Started now. Welcome back to the 46th annual TD Cowen Healthcare Conference. I'm Marc Frahm from the biotech team here at TD Cowen. Very happy to have with us Mark Goldsmith, President and Chief Executive Officer of Revolution Medicines for the next session, where we're gonna talk a lot about different ways to target RAS. Maybe to start off with, Mark, you can kind of just level set people, high level overview and kind of what you see as the key value creation events for investors over the next 12-18 months or so.
Well, thanks for having me here today. It's a pleasure to talk to you. Well, I think the most standout event of the year is gonna be the readout of the RASolute 302 trial, which is our trial in previously treated pancreatic cancer with daraxonrasib monotherapy versus chemotherapy. We expect that readout to occur in the first half of this year, which is marching along through the first half of the year right now. That's probably the most notable and substantial readout, which then of course would drive a variety of other activities. We have a lot of other studies that are already underway. In fact, now a total of five phase III studies have been initiated, four of them in pancreatic cancer and those should make progress this year in enrollment.
They won't have particular readouts this year. In first-line pancreatic cancer, we had shown previously monotherapy daraxonrasib and daraxonrasib plus chemotherapy response rate data from a small cohort earlier last fall, and we do expect to provide some initial durability data for those two cohorts sometime in the first half of this year. I think those are some things to anticipate. We also expect later in the year to provide some initial data on colorectal cancer that would provide some guidance about where we're headed from a registration strategy point of view.
We also expect to provide clarity around elironrasib, an exciting G12C (ON) inhibitor, in a much more competitive space, but we're developing our strategy around that and should be able to provide more clarity as the year goes on.
As you mentioned, the RASolute 302 trial is gonna read out here shortly. Just what should maybe can you help set, explain expectations for investors as to kind of what we should expect in an initial top line release versus what, you know, needs to be held for later presentations and medical meetings and stuff, which are obviously also important to the business? There's a lot of nuances in this trial, right, between different mutation subtypes and things in different hierarchical analyses there.
Right. The trial design is a little bit complicated because we dealt with the fact that we simply have had more clinical data and also preclinical data in the subset of pancreatic cancer that carries a G12 mutation. We sometimes call that a G12X mutation for all the different amino acids that can show up in the G12 position. That represents about 85% of pancreatic cancer, so it's a large subset, but it's the subset for which we had the most data. Therefore, we have the most confidence, therefore we designed a trial in which those patients are kept together in a cohort that is at the core of the trial. That undergoes initial statistical analysis in the readouts.
There's a second readout or a second analysis which involves that core plus everybody else in pancreatic cancer, which could include mutations at positions G13 or Q61, and also, potentially patients who don't carry a RAS mutation, and those get lumped back in together in the whole analysis. There really are potentially two different analyses and outcomes from each of those. This first analysis is a first analysis. It's the interim analysis number one. It could also be a final analysis. It just all depends on what it shows. It's set up so that there are other opportunities to do later analyses, but we'll just have to see. It's possible that there could be a range of potential scenarios just being objective and not leaning into any particular scenario. We could not pass PFS and therefore not pass OS.
We could pass PFS statistical significance and not yet be significant for OS, or we could pass statistical significance for both PFS and OS. Those are just three objective potential outcomes, and they lead to different, to different consequences. As to what we would show at what time, that's TBD because of the complexity that you raised, and we really don't have a matrix we can share with you that says if this, we'll do this, and if that, we'll do this. Generally, we would like to show data from that trial. It's obviously a very important trial. We're excited about it. It could potentially have far-reaching impact on standards of care for pancreatic cancer.
We'd like to be able to share the actual data in a scientific context, i n a, you know, in a meeting context in which peers can challenge it and review it. We'll see. Let us see the data when it's unblinded, and then we'll be able to make a decision about how to present it.
One question we often get from investors is how to, you are starting first line trials including with the monotherapy, but how to think about kind of translating across lines. When we see this data, obviously it'll have a huge impact potentially on second line patients, how does Revolution approach that question of, you know, what does this mean for the probability of success in a first line trial when we see second line data?
