside of G12, including a Q61 with some level of confidence, and then also there was a case that contained a G13 mutation in the colorectal cancer case.
Stephen M. Kelsey: Presented.
Stephen M. Kelsey: And again it was really primarily to make a mechanistic point that really across now multiple isoforms of Ras across mutations at.
Stephen M. Kelsey: Different mutations, even with Engie 12, and different mutations outside of <unk> 12, including <unk> 61.
Stephen M. Kelsey: With some level of confidence and then also there were there was a case of it contained in G 13 mutation in colorectal cancer case, so from a mechanistic point of view I think we can sort of check the box that pharmacy $63 six behaves as it does pre clinically active against all of those mutations.
Stephen M. Kelsey: So from a mechanistic point of view, I think we can sort of check the box that RMC636 behaves. But what we won't be reporting on later this year is any sort of quantitative response rates across different mutations. I'm just not even sure we'll collect enough data to really come to stable estimates of what that might be.
Stephen M. Kelsey: What we won't be.
Stephen M. Kelsey: Reporting on later this year is there any sort of quantitative response from rates across different mutations.
Stephen M. Kelsey: I'm just not even sure we will collect enough data to really come to stable estimates of what of what that might be so I think where we're done with that question now and now we're moving into trials signs and so on.
Operator: So I think we're done with that question now, and now we're moving into trial design. Great, thank you very much. Thank you. And our last question.
Operator: Okay.
Speaker Change: Thank you.
Speaker Change: Our last question.
Benjamin Jay Burnett: And from Ben Burnett.
Stifel: With Stifel.
Benjamin Jay Burnett: One, the RMC 6036 program. You've talked in the past that you're seeing ORR trends that have sort of tracked more favorably since ASMO as you expanded the higher dose cohort. Just curious if you can comment further today; are you still seeing similar trends as you accrue more or follow up here? I bet that will be the first question that I won't comment on since we're not reporting any new data today. Apologies. I think we've lost you. Are you still there? We're still here. Could you hear us?
Speaker Change: Just one RMC $63 six program.
Benjamin Jay Burnett: You've talked in the past that youre seeing or trends in sort of tracked more favorably since ESMO as you've expanded the higher dose cohort. Just curious if you can comment further today are you still seeing similar trends as you accrue more follow up here.
Speaker Change: Hi, Beth.
Benjamin Jay Burnett: That will be the first question that I won't comment on since we're not reporting any new data today.
Benjamin Jay Burnett: Yeah.
Speaker Change: Apologize I think I made last year are you still there.
Speaker Change: We're still here could you harriss.
Operator: Yes. Sorry about that. I wanted to ask also about the G12D dose escalation study. If you just speak to the types of patients that you're enrolling, you expect to enroll, I guess, should we expect this to be largely in line with the epigenetics of G12D? So, mostly CRC or PDAC?
Speaker Change: Yes, sorry about that I think my question May not have gone through I wanted to ask also about the <unk>.
Operator: The <unk> dose escalation study if you could just speak to the types of patients that Youre Rolling do you expect to enroll I guess should we expect it to be largely in line with the epigenetics beautiful D. So like most of the CRC or Pete ACA are you focusing more specifically on one tumor type versus another.
Benjamin Jay Burnett: Are you focusing more specifically on one tumor type versus another? Oh, I see. I'm sorry. So you're asking: for the RMC9805 trial for our G12D selective inhibitor, do we expect the demographics of the patient population to match the demographics of the real world patient population?
Speaker Change: Oh, I see I'm, sorry, so you're asking about for the RMC non NATO five trial for our.
Benjamin Jay Burnett: <unk> selective inhibitor do we expect the demographics of the patient population to match the demographics of the.
Mark A. Goldsmith: Is that what you're asking? Exactly. Yeah, I think to a large degree, that's true.
Benjamin Jay Burnett: But the real world patient population that is that what youre asking exact.
Mark A. Goldsmith: Exactly.
Mark A. Goldsmith: You know, I don't think it's specifically designed that way. It's an old, old, old tumor eligibility. But that basically ends up meaning that you'll get something that represents the real world.
Mark A. Goldsmith: Yeah, I think to a large degree that's true true.
Mark A. Goldsmith: I don't think it's specifically designed that way if that had been all all the all tumors.
Mark A. Goldsmith: Eligibility.
Mark A. Goldsmith: Basically ends up meaning that youll get something that represents the real world and G. 12 D. Mutations are predominantly found in gastrointestinal tumors.
Operator: And G12D mutations are predominantly found in gastrointestinal tumors. G12D is the, I think, the third most common blood cancer mutation, but it's the first most common mutation across all solid tumors and across all gastrointestinal tumors. So yes, I think gastrointestinal tumors will be the most common.
Benjamin Jay Burnett: Okay. Okay. Thank you very much. Great. Thank you.
Operator: Thank you. This concludes the question and answer session. I'd now like to turn it back to Marc for his closing remarks. Thank you, operator. And thanks to everyone for participating today and for your continued support of Revolution Medicine. This concludes the program. You may now disconnect.
Benjamin Jay Burnett: <unk> is the third.
Operator: Third most common cancer mutation, but its the first most common mutation.
Operator: Ross all solid tumors and across all.
Marc: Our gastrointestinal jumpers. So yes, so I think gastrointestinal tumors will be most common.
Marc: Okay. Okay. Thank you very much I appreciate it.
Marc: Great. Thank you.
Marc: Thank you.
Marc: This concludes the question and answer session I would now like to turn it back to Mark for closing remarks.
Marc: Thank you operator, and thanks to everyone for participating today and for your continued support of Revolution medicines.
Speaker Change: Thank you for your participation in today's conference. This concludes the program you may now disconnect.
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