Thank you, operator, and welcome everyone to the first quarter 2026 earnings call. Joining me on today's call are Dr.

Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer, Dr. Alan Sandler, our Chief Development Officer, and Jack Anders, our Chief Financial Officer.

Dr. Steve Kelsey, our President of R&D, Dr.

Wei Lin, our Chief Medical Officer, and Anthony Mancini, our Chief Global Commercialization Officer, will join us for the Q&A portion of today's call. We would like to inform you that certain statements we make during this call will be forward-looking.

Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly report on Form 10-Q that are filed with the US Securities and Exchange Commission.

This afternoon, we released financial results for the quarter ended March 31st, 2026, and recent corporate updates. The press release and updated corporate presentation are available on the Investors section of our website at revmed.com.

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

Mark?

Thanks, Ryan. It's good to be with you this afternoon to discuss the tremendous progress we've made in 2026.

This is a pivotal moment for our organization and for patients worldwide living with pancreatic cancer who are in need of new therapeutic options. It is anchored by the top-line readout for RASolute 302 last month, in which daraxonrasib monotherapy demonstrated an unprecedented improvement in overall survival compared with chemotherapy in patients with previously treated metastatic pancreatic cancer.

The RASolute 302 results represent a transformative advance for patients. They also firmly validate our pioneering RAS(ON) inhibitor strategy and reinforce its potential to improve outcomes in RAS-driven cancers.

High investor conviction enabled an historic $2 billion dual-tranche capital raise that will allow us to continue our important work broadly, advancing our current portfolio of four groundbreaking clinical-stage oral RAS(ON) inhibitors and bringing forward the next wave of innovation targeting RAS-addicted cancers, including our new class of catalytic RAS(ON) inhibitors. On today's call, following my remarks, I'll pass the call over to Dr.

Alan Sandler, who will provide an overview on the recent clinical progress we've made across our portfolio, including the most recent data presented at the American Association for Cancer Research annual meeting. Jack Anders will then summarize our first quarter financial results before we open the call to Q&A.

Let me first spend a few moments talking about RASolute 302, the global Phase 3 trial evaluating daraxonrasib monotherapy in patients with previously treated pancreatic cancer. The top-line readout for daraxonrasib marked a major milestone in this disease, significantly raising the bar in the development of new treatments for patients living with pancreatic cancer, the most RAS-addicted of all human cancers.

In RASolute 302, daraxonrasib demonstrated unprecedented impact, meeting its primary and key secondary endpoints and showing statistically significant and clinically meaningful improvement in progression-free survival and overall survival compared to standard of care chemotherapy. In the overall intent-to-treat study population, which includes patients carrying tumors with or without an identified RAS mutation, daraxonrasib drove a 60% reduction in the risk of death compared with chemotherapy and with a median overall survival exceeding one year.

Daraxonrasib was generally well tolerated, and no new safety signals were observed. These are dramatic, practice-changing results, and our focus now is on moving with urgency to bring this potential new option to patients.

We intend to submit a New Drug Application to the US Food and Drug Administration under the FDA Commissioner's National Priority Voucher Program and will also execute our plan to file with other global regulatory authorities. Last week, we reported that the FDA issued a safe to proceed letter, allowing us to initiate an expanded access treatment protocol for daraxonrasib in patients with previously treated metastatic pancreatic cancer.

This will allow us to move as quickly as possible to ensure safe and equitable access to daraxonrasib for eligible patients in the US. We were also pleased to announce recently that RASolute 302 will be featured in the plenary session of this year's American Society of Clinical Oncology, or ASCO, annual meeting in Chicago.

We and the investigators look forward to sharing detailed results with the scientific community at that time. I'll now pass the call over to Alan to walk through some recent clinical program updates.

Alan?

Thanks, Mark. The extraordinary results from RASolute 302 validate our tri-complex inhibitor platform and give us increased confidence in daraxonrasib's potential in earlier treatment lines in pancreatic cancer.

This confidence was reinforced at AACR, where we shared updated clinical data from the Phase 1/2 studies for daraxonrasib monotherapy and in combination with chemotherapy in first-line metastatic pancreatic cancer. Both the monotherapy and combination cohorts demonstrated encouraging preliminary durability data.