Yeah, it's hard to give a formulaic answer to that question. Pancreatic cancer is a RAS driven disease. It's RAS driven when you're first diagnosed, it's RAS driven after you've had a treatment and you come back for follow-up treatment, it's RAS driven in third line, it's RAS driven in fourth line. It's a RAS driven cancer. That doesn't go away. And I think that's a really important point to make. For about one year ago, there was sort of this rumor spreading that, you know, it was really second and third line that would benefit from a RAS inhibitor, but not first line. I never really understood the biological plausibility of that statement, and I think it makes no sense.
In reality, the data that we've shown so far, albeit a limited data set, show that indeed in first-line treatment, treating with either RAS inhibitors or monotherapy or in combination with chemotherapy, delivers an encouraging impact. We do think it's important to suppress RAS regardless of your stage of disease, regardless of whether you've had prior treatment or not.
With that in mind, if one looks at the previously treated pancreatic cancer population that we've reported on with response rates, with PFS and with OS that appear to be numerically quite significantly different from that of chemotherapy and even surpassing numerically the same parameters in first line treatment with chemotherapy, that it's pretty easy to make the draw the conclusion that we'll see benefit from a RAS inhibitor in first line treatment. Those are cross-trial comparisons. They're from single arm trials and all the limitations associated with that, so we can't really make such a claim. It just seems obvious that one could draw those inferences.
Have you gotten a sense when you look across the broader landscape, you know, of targeted therapies since, as you said, pancreatic is the seems from the clinical data, but also the genetic data to be very clearly RAS driven broadly. But when you look at broader targeted therapy space, just how much better does efficacy tend to get when you move up lines versus, look, it's the same disease, it's the same mutation, it's kind of?
Yeah.
Yeah. You hit it whenever you hit it, and it's the same.
Yeah. It, in targeted therapies, if you, if you look across the board, that generally, the benefits in earlier lines are similar to sometimes they're somewhat better, but at least similar to hazard ratios tend to stay the same. Because the overall outcomes in earlier lines generally are higher, the same hazard ratio leads to absolute benefits in terms of number of months, if you want to calculate in those terms. That's the general trend. I'm not sure why that should be different for pancreatic cancer and for RAS treatment, but we'll just have to see. We'll have to establish that. We did see such a trend in the, in the response rates. You know, we've made the argument now for three or four years that response rates are really not the proper readout for pancreatic cancer.
Durability is the readout. Although we've only shared response rate data in the first line cohort, that's because that's what we had at the time that we could share it. Ultimately, patients aren't really asking, "Doc, am I gonna have a 32% or a 37% response?" They're asking, "How long am I gonna live and how am I gonna feel as long as I'm living?" That's all about durability, and that's what we're focused on.
Okay. Once this trial reads out and is hopefully positive, you know, what's the status of everything else that needs to go into an NDA, and how quickly do you think Revolution can kinda turn around from data to an actual NDA submission?
I mean, independent of the Commissioner's National Priority Voucher that we have, we had been set up to move as swiftly as possible because there's a clinical and public health imperative to do so. you know, that got heightened when the Commissioner awarded us the National Priority Voucher for review. It hasn't really changed that much from our perspective. We had already lined up our manufacturing to be supportive of a potentially early launch. We have our systems in place to be able to prepare reports and things that are required as part of the documentation. We have gotten guidance from the FDA. We're very engaged with the review division.
It's the same review division that had recommended us to the Commissioner for the voucher, it's not as if something was handed to them that they didn't expect. On the other hand, it's a new policy, it's a new program, it's a pilot program, they don't really have a pre-established mechanism in place. I think everybody's read about that. It's being created, you know, in real time. Everybody is incentivized here to move as swiftly as possible. Everybody, including the FDA. They wanna do a good job, they wanna make sure that they don't make a mistake, we support that. From a commercialization point of view, we have been investing for two years to build a platform and a presence, sort of a pre-market presence.
We have had medical affairs operating in the United States, really across all regions of the United States for a year now, MSLs covering all territories. That has been important to establish relationships and to be teaching practitioners what they need to know about pancreatic cancer as a RAS-driven disease. Not every doctor knew that. Many doctors who learned that at some point probably forgot it because they got flooded with other information about something else. We've had to remind people of that. We have an ongoing unbranded educational campaign called Expect RAS, which has had impact. It's caused practitioners to be anticipating daraxonrasib as a potential product.
