Revolution Medicines at Stifel Forum: RAS-Driven Cancer Insights

On Wednesday, 09 April 2025, Revolution Medicines (NASDAQ: RVMD) participated in the Stifel 2025 Virtual Targeted Oncology Forum. CEO Mark Goldsmith shared insights on their innovative approach to treating RAS-driven cancers. The discussion highlighted the potential of their lead asset, doraxonrasib, in improving outcomes for pancreatic and non-small cell lung cancer patients. While the company is optimistic about its progress, it faces competition from emerging KRAS inhibitors.

Key Takeaways

• Revolution Medicines is advancing Phase 3 trials for doraxonrasib in pancreatic and lung cancers.
• The company emphasizes overall survival as a critical measure for pancreatic cancer treatment.
• A strong financial position allows for strategic ex-US partnerships.
• Combination strategies are being explored to enhance treatment efficacy.
• Upcoming data for zolonrasib in lung cancer will be presented at AACR.

Operational Updates

Doraxonrasib

• Two pivotal Phase 3 trials are underway for pancreatic and non-small cell lung cancer.
• The drug is orally available and taken once daily.
• High interest in the pancreatic cancer trial is driving enrollment.
• The company aims for full registration based on robust trials.

Zolonrasib

• Targeting RAS G12D mutations, with data to be presented at AACR.
• It is an oral, selective covalent inhibitor.

Ex-US Strategy

• Exploring partnerships to navigate complex regulatory and pricing challenges.
• Retaining full US rights while evaluating global opportunities.

Future Outlook

Doraxonrasib

• Optimistic about achieving statistical significance for overall survival in trials.
• Considering a chemotherapy combination arm in trials.
• Aims to establish doraxonrasib as a first-line treatment.

Commercialization

• Committed to substantial US commercialization efforts.
• Plans to expedite doraxonrasib availability, pending regulatory approval.

RAS Targeting

• Combination therapies are seen as key to extending patient survival.
• The field is still in early stages, with potential for significant developments.

Q&A Highlights

Pancreatic Cancer Treatment

• FDA prioritizes overall survival benefits in treatment evaluation.
• Doraxonrasib shows an encouraging tolerability profile.

Competitive Landscape

• New pan-KRAS and KRAS-selective inhibitors are emerging.
• Durability is crucial for assessing clinical benefit.

AACR Data

• G12D lung cancer predominantly affects nonsmokers.

In conclusion, readers are encouraged to refer to the full transcript for a detailed understanding of Revolution Medicines' strategic initiatives and developments.

Full transcript - Stifel 2025 Virtual Targeted Oncology Forum:

Brad Camino, Senior Analyst, Stifel: Hey. Thanks, for continuing to join us here at the Stifel two day virtual oncology event. My name is Brad Camino, senior analyst here at Stifel. Very happy to be joined for the next fireside chat with Revolution Medicines. We have CEO Mark Goldsmith.

Mark, thank you so much for joining us.

Mark Goldsmith, CEO, Revolution Medicines: Pleasure to be here. Thanks for having me.

Brad Camino, Senior Analyst, Stifel: Can you just kick off with an introduction to RevMed and and overview the state of the portfolio today?

Mark Goldsmith, CEO, Revolution Medicines: Sure. Well, Revolution Medicines is a company focused essentially exclusively on the most common genetic driver of human cancers, which are mutations in in RAS proteins. We have developed a novel set of approaches, to inhibiting the RAS pathway and specifically targeting the RAS cancer drivers. We've introduced the concept of inhibiting the on or activated form of RAS and today, have three clinical stage assets, all of which each of which has shown essentially clinical proof of concept, one of which has moved into two late stage pivotal trials with two additional pivotal trials expected to initiate later this year, and the other two assets are are moving along very well as well. So we have a very comprehensive approach to targeting the wide range of mutations that do drive RAS addicted cancers, and we're excited about the progress we've made so far and the promise of of things going forward.

Brad Camino, Senior Analyst, Stifel: Now the lead asset, doraxone rasib, it's in a phase three trial for second line pancreatic cancer. Can you just discuss some of the key design elements of that study and the data that support the trial?

Mark Goldsmith, CEO, Revolution Medicines: Sure. Well, there are actually two pivotal trials underway, two phase three pivotal trials, one in pancreatic cancer and one in non small cell lung cancer with doraxonrasib. Let me just remind everybody that doraxonrasib is a RAS multi inhibitor. It's specifically designed, to inhibit all forms of RAS. It certainly has proven to do so in every experiment we've ever done.