In the monotherapy study, while median progression-free survival and median overall survival were not mature as of the data cutoff, the Kaplan-Meier estimates at 6 months were 71% and 83%, respectively. In the combination of daraxonrasib with gemcitabine and nab-paclitaxel, the Kaplan-Meier estimates at 6 months for progression-free survival and overall survival were 84% and 90%, respectively.

Across both studies, daraxonrasib's safety and tolerability profile remained consistent with earlier findings in this patient population, with no new safety signals observed. These compelling results strongly support our decision to rapidly advance RASolute 303, our Phase 3 study evaluating both daraxonrasib monotherapy and daraxonrasib in combination with chemotherapy in first-line metastatic disease.

The trial is enrolling globally. In addition to our first- and second-line daraxonrasib registrational studies in pancreatic cancer, patient enrollment is ongoing in RASolute 304, our registrational trial of daraxonrasib monotherapy in the adjuvant setting in patients with resectable disease following conventional surgery and perioperative chemotherapy.

We're also making progress in two registrational studies for zoldonrasib, our covalent RAS(ON) G12D-selective inhibitor, in first-line pancreatic cancer. We have initiated RASolute 305, a randomized, double-blind, placebo-controlled registrational trial evaluating zoldonrasib in combination with investigator's choice of chemotherapy, either gemcitabine and nab-paclitaxel or modified FOLFIRINOX, compared with placebo plus chemotherapy.

We remain on track to initiate RASolute 309, our first registrational study to evaluate the RAS(ON) inhibitor doublet combination of zoldonrasib with daraxonrasib in the second half of the year. Moving to non-small cell lung cancer, another focus of development for RAS(ON) inhibitors.

With approximately 30% of non-small cell lung cancers harboring a RAS mutation, including 18% with non-G12C mutations, unmet needs in non-small cell lung cancer remain a priority that we aim to address through several ongoing and planned registrational studies. Beginning with daraxonrasib, we continue to enroll patients globally in RASolve 301, our global randomized trial evaluating daraxonrasib monotherapy in previously treated patients.

Based on the strength of the Phase 1 results for daraxonrasib monotherapy in non-small cell lung cancer, as well as additional confidence from the recent positive RASolute 302 results, we are expanding the RASolve 301 study to increase the statistical power of the overall survival component of the dual primary endpoint. Enrollment is going well, and we anticipate substantially completing enrollment in the expanded study this year.

We also expect to disclose our plans regarding daraxonrasib combination therapy in first-line non-small cell lung cancer this year. Turning to G12D non-small cell lung cancer, at AACR, we presented updated clinical data for zoldonrasib monotherapy in a subset of patients who had previously been treated with immune checkpoint inhibitors and platinum chemotherapy.

Zoldonrasib was generally well tolerated and demonstrated a safety profile consistent with previously reported findings. Zoldonrasib demonstrated encouraging clinical activity, with a confirmed objective response rate of 52%, disease control rate of 93%, and a median progression-free survival of 11.1 months.

Overall survival data were immature at the time of analysis. The estimated survival rate at 12 months was 73%, while the median had not yet been reached, which is encouraging data at this early look.

We continue to believe deeply in the potential of zoldonrasib given its compelling safety and tolerability profile and encouraging clinical activity, which strongly support our plans to advance zoldonrasib across monotherapy and combination settings in lung cancer and other RAS G12D-driven cancers. Building on the strength of our monotherapy data, we are preparing to initiate in the first half of this year RASolve 308, a global, double-blind, placebo-controlled registrational trial evaluating zoldonrasib in combination with the KEYNOTE-189 regimen, which is the standard of care in first-line treatment for metastatic non-small cell lung cancer, compared to the KEYNOTE-189 regimen with placebo.

For patients with G12C non-small cell lung cancer, elaronrasib, a RAS(ON) mutant-selective inhibitor, has demonstrated a differentiated and compelling clinical profile in both G12C inhibitor-naive and G12C inhibitor-experienced lung cancer patients. We remain on track to share an update on our elaronrasib registrational strategy this year.

Our third RAS-addicted cancer focus is colorectal cancer, which remains an area of high unmet need and interest for the company. We have a range of combination studies underway designed to better understand this genetically complex and heterogeneous disease, including studies to evaluate RAS(ON) inhibitor doublet combinations and RAS(ON) inhibitors in combination with current standards of care and with other targeted drugs.