From a true commercial point of view, we have strong leadership in place in the U.S., both at the top level with the chief global commercialization officer. We have a general manager for the U.S., who's been in place for two years, who's fantastic. We have a marketing team. We have access. All of the pieces that are needed are in place. The only thing that was really left is the field sales team. We have a leadership organization across the U.S., but we haven't had a field sales team in place. We announced those positions opening in January at the JPMorgan conference. We're moving to be in full position. There's a whole range of potential scenarios for timing. I can't speak to that. We'll move as swiftly as we possibly can.
There's some sort of physics involved that you can't overcome. You just have to do certain steps, but we'll be as prepared as you possibly can be to move once the data are unblinded. We're pretty hardwired for analysis, interpretation, preparation of information, and we are providing material to the FDA in a sequenced and phased way. It's not gonna come all at once at the last minute. Part of their trick for making this accelerated process work is to have information come in more like a rolling submission.
I don't know if it's formally called that, but more like a rolling submission, where certain pieces that can be provided earlier than the clinical data will get provided earlier so that they can have their teams reviewing those parts and then let the final clinical data be the dispositive piece towards the end.
Is that process already started because you have visibility to when the data is coming or is that-
Yeah, I'm not gonna speak to the details of-
Okay.
... what we're doing on any given day. I think we just generally wouldn't share that. Can just tell you it's pretty well laid out, what needs to be submitted, when, in what form, and so on. Again, as I mentioned, I think the FDA, we have every reason to believe that they're highly incentivized to wanna do this swiftly, to do it rigorously, but to do it swiftly as well.
Okay. On the first-line trial that we started to touch on a minute ago, just I think you announced that the trial was initiated in November. Have patients been dosed yet? How should investors think about kind of the enrollment timeline there? Obviously it was quite fast in second line, you know, there's far they're not great options in first line, there are options in first line. How should investors think about likely enrollment timeline there?
Yeah, we haven't commented about enrollment yet, but we initiated the trial, which for us means operationalizing, which has a number of months involved in doing that, getting sites set up, getting through IRBs, and doing all the mechanical pieces. Again, there's a physics associated with that that you can't just skip over. I'd love to be fully enrolled by now, but that's not the case. Once that platform is fully up and running, meaning that there are sites in the U.S. and ex-U.S., it will enroll quickly. You know, sadly, the demand for access to daraxonrasib is extremely high. We hear about this on a daily basis. Patients, across the spectrum of lines of treatment, they want access, and their physicians want access.
We don't anticipate any barriers to enrolling that trial. I don't have any high-resolution information today.
I think one of the concerns that's come up just broadly in oncology is often is, you know, concern about crossover and-
Yeah.
A nd patient, particularly drugs that patients are very excited about once they're approved in a later line that, you know, patients who find themselves randomized to not receive the drug that they really wanted.
Yeah.
Kind of figure out a way to get to that second line therapy. How is that dealt with in the first line design, you know, particularly because you could have fairly rapid approval here?
I mean, it's an issue. It's sort of an intellectual conundrum that you want drugs to be very effective and to provide benefit to patients, we wanna keep patients on, you know, an inadequate standard of care as a comparator group because we have to do a formal comparison. I mean, that's just, there's no way to sort of reconcile those. It's just a fact, those two are in tension. The, that particular trial is designed with two treatment arms that are experimental and then the control arm. If you're randomized in that trial, if you enter that trial, you have a 2/3 chance of getting access to daraxonrasib. That's better than a 50% chance.
If you are randomized to chemotherapy, it's not so much that patients may look for an alternate treatment because generally there aren't really alternate treatments, but they may choose to get chemotherapy in their home setting. If they've traveled a distance to go to a clinical trial and then find out that they're getting the same treatment that they might get at home, many patients, I'd be one of those, would prefer to get it, you know, at home. We've learned from the ongoing RASolute 302 trial. We learned early on that some patients did that. They might travel across the country to get a slot in a clinical trial, and if they don't get the experimental treatment, they might quit the trial and go home to get chemotherapy.