It is an orally available drug. It's once a day, and it clearly has shown significant activity against both of these tumor types. In pancreatic cancer in particular, we've shown a substantial dataset in second line, as well as in later lines beyond second line, but particularly focused on second line pancreatic cancer treatment. We've reported from a single arm trial of PFS and OS and ORR values that are all quite exciting and significantly differentiated from the well established standards of care in pancreatic cancer, which is exclusively a chemotherapy driven chemotherapy treated disease today, but it is also nearly exclusively a RAS driven disease. It's the cancer for which there is most likely to be a RAS driver.

More than ninety percent of all pancreatic cancers have a RAS mutation. The ORR typically has been for these patients with chemotherapy in the range of less than ten percent. Median PFS, has been in the range of three to three and a half months, and median OS in the range of six to seven months. With diraxonerasib, we've established an overall response rate that's greater than thirty percent, a very high rate of disease control, a median PFS value in the eight month range, and a median OS value in the fourteen plus month range. So, again, it depends on exactly what dose and so on, but without getting into that level of detail, very compelling numbers.

Of course, they are based on a single arm trial, and there are limitations to comparing that to standards of care in the absence of a head to head comparison. But we are now moving into and enrolling patients and treating patients in a second line pancreatic cancer trial. It's a global trial. Enrollment is benefiting from extremely high interest. This is an area of very deep unmet need across the globe, and it is currently enrolling quite well.

Brad Camino, Senior Analyst, Stifel: K. And on that that last part there, for second line pancreatic, to deliver value to those patients, how important is it to match the phase one PFS of eight point eight months for the diraxoneuracid arm in the phase three trial?

Mark Goldsmith, CEO, Revolution Medicines: Oh, I think there's a lot of room for improvement above standard of care, three to three and a half months of median PFS and six to seven months of median OS. Really, I think we can achieve clinical impact regardless of whether our PFS and OS values exactly match. In fact, I'm quite sure they won't exactly match what we've reported so far just by by going to a larger study and a global study. I think there's quite a lot of room for improvement here within the window between what we've shown so far and and what's been what's been reported over the years for chemotherapy.

Brad Camino, Senior Analyst, Stifel: And in pancreatic cancer, there does seem to be a little bit of a disconnect between ORR and PFS values. And maybe we think about the pan RASP mechanism specifically in this cancer type, why might it produce a longer PFS than historically would be associated with a mid thirty percent response rate?

Mark Goldsmith, CEO, Revolution Medicines: Yes. Well, I think it it probably has most to do with pancreatic cancer per se rather than the genotype that's driving the cancer. Pancreatic cancer biology has only been studied in the context of chemotherapy for all these years, with limited response rates and limited PFS and limited OS, there really hasn't been the possibility of establishing any, you know, good biological or or pharmacologic understanding of the relationship among those. I think diraxone rasib is really the first to to do so. It inhibits all forms of RAS, and we believe in many RAS cancers, not only the initial defined genetic driver of the cancer is a RAS mutation, but also tumors may be sustained by other forms of RAS, including wild type forms of RAS and potentially other mutant forms that are lurking inside a heterogeneous tumor.

And therefore, our thesis has been that diraxone RACEP is a multi RACEP inhibitor, will have the greatest chance of suppressing all of these different ways in which a RACEP addicted tumor can get its fix for RAS signaling, and that's essentially exactly what happens biologically. As to why that doesn't lead to much higher objective response rates, I I think that that seems to come from the criteria that are used for defining response rates. We have a set of resist criteria that are established by consensus. They're fairly simplistic. A 29% reduction in tumor volume, which could have huge clinical benefit for a patient, doesn't count as a response, and a 30.1% reduction does.

It doesn't really make any sense. Also, keep in mind that pancreatic cancers really are a combination. The tumor itself is a combination of actual cancer cells, but also a significant inflammatory and stromal response, which is a natural response within the pancreas to the various factors that are elaborated by the tumor cells. Shrinking a tumor may require much more than just killing the tumor cells, but may take time for the overall bulk of the tumor to shrink as the inflammatory or sclerotic response gets resolved much more slowly. And indeed, with doraxonerasib, we've seen that the longer a patient stays on the medicine, on the investigational drug, the more likely that their tumor will shrink, and in many cases, it continues shrinking over multiple cycles of treatment and multiple scans.