We remain on track to share combination data this year as we work to prioritize registrational opportunities. I'll conclude with brief highlights on two of our early-stage programs.

We continue enrolling patients in the first-in-human trial of RMC-5127, our fourth RAS(ON) inhibitor. RMC-5127 is selective for RAS G12V, the second most common RAS variant in solid tumors.

We expect to identify a recommended monotherapy Phase 2 dose for this compound in the second half of 2026. Finally, AACR brought with it the opportunity to showcase our new class of innovative mutant-targeted catalytic RAS(ON) inhibitors.

These inhibitors are designed to promote the conversion of mutant RAS in its active GTP-bound RAS(ON) state back to the inactive GDP-bound RAS(OFF) state, thereby mimicking the normal physiologic regulation of wild-type RAS. These preclinical data demonstrated that at well-tolerated doses, RM-055 achieved robust and durable anti-tumor activity across KRAS G12 mutant xenograft models of pancreatic cancer, non-small cell lung cancer, and colorectal cancer.

Notably, tumors that had escaped prior RAS inhibitor treatment were sensitive to RM-055, which drove deep and durable regressions. Its compelling, differentiated profile warrants clinical investigation of its potential to counter emergent drug resistance and to extend clinical benefit, and we remain on track to initiate a first-in-human clinical trial in the fourth quarter.

With that, I'd like to pass the call back over to Mark. Mark?

Thanks, Alan. In addition to the substantial R&D progress we've made across our pipeline, we continue to be very gratified by the buildout of our commercialization infrastructure and operational capabilities to support the company's global commercialization ambitions.

We've established the operational wherewithal required to move with speed and agility, focused initially in the US and extending into priority international regions. We are resourcing our efforts to ensure that we have the best strategies, tactics, operational capabilities, and people to bring daraxonrasib with urgency to patients, pending regulatory approvals.

We expect to be launch-ready under best-case approval timing scenarios. We have experienced and talented executives leading our commercialization team across medical affairs, market access, marketing, and sales.

These groups are deeply engaged in market preparedness and assessment, planning, physician and advocacy engagement, sharpening operational capabilities, and conducting other launch-readiness activities. We've recently appointed several experienced leaders across the Asia-Pacific and European regions, including Neil MacGregor as our General Manager for APAC, Tetsuo Endo as General Manager for Japan, and Martin Völkel as General Manager for Germany.

I'd now like to turn the call over to Jack Anders, our Chief Financial Officer, to summarize our first quarter financial results. Jack?

Thanks, Mark. We ended the first quarter of 2026 with $1.9 billion in cash and investments and further strengthened our financial position after the quarter with $2.1 billion in net proceeds from our concurrent upsized offerings of common stock and convertible debt in April.

Before we dive into the income statement for the quarter, I'd like to highlight that our stock-based compensation expense for the quarter was higher than usual and explain the reason behind it. Stock-based compensation expense was $87.3 million for the quarter ended March 31st, 2026, compared to $25.1 million for the quarter ended March 31st, 2025.

In the first quarter of 2026, the company updated its equity compensation program to introduce competitive retirement benefits for employees who meet specific minimum age and service requirements. The modification of this program resulted in an incremental $44.6 million in stock-based compensation for the first quarter of 2026.

This incremental expense was primarily due to the accelerated timing of recognition of stock-based compensation expense originally scheduled in future periods for outstanding eligible awards. As a result of this timing pull-in, we expect higher non-recurring lumpiness in stock-based compensation expense for the first half of 2026, with stock-based compensation expense decreasing and returning to a more normalized trajectory in the second half of the year.

As a result of this change, the company is increasing its estimate of full-year 2026 stock-based compensation expense by approximately $80 million and now expects full-year 2026 stock-based compensation expense to be between $260 and $280 million. Additionally, the company is also updating its projected GAAP operating expense guidance to reflect this expected increase in stock-based compensation expense and now expects full-year GAAP operating expenses to be between $1.7 billion and $1.8 billion.