That's one form of sort of dropout, if you will. We discourage that. We've encouraged investigators to treat people who are living within their locale, to minimize that chance, and that's actually helped quite a bit. In terms of accessing daraxonrasib if it's approved for second line, well, it's a conundrum. The approval would be on label for whatever the label says. I can't speak to that. We don't have a label yet, but whatever label says is what we'll be able to support. If that doesn't include first line, that doesn't mean patients and their doctors won't try to find a way to get access to it.
If somebody's had some form of chemotherapy, even if it's less than a full course of chemotherapy. They may find a way to declare themselves having been previously treated and therefore eligible for second line. I think that's really the point that you were making. Long-winded way to get to that. That may happen. We have heard that that will happen. We can't really address it. You know, all we can do is promote to label. We can't even really support those doctors if they do that. I understand it. I mean, we can all understand it. I'm sure the FDA understands it too. They're humans as well.
Our approach to it, your real question, what are we gonna do about it, is to enroll as quickly as we can into the phase III trial here in the U.S. before the product is approved, and also build a footprint outside the U.S. where daraxonrasib would not be available until their approvals in Europe, which would come outside the U.S., after the U.S. We think from an operational point of view that we'll be able to squeak by and get this done, and that there may be some degree of dropout, there may be some degree of crossover, but that it would not impact our trial given the way that it's designed and operationalized.
Just I think you've spoken a number of occasions of the importance, right, of the second line trial that we're about to see.
Yeah.
That is, you think it's a very high strategic importance that you show a survival benefit. How important is that in the first line?
Well, we assume it's the same in first line. We're not sure the FDA would be excited about having something less than overall survival. Outside the U.S., to be honest, in pretty much every country of the world, an overall survival is very important for approval and for terrible things like pricing. We'd like to show overall survival in anything that we can before it's too late. Once we show those benefits, it's gonna be hard for our trials and it's gonna be hard for everybody else's trials, too. I mean, it will. That's the moat that gets created, sets a whole new standard that people have to overcome. There's a lot of value in establishing OS, starting with patient value. I mean, we really do.
That's what matters to us, is establishing real benefits for patients. That will affect uptake in the market, that will affect how long people can benefit from it, and it sets a new standard and barriers for approving new products. That's just the way things work. Again, we can't overcome that. I would mention here that informally, anecdotally, we have heard from a number of investigators that they have seen daraxonrasib continue to perform in some patients who had actually progressed radiographically but were still doing well clinically. Just a reminder, a patient has a 10 cm tumor, and you drop it down to 1 cm, that's a PR, and if it goes up to 1.2 cms six months later, that's suddenly disease progression.
That's the criteria that are established under RECIST, yet the patient may not even know about that, other than being told, "You have radiographic progression." In some cases, some of our investigators have said, "Hey, you're doing well on this drug, and even though your CT scan says you've progressed, let's see what happens." In some of those cases, patients have stayed on for a very long time afterward. For a very long time. Now, I can't really report on that quantitatively. I don't know what the numbers are. We haven't formally studied this, but we have heard it from a number of investigators. Now, for a number of trials we have underway, we have encouraged physicians who are running sites, to consider treatment beyond progression, for those patients who are doing well, on drug.
Biologically, it makes sense. If a tumor's driven by RAS, and you're putting the brakes on RAS, yet the tumor somehow finds a way to break through, does it make sense to take your foot off of the brake? I mean, that's just gonna cause explosive regrowth. This concept makes sense to us, even though we were kind of caught off guard by it when several investigators introduced us to it. We'll just see over time whether we can generate enough information to be able to formally declare whether or not that's a benefit or not.
In, talking about the encouragement in your ongoing trial, does that include the 302 trial?
It does not include the 302 trial.
Is there allowed treatment path reduction?
They are not, no.
Okay.
The 302 trial is strictly treat-to-progression , and the reason for that is we didn't know about this when we designed the trial and initiated it, and you can't change the criteria halfway through the trial. That trial stays traditional, but in other trials, we've encouraged investigators to consider treatment beyond progression.
Okay. In first- line pancreatic, you're also starting two trials with the G12D inhibitor with chemo, but then also. That trial's, I guess, being initiated right now.