So I think at this point, we've come to believe that durability is the most important measure of the clinical benefit, and that is indicated by both PFS and OS, and we're quite encouraged by what we've seen so far.

Brad Camino, Senior Analyst, Stifel: Right. And as I think about the potential registration of this drug, how important in second line PDAC is it to deliver a statistical OS benefit versus a trend of benefit slash no detriment?

Mark Goldsmith, CEO, Revolution Medicines: Well, that's a review question, of course. That's an that's an that's a question best addressed to the FDA, but they have made it clear publicly that they view OS as the right measure for pancreatic cancer. And I think that's largely due to the fact that the gap between progressing in with your disease and succumbing to it is pretty narrow. And so I think the FDA has taken the position, why should they rush to make a decision on the basis of of progression free survival when just a few months later, in principle, they would have an OS result? Now that, again, is based on the historical standards with chemotherapy, and we're seeing a widening of that relationship with the targeted therapy directed against RAS, particularly from diraxonerasib, and so that relationship may not hold.

But I think that might be partly where the the excuse me, Partly where the FDA is coming from. Also, there have been historical examples of early signals of response rates or or PFS in single arm trials that then didn't pan out over time as as they moved into more definitive studies. I think for all those reasons, the FDA's made it clear they prefer to see an OS. What would happen if they saw a strong PFS value and an encouraging OS value, but wasn't statistically significant? I have no idea.

That would be a review issue for the FDA to decide at that point in time. We feel very confident about diraxonerasib and feel like the most appropriate thing for us to do is to test PFS and OS to do it rigorously. We've powered the study around, OS, and, we are we're optimistic. Of course, we'll have to see what the results actually show, but we're optimistic that we'll be able to demonstrate that. And if we do, that would establish a major paradigm shift in in thinking about pancreatic cancer and converting it from, you know, a near term sentence to something that might be managed on a more longer term basis.

Brad Camino, Senior Analyst, Stifel: Yeah. And could you talk about the patient experience under axonurasib when it's received in that second line PDAC setting, especially relative to the available standard chemotherapies?

Mark Goldsmith, CEO, Revolution Medicines: Well, the only thing worse than chemotherapy in pancreatic cancer is the pancreatic cancer itself. It's a terrible disease. Patients really suffer from it. The treatment is considered to offer some benefit, which is why it's provided by oncologists, but it's quite minimal. And you replace the symptoms of pancreatic cancer with the symptoms of the treatment of pancreatic cancer.

Most patients experience significant side effects from the chemotherapy itself and often require dose reductions, dose holds, and often don't make it even through the full planned cycle of treatment with chemotherapy. That's not what we've seen with doraxonrasib. It has shown so far an encouraging tolerability profile. Patients have often reported to their physicians who have shared with us the news that patients are often feeling much better on doraxonrasib, that their disease induced manifestations become much more manageable. Patients, we've heard, can come in anoretic, weight loss, limited mobility, and really sort of down and out and are turning around on on drug and starting to eat again, becoming active, and resuming some important aspects of their lives.

That's what we've heard. We don't have a quantitation of that. That's a qualitative description, but we have heard that from many investigators and and frankly even some from some patients who have, you know, communicated that. So I I think there's the possibility that patients might see a significant change in in their outlook on life, the quality of life. We think that's extremely important, and we also hope to provide more more lifetime as well.

Brad Camino, Senior Analyst, Stifel: K. Beyond your own programs, there is a wave of emerging competitive pan RAAS, pan KRAS, g twelve b selective inhibitors. Yeah. And we'll likely get some emerging results from them on how they shrink tumors, especially in pancreatic cancer. So what is your view on whether or not another molecule could reach a higher ORR threshold at a cancer specifically compared to daraxon rasid?

Mark Goldsmith, CEO, Revolution Medicines: Yeah. I I don't know the answer to that. We we don't have any clinical data yet. It is certainly possible that the pan k, which let's just define what that really means. I think it's a confusing term.

It's not really pan. It's k. It's k selective. Maybe we should have called those KRAS spectrum selective compounds, and they can be very potent. They typically are directed largely to the off state, not to the on state, although there may be some exceptions to that among the various compounds that have come forward.

And we do know that the off state inhibitors have had, you know, some significant limitations. They've not generally lived up to at least initial expectations in the field. But the KRAS inhibitors may show initial response rates that are encouraging, and whether they're lower than equivalent to or or higher than what we've seen, I have no idea. We'll have to find out. The most important thing, though, is going to be what do we see in terms of durability.