Moving to expenses for the quarter, R&D expenses for the first quarter of 2026 were $344.0 million, compared to $205.7 million for the first quarter of 2025. This increase was primarily due to higher clinical trial and manufacturing expenses for daraxonrasib and zoldonrasib due to acceleration of the pace and expansion of these programs.

R&D expenses were also higher as a result of increased headcount costs and higher stock-based compensation expense, as described earlier. G&A expenses for the first quarter of 2026 were $101.3 million, compared to $35.0 million for the first quarter of 2025.

The increase in G&A expenses was primarily due to higher stock-based compensation expense, as described earlier, increased headcount costs, increased commercial preparation activities, and higher administrative costs. Net loss for the first quarter of 2026 was $453.8 million, compared to $213.4 million for the first quarter of 2025.

The increase in net loss was due to higher operating expenses. That concludes the financial update.

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

Thanks, Jack. The remarkable start to 2026 is the result of years of unwavering dedication, relentless perseverance, and hard work by our team and collaborators, standing on the shoulders of others.

With the unprecedented performance of daraxonrasib monotherapy in the RASolute 302 study, we believe we are in the position to change the standard of care for patients living with pancreatic cancer, subject to regulatory review and approval. The global response to the RASolute 302 data has been overwhelming.

The news brings with it hope and possibility for patients, physicians, and the advocacy community that have all been waiting too long for new, more effective treatment options. We are now an important step closer to fulfilling our mission of discovering, developing, and delivering innovative targeted medicines to patients living with cancer.

We have an extraordinary opportunity, and we take very seriously the responsibility that goes with it. Before I close, I'd like to recognize our continuing partnerships with patients and caregivers, healthcare providers, and investors, as well as the remarkable dedication and efforts of RevMed employees.

It requires the ongoing support of all of our partners and constituencies to do revolutionary work on behalf of patients. With that, I'll turn the call over to the operator for the question-and-answer portion of the call.

Great. Good afternoon, guys.

Thanks for taking the question, and congrats on all the recent, very exciting progress. Wanted to ask, you recently noted you could share data at a medical meeting that supports the rationale for RASolute 309, the Phase 3 front-line PDAC trial looking at zoldonrasib plus daraxonrasib versus chemo.

Would this include durability data, or just response rate, as we've seen with some of your initial disclosures? Maybe more importantly, how much additive efficacy would you be looking for here to say it's clinically meaningful to justify the combination over the exciting monotherapy results we've seen with both of these agents?

Thank you.

Thanks, Cory. Appreciate your comments and question.

It's probably too early for us to lay out what that presentation would look like. We typically don't forecast it.

We'll show what we have. We think it will justify our plans, and we'll provide that in due course.

The second question also probably, unfortunately, I can't be too helpful about what's the threshold for added value that justifies doing that. Of course, we look at the totality of the evidence.

We look at the historical benchmarks. Ultimately, as you sort of implied in your question, durability is the most important parameter.

Got it. Thank you.

Good afternoon, everyone. Thank you for taking my questions and congrats on everything.

I got a couple kind of at the opposite end of the spectrum. One, how many patients do you think you can accommodate under expanded access program for daraxonrasib following RASolute 302?

What are the potential implications as you start thinking about potentially [unclear]

Hey, Charles. Charles, we're not able to pick up what you're saying.

Operator, I don't know if there's anything you can do on your side to improve the audio quality.

Why don't we move on to the next caller and come back to Charles?

Hey guys. Thanks for taking my questions.

Again, congrats on the RASolute 302 data. Looking forward to the full data presentation at ASCO.

A question on the EAP program. I know this was just announced a few days ago, but Mark, I don't know if you could comment what you're seeing so far in terms of demand for the EAP program and how many patients could potentially benefit from this prior to officially receiving FDA approval?

Then maybe just if you could share your view of the size of the second-line pancreatic cancer opportunity based on your market research, how many patients in the US do you think would be treatment-eligible for daraxonrasib based on the 302 study? Thanks so much.

Thanks, Michael. Nice to hear from you.

On the first question, of course, we're working hard to get in a position to be providing drug to those who need it. The demand has been very clear from the moment that it was announced, and we don't expect that to slow down anytime soon.

We're putting all the resources that we can on it to help meet that need. I can't really give you a projection as to the number.

I don't know how we could make that projection. We'll just have to play it out.

I think there is clearly widespread awareness of daraxonrasib, and those calls started coming in within minutes after the announcement. The size of the second-line opportunity, Wei might want to talk about this.

We can't characterize it for you with great depth, but we typically think about roughly 60,000 new cases in each year, and then maybe Wei can comment on both what's historical attrition and then also whether or not daraxonrasib might affect that.

Happy to do that. These are obviously just estimates based on clinical practice.

As Mark commented, about 60,000 Americans are newly diagnosed each year with pancreatic cancer. About 50% to 60% of those patients are diagnosed with metastatic disease.

Those patients are eligible to receive first-line therapy for metastatic disease. Typically, because of both the aggressive nature of disease as well as the toxicity of chemotherapy, about half of the patients who receive first-line metastatic treatment receive subsequent second-line treatment.

That gives you a sense of the overall attrition as well as the size.

Just to add to that, that could certainly change in the context of first-line treatment, but we don't have anything to address on that point today.

Thank you.

Hey guys, thank you so much for taking the question. Just wanted to ask on the RASolve 301 upsizing.

Could you clarify what exactly led to the upsizing? What were you powered for before, and what are you powered for now?

Does this change the timeline from enrollment completion to readout? Thank you.

Thanks a lot for your question. I'm going to answer the second question, and then Alan Sandler going to talk about the first.

We don't think it will change the timing of the readout given the high pace of enrollment and where we stand today. We don't expect to impact our projection that we'll complete or substantially complete enrollment this year.

The more subtle question about the sizing of the trial, Alan can comment on.

Sure. Thanks.

An important point is when we've realized the importance of overall survival. Given the results that we've seen in 302, and also the Phase 1 monotherapy data, we have a very high conviction on our ability to obtain overall survival benefit.

As a result of that, we're going to further prioritize overall survival in 301 by expanding the enrollment, as you've noted, going from 420 to 590 patients. That will increase the statistical power of that component of what is a dual primary endpoint.

Then again, as Mark has mentioned, there's a great pace in terms of the patient enrollment, and we think that we will substantially complete the enrollment even with the expanded study this year.

Got it. Thank you.

Hey guys, thanks for taking our questions this afternoon. Mark, during the call you said the best case timing scenario for darax launch across the globe.

How should we think about the timing and the cadence then for the filing and launch specifically across APAC and European regions? Just on the NDA application towards the FDA, can you give us a little bit more color, a little bit more granularity in terms of the things that are left to complete?

Thank you.

Thanks, Brian. Can't really give you any specific timing with regard to the filings outside the United States.

Just generally speaking, we are starting with the US filing as the initial priority. There will be some sequential framework for filing in other countries, and we're already engaged with regulatory authorities outside of the United States in order to make sure that we can deliver what they need and in as timely a manner as possible.

For the NDA, your question was what's left to deliver? Is that how you put it?

What are the things that are left to complete before you complete the NDA application?

We've been fully engaged with the FDA for a long time, as and of course with the CNPB and the Breakthrough designation, we've had a higher level of engagement than you might otherwise have. We are providing them information as it becomes available and mature enough to provide to them.

Ultimately, the clinical package is the thing that will be provided. I can't give you a specific timing on that.

There's a full-throttle effort to do it. We feel the urgency around it.

Certainly, the question earlier about the EAP provides a pretty strong signal about how urgent that is, and we'll continue to move this forward as fully as we possibly can.

Great. Thanks, Mark.

Thanks for taking my questions. Maybe following up a little bit on Corey's question earlier just on the zoldonrasib plus daraxonrasib combo.

Can you maybe speak to the 309 design, particularly in light of the 302 finding and the survival data looking better than anything we've ever seen even in first line? Just why is 309 comparing to chemo still the right design?

Should it really be switched over to consider daraxonrasib monotherapy as the comparator arm there at a minimum, one to get the contribution of parts, but also just from a clinical execution perspective of where the ball seems to be headed in pancreatic cancer?

Thanks, Marc. That's a good question.

It's a subtle one. Of course, today standard of care is chemotherapy, and until there's a dataset that moves the FDA to approve a different treatment, and a different treatment at the level that people consider the new standard of care, then chemotherapy is the standard of care.