That's the really important measure. We've we've said that. We didn't come up with this recently as a response to a pan k RAS inhibitors. We've been saying this for years that that's really the important measure, and the FDA says it's the important measure. And we don't really have much confidence that they will deliver superior PFS or OS, and it will take some time to establish that.

In the meantime, we're moving forward to pursue, you know, full registrations based on randomized, significant robust randomized controlled trials. I think it's also worthwhile to consider that RAS is a very wily driver of human cancers. Once a cell is addicted to RAS, it will do everything in its power, anthropomorphosizing a little bit, but everything in its power to get access to RAS signaling. There's strong selection for those few cells that can upregulate RAS signaling and work around the inhibitor. The way they do it is they can increase the signal through the original mutation and try to overcome the inhibitor.

That clearly happens. They can engage wild type RAS. That clearly happens. They can engage new mutations that emerge in the setting of a of a mutation selective or even a KRAS selective inhibitor potentially. And therefore, we have a long way to go before we're curing patients who have RAS cancers.

It is really one of the most challenging biologic mechanisms behind cancer, and therefore combination strategies will ultimately be the most useful way to prolong people's lives and give them the, you know, the lifestyle that they that they'd like to have. And exactly what those combinations are are yet to be determined. We have a number of very good ideas about it and are exploring many of these combinations. One of them might ultimately be a combination of a so called pan KRAS inhibitor with a doraxonrasib or even with our mutant selective inhibitors and so on. So there's a wide variety of things.

The field is wide open at this point. I'd like to say we're in the second inning of this baseball game, and so we have much more to play out over the coming years.

Brad Camino, Senior Analyst, Stifel: K. Mark, in your four q earnings, you you mentioned the plan to build out commercial in The US and are exploring ex US strategies that could include partnership opportunities.

Mark Goldsmith, CEO, Revolution Medicines: Yes.

Brad Camino, Senior Analyst, Stifel: So on that ex US element, I'd like to give you the chance to elaborate and describe your thinking around this potential strategy.

Mark Goldsmith, CEO, Revolution Medicines: Sure. Well, let me start with The US since that is that is the starting point both in time and and as the core value driver for the company. We all recognize that, and we are very committed to retaining the full US rights, value, responsibilities, and control of the portfolio in The US for building the clinical impact in the long term value for shareholders. We're resourcing our US effort quite substantially, and making fantastic progress to really making sure that we have the best strategies, commercialization strategies, the best tactics, the best capabilities, and the best people so that we can bring Draxonrasib with urgency to patients in The US, of course, subject to regulatory approvals. The other half of the world, from a market perspective, is is outside The US, and we are very committed to the global providing global access to our drugs.

And the question at hand is what's the best way for us to deliver that? And I think we are we're continuing to study that question. It could include a partner or multiple partnerships outside The US. It's a more complex environment to operate in because of the number of different regulatory authorities, the pricing factors that go into it, and so on. And so there is kind of a set of special skills needed in a platform to operate outside The US.

So we, of course, are considering whether or not a partnership should should be part of our plan. We don't feel any urgency to rush these decisions. We are in a very strong place with our pipeline. It's getting stronger by the day. Our confidence about it gets stronger by the day.

Our organization's getting stronger by the day. We're growing quite dramatically to serve the the the goals of the company, and we have a very strong financial position that gives us the flexibility to make those decisions, and we haven't done so yet. There is widespread interest in our pipeline as you can imagine. We feel that interest. We've seen very interesting ideas from a variety of parties, any one of which could be interesting and and useful to us.

But we've just not made any decisions yet, and we won't make it until we feel we have enough understanding of the diverse set of possibilities, and that will maximize both our global impact and, of course, our commercial value, the commercialization and the value for our shareholders.

Brad Camino, Senior Analyst, Stifel: Beyond second line PDAC, could you talk about the goals of the ongoing diraxonrasib chemo combination work that you're doing and how you believe that will position it for a successful frontline PDAC trial and a compelling combination for physicians?

Mark Goldsmith, CEO, Revolution Medicines: So going beyond doraxonerasib or beyond monotherapy? Make sure I understand

Brad Camino, Senior Analyst, Stifel: Beyond monotherapy. Yeah. For frontline PDAC, the chemo combo work that you're doing now. What's the

Mark Goldsmith, CEO, Revolution Medicines: it. Okay. Well, again, returning to the data we've reported so far in pancreatic cancer, although it was all in second line or even later lines, it clearly gave us the confidence that drexone rasib could make a real difference as monotherapy. And in fact, numerically, the numbers that we reported are superior, if you're willing to make that cross cross study comparison, superior to the numbers delivered by chemotherapy in first line. And that's both for PFS and for OS.