I think you're sort of inviting me to comment that of course we think daraxonrasib has a real potential in monotherapy, but also in combinations in first line. Among those combinations, chemotherapy is one that we've already provided some early-stage data on and we're quite excited about.

That combination is in the 303 trial. We're already going into combinations, and it's really just a question of when that bar moves.

We have high confidence that the combination can deliver something that is differentiated from chemotherapy, but also even from monotherapy. I think the other thing to keep in mind is we do a lot of things where there's overlap in the patient populations that we might be able to serve in different ways.

We don't shy away from that, as we've discussed that before, because every patient has his or her own specific needs, and giving doctors options even if the outcomes on paper may look fairly similar across broad populations, there still may be reasons why one particular patient would benefit or would be perceived to benefit from one particular combination or monotherapy approach versus another. Providing the most fulsome set that we can based on the science and then ultimately on the clinical data increases the chance that we're the ones who are delivering the best possible options for patients.

That's the high-level comment.

Hi guys, thanks for taking my questions and congrats on the progress. Can you talk about your latest thinking on getting to a chemo-free option in frontline pancreatic cancer?

What gives you confidence in being able to achieve this, and what do you think is the best strategy for getting this?

Thanks, Jonathan. Nice nice to talk with you.

We just talked about one of those strategies for a chemo-free frontline, which is monotherapy daraxonrasib. I think the data single-arm data we've shown so far are compelling enough that it just very much justified incorporating that into the Phase Phase 3 first-line trial, and we'll see how that performs.

We have every expectation that it could deliver a chemo-free regimen. Then the second option is also one we just talked about, which is combining a mutant-selective inhibitor with daraxonrasib.

That would be a chemo-free strategy. That specific combination of zoldon plus darax, of course, is for the 40% of pancreatic cancer cases that are carrying a RAS G12D mutation.

We have other mutant-selective inhibitors directed against additional mutations that are common in or can be found in RAS cancers, we could and would likely fill out that collection of regimens. It just happens that zoldonrasib plus darax(ON) is on the vanguard of the work because of the maturity of the of the compound and the data that we have so far.

I think those are two very compelling chemo-free regimens. There are others that one can consider.

There are immunologic agents that can be combined. There are other targeted agents that could be combined.

We're already exploring, as PRMT5 combination, PRMT5 inhibitor combination, etc. I'm sure there will be other things to come over time.

Understood. Thank you.

Hello. Thanks for giving me another stab at this.

Can you hear me now?

All righty, perfect. I believe a bunch of clinical type questions were taken, I'll ask one a little bit earlier.

RM-055, nice to see your presentation at AACR as well as some of the work you helped support over at Pier Paolo Pandolfi's lab that was just published yesterday. Can you comment a little bit perhaps on RM-055's ability to potentially address daraxonrasib resistance mechanisms that go beyond that of KRAS amplification?

Can you also talk a little bit about perhaps how you might be achieving what appears to be at least preclinically a wider therapeutic window for RAS mutants over RAS wild types over that which daraxonrasib can achieve? Any color as to how you're accomplishing that mechanistically and if you can also kind of see that in your preclinical models as you advance that into the clinic?

Thank you.

Thanks, Charles. Those were loud and clear.

Steve Kelsey, I think, will comment on both of those important topics.

Sure. I think the RAS amplification can be perceived as a standalone mechanistic basis for escaping daraxonrasib.

It also acts as a surrogate for increasing flux through the RAS pathway generally. In most of the experiments that we've done, RM-055 is a better inhibitor of increased flux through the RAS pathway generally, particularly when it's mediated through a G12 mutation.

I think there is a general principle of escape from daraxonrasib occurring through reactivation of RAS pathway signaling. It's not just amplification of the mutant allele that can do that, and I think there's every reason to believe that RM-055 may be effective beyond just pure RAS mutant amplification.

Your point about therapeutic index, it's all to do with the relative importance of hydrolysis of RAS(ON) back to RAS(OFF) between cancer and normal tissue. Normal tissue, most of the RAS in normal tissue is already in the OFF state anyway, but it's being catalyzed back.

The active RAS is being catalyzed back to RAS(OFF) very effectively by the naturally occurring GAPs. The whole point of RAS mutant cancer is that that just doesn't happen.

The ability of the mutant RAS to withstand that hydrolysis back to the RAS(OFF) state is very different, and it varies from mutation to mutation. What we've done is very selectively targeted the inability of particularly, as I said, G12 mutant RAS to be hydrolyzed back to RAS(OFF) by forcing it to be hydrolyzed back to RAS(OFF).

This drug has almost negligible effect on normal tissue in that respect, and a very significant increased deactivation of mutant RAS in cancer cells.

Got it. Thanks for taking the questions, and congrats again on everything.

Thank you.

Great. Thanks, guys.

Congrats on the progress. Two quick ones.

On colorectal cancer data coming up, can you help guide expectations on how to think about combination with EGFR given overlapping rash and how to think about mitigation or how to interpret results given higher efficacy, but also trying to mitigate rash in that strategy? Then also, in the first-line panc study which is enrolling, we definitely get huge feedback that it's going to enroll super fast in a number of different sites.

Is it safe to assume that there's probably an interim in that study as well, eventually, once you complete enrollment? Thanks.

Thanks, Michael. Nice to hear from you.

Wants to address the CRC. Maybe I'll just make the comment that it is true that daraxonrasib itself has essentially overlap with the EGFR antagonist from the perspective of suppression of RAS signaling that drives the skin side effects.

That is a harder combination to contemplate. That really doesn't apply at all with mutant-selective inhibitors.

That's why the G12C selective inhibitors that launched the field essentially, adagrasib and now others, can be combined pretty readily, and it really fundamentally addresses the whole gap in the EGFR coverage that occurs in the RAS-mutant tumors. The whole reason why EGF receptor antagonism is contraindicated typically in RAS-mutant tumors, you really need the RAS inhibitor.

That combination is in principle something that can be pursued. Stay tuned.

We'll talk about it when we're able to do so. Question about the first line, I forgot the tail end of the actual question part of it.

Does it have an interim analysis built into [unclear]?

Oh, does it have an interim analysis. Wei, you want to comment on that?

I guess at this current stage we don't plan to disclose the analysis plan.

Okay. There, you've heard it from our Chief Medical Officer.

Thank you.

Hey, guys. Thanks for the update.

I was curious what are some of the top variables still under consideration for daraxonrasib in first-line lung cancer as far as strategy goes? Then, on the back of RASolute 302 showing such a unprecedented OS, what kind of pricing power are you guys thinking this could unlock?

Are there any benchmarks for pricing that you guys are most focused on?

Hi, Laura. Nice to hear from you.

Don't think we can really comment on the pricing. Of course, the OS impact is something everybody's interested in, starting with patients and their families, and all the way up to insurers and payers in other geographies.

It will be relevant to their considerations, but that's about all we can say about pricing today. Then your question on first-line non-small cell lung cancer, which was what?

What are the variables?

Oh, I see, with regard to daraxonrasib in first line. We've alluded to it.

We commented that there are a couple of things going on. Probably one of the most important is that we're now dosing patients with ivonescimab, we're all waiting to see how that progresses, but it points towards potentially becoming the new standard of care for frontline non-small cell lung cancer, in which case that's something we need to take into account, which we hadn't really taken into account before we had the real relationship with Summit that's now very much active and we're dosing patients.

That's probably the main variable. I think the other thing just conceptually to comment on is the mutant-selective inhibitors are already pretty well established simply because of the G12C inhibitors that launched the field, and that sort of a paradigm that lung cancer doctors are now used to thinking that G12C is its own disease, which means G12D will be its own disease, and G12V will be its own disease, and pretty quickly you've covered most of the mutations in RAS lung cancer.

We happen to have a G12D-selective inhibitor, which is performing particularly well. We happen to have a G12C-selective inhibitor, which is quite differentiated and compelling.

We have a G12V-selective inhibitor that's in the clinic now, and we expect good things from that. There are multiple ways to cover that, and a field in which it's already broken down by genotype.

That's one possible strategy. Those are kind of several of the major considerations.

Understood. Thank you very much.

Hey. Thanks for taking our questions and congrats on the trial ahead.

For RASolute 303, how should we think about that study's enrollment ramp versus the second-line study that you just completed in terms of timing of enrollment completion? Then, can you remind us if crossover is allowed in that RASolute 303 study?