And so we believe based on the underlying biology, the substantial body of data that we have so far, and the mechanistic rationale that drexone rasib as monotherapy is likely to outperform or has a good chance of outperforming chemotherapy even in first line as well. So why bother with anything else? Well, as I mentioned, we haven't cured many RAS cancers yet, and There is some mechanistic reason to believe, and even some preclinical evidence, that combining chemotherapy with a targeted RAS agent, specifically drexone rasib, could increase the impact on tumors. That's one justification for evaluating it. We'd hate to not answer that question if that actually could deliver something that's more impactful than monotherapy.

We'd like to know that in patients. A second reason for considering a chemotherapy combination is that it is the standard of care in this very threatening disease. Patients often progress while they're on chemotherapy and sometimes even die during chemotherapy, which is quite a miserable thing to think about, starting a very difficult chemotherapy and having your cancer progress while you're still being treated. But it does have some impact compared to no treatment at all, doctors are used to using that, particularly in The US, but even globally. They're used to using chemotherapy.

And so there's some logic for those physicians who are most comfortable with chemotherapy to provide an option in which chemotherapy plus doraxonerasib is available. And maybe ultimately, if that succeeds as well as monotherapy, that then leaves physicians the choice based on the performance status of a patient, based on a Do they want to undergo the challenges of chemotherapy, or should they not? And to tailor treatment regimens to the individual patient. So we see no real downside to evaluating that that realm and and maybe even some upside on behalf of patients.

Therefore, we're going to make a decision about whether to include a chemotherapy combination arm in the trial. We're certainly leaning in that direction, and the initial evidence suggests that that's a reasonable thing to do. We've not made a final design for our our our our first line trial. It's currently in, you know, in in underway. And once we make that decision, we'll declare exactly how we're proceeding.

Brad Camino, Senior Analyst, Stifel: Out in the interest of time, your next data event is for a second asset, zolonrasib, in lung cancer at AACR. Could you quickly introduce this asset and and talk about where you think it could have the most utility as a therapy, both as monotherapy and potential combinations?

Mark Goldsmith, CEO, Revolution Medicines: Big question. I'll try to answer it very briefly, but zoldonrasib is a KRAS is a RAS g twelve d selective covalent inhibitor oral. It is has been shown to be quite well tolerated in the initial study in pancreatic cancer and showed a significant response rate in pancreatic cancer that was sort of competitive with doraxone rasib. We will report on lung cancer in the g 12 d population, which represents about four percent of non small cell lung cancer, about the same size as the ALK mutant population, so it's a significant subgroup. Similarly, we're proceeding with, by the way, our mutant selective g twelve c inhibitor as well and continuing to evaluate that.

The overall idea that we have is having a robust set of inhibitors, both the multi and mutant selective, will give us the greatest range of possibilities, including potentially combining those two, any two of those in an individual patient. And we've now reported the first ever data from treating patients with two RAS inhibitors in advanced colorectal cancer back in December, and it was compelling and exciting and I think forms the foundation of a longer term strategy.

Brad Camino, Senior Analyst, Stifel: Maybe last for me is as investors think about the AACR data that's coming up, you know, I think a lot of us are anchored to the experience of g twelve c inhibitors, where there has been a spectrum of response rates and profiles with kind of sotorasib being at the low end, devaracid and some of these newer drugs being at the high end. Yeah. How applicable is that spectrum of activity likely for G12D tumors? Is there any biology difference that we should think about?

Mark Goldsmith, CEO, Revolution Medicines: Well, one one difference to note, and it will require that folks thinks think about this carefully, but g twelve d lung cancer often occurs in patients who are nonsmokers, and so that has some impact on the overall genetic diversity of their tumors. But I can't really give you any predictions as to what we'll be able to present. It's coming up soon, and we're looking forward to it.

Brad Camino, Senior Analyst, Stifel: Okay. Great. Well, Mark, thank you so much for spending some time with us to overview the portfolio. A lot of interesting things going on. I look forward to tracking it for the rest of the year.

Mark Goldsmith, CEO, Revolution Medicines: Thanks very much. Thanks again for having us.

Brad Camino, Senior Analyst, Stifel: Alright. Thanks, everyone, for joining in. Bye now.

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