Separately, any comments on potentially starting a registrational trial with darax and a PRMT5 inhibitor? Thank you.

Thanks very much for your questions. The timing of completion, we can't comment on that now.

We're just not at a stage where we can project a timeline with any confidence. Maybe the even more important point would be, we know there's very, very high interest in this.

Sites that have activated are enrolling, but there are plenty of sites that still are yet to be online, and they're a patient lined up at many of these facilities. We're aware of that.

We expect there to be very high demand for this for a variety of reasons, not the least of which is the disclosure of the 302 key findings, which encourages people to do it. Crossover is not allowed in the trial design.

As of course, it's up to any individual patient. They can cross over on their own if there is an approved therapy to cross over to.

In terms of actual crossover design, we can't really provide it when OS is the standard. That's the sort of conundrum of a Phase 3 trial for which overall survival is the endpoint.

We're currently kind of in the process of transitioning from equipoise to out of equipoise. Where we stand in that is sort of a matter of judgment, and it's really a question for the regulatory agency.

They have to make that determination. As long as OS is required, it's very difficult to achieve that with a crossover design.

Anything you want to add to those points?

The only additional comment that I would make, again, because of the concern for overall survival being a primary endpoint, is we've established a broad geographic footprint in order to mitigate the potential for impact of second-line therapy with darax moving forward. Smaller US footprint, larger ex-US moving forward.

Good comment. Then the last thing was with regard to PRMT5.

We don't have any update to provide on that today. We're enthusiastically engaged in collaboration with several companies now who are evaluating PRMT5 inhibitors in combination with RAS inhibitors, and we're keenly interested in how that all goes.

Thank you.

Hey, guys. Thanks for taking my questions and for squeezing me in here at the end.

I guess two for me. First, would be interested to hear from your experience whether the initial ORR with daraxonrasib was a good metric for predicting PFS and OS benefit in larger studies?

Does a higher numerical ORR translate to better survival, or is duration of response or time on therapy maybe more telling for this? Just trying to think through some headline numbers we're seeing from others in the space.

Quickly, will you be allowing third-line-plus patients into the EAP as well? Thank you.

Thanks, Alec. On the last question, yes, the eligible population includes previously treated, and goes beyond the pure second line that were in the 302 trial.

Is ORR predictive of PFS or OS? Who wants to comment on that?

We don't have analysis on that. ORR is broadly correlates with PFS.

It's not such a tight stoichiometric relationship that you can actually say that if the ORR is 5 percentage points higher that the PFS is going to be 5 percentage points higher. It is broadly correlate.

There are better ways of predicting PFS, which involve multi-parametric analyses that include ORR, but are not restricted to ORR. We have not made those broadly available to other people, because, obviously, it's a competitive advantage for us to know that and not share it with our competitors.

Definitely ORR is a component of that framework, for sure. I think as we're learning more and you're right.

We're learning a lot more now that we have decent drugs for pancreatic cancer, we're learning a lot more about the relationship between all of these outcomes. In other diseases like lung cancer, breast cancer, and colorectal cancer, it took years and years and years to figure out these relationships, and they're still not totally clear.

I think that you will see relationships emerging, whether they're causal or otherwise. I wouldn't draw too many straight lines.

Yeah. I'll pile on that.

There's obviously some relationship, but what you can do with that and how you should interpret ORR data and have vision for what that's going to translate into, premature.

The other thing is, of course, with RAS inhibitors, the numerical value of ORR at any point in time isn't very accurate anyway. Patients can take up to, and sometimes beyond, 6 months to fulfill the RECIST definition of response.

At any given point in time, there may still be people who might become responders who have not yet become responders. The RECIST definition of response isn't a particularly robust endpoint in its own right.

There's a lot of wiggle room and uncertainty around all of these analyses. It's very tempting to believe that the overall response rate determined by RECIST is a pure and absolute and accurate measurement, but I can tell you it absolutely is not.

If you look at those CT scans and try to compute unidimensional measurements of the target lesions, then you'll realize just how fraught with uncertainty the whole thing is.

Alec, I'm glad you asked.

Very good. Thank you, guys.

Sorry, Alec. Can't resist that one.

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