Yeah.
the, also the daraxonrasib combo. Just, how do all these trials fit together for that, you know, call it roughly half of the pancreatic patient population that has a G12D mutation?
Yeah. Well, we're not taking a parsimonious approach to this. Because pancreatic cancer is such a devastating disease, every patient's different, and it's better to provide multiple options to each patient, which also means potentially providing at least one option to every patient. We also don't know how a mutant selective inhibitor behaves differently from a RAS multi-inhibitor. We know the potential benefits of each of them, but we just don't know how they stack up against each other. We know that there are biases, there are assumptions in the field about it based on prior targeted therapies, but we don't know which assumptions are true.
Our approach is to be agnostic and to go test every compelling strategy that we have in our hands, and you've mentioned several different ones: daraxonrasib monotherapy, daraxonrasib combination with chemotherapy, zoldonrasib, our G12D selective inhibitor. Combines very well with chemotherapy because it's so well-tolerated. In fact, most investigators have told us they can't differentiate between zoldonrasib and placebo, that their patients can't. The funny story is a patient who gets put on zoldonrasib, they come into the office very sick. They start zoldonrasib. They leave. They come back a month later. They walk in the door carrying a tennis racket. They're saying, "I feel great. Oh, by the way, Doc, am I on placebo?"
That's because they're not experiencing side effects that tell them that they have an active drug even though they're getting the clinical benefit. That's quite remarkable.
That's very uncommon in oncology drugs. It means that we can design trials around zoldonrasib with a placebo, a blinded placebo strategy as opposed to taking a drug versus not taking the drug. Everybody knows if they're on daraxonrasib, but they don't know if they're on zoldonrasib, so we can design placebo-controlled trials. Zoldonrasib is being evaluated in combination with chemotherapy in first line, and the way the trial works is it's chemotherapy plus zoldonrasib versus chemotherapy plus placebo, and it's blinded to the patients, and it's blinded to the investigators and to us. That's that first trial that you're alluding to. That's the RATIONALE 305 trial which we've initiated, and we're excited about it.
We also will initiate a second trial with zoldonrasib which is combining it with daraxonrasib as you mentioned, and that brings potentially two different ways to hit the mutation, the mutant driver as well as any other potential escape mutants that could come up in the setting of a mutant selective inhibitor, and that combination's exciting. We expect to initiate that later this year and to share data that support that strategy.
Can that be a simplistic design just against chemotherapy, or do you need to, within that trial, gonna really define the contribution of the components?
Yeah. The contribution of components is a regulatory topic. There are various ways to deliver the information the FDA needs to be able to convince themselves that the combination is delivering more than either agent alone. We of course will have lots of monotherapy data with daraxonrasib. We have not reported a zoldonrasib monotherapy cohort in the first line, so we haven't reported those data. There are various ways to solve for that. It doesn't necessarily have to be within the phase III trial itself.
Okay. On your earnings call the other day, I think a number of investors kind of came away with the conclusion that you seem to be a little less aggressive about pushing daraxonrasib forward in first-line lung cancer. I think, but also you were disclosing a first-line plan for the G12D inhibitor. You wanna talk about kinda how those fit together and how that decision-making process is happening as to what to do in first-line lung cancer?
Yeah. They're unrelated even though I understand why they get, why they get related to each other. Really were unrelated decisions. daraxonrasib we mentioned in the fall, we need to conduct further dose optimization. daraxonrasib is not quite as well-tolerated in lung cancer as it is in pancreatic cancer, for reasons we don't fully understand. We need to make sure we get the dosing just right, whereas with the, in pancreatic cancer we were able to just push it up to 300, and patients do pretty well with that. That's not really news, and we're continuing that dose optimization in combination with platinum-based chemotherapy, and Keytruda, pembrolizumab. That work's ongoing.
At the same time, everybody knows we initiated a partnership with Summit Therapeutics around their compound ivonescimab, which is really the leading bispecific anti-PD-1, anti-VEGF antibody. We initiated that last in the second half of last year, but the trial took some time to get started. We now have that trial underway. We're dosing patients with ivonescimab plus our RAS(ON) inhibitors, and it's a really exciting thing to take the leading RAS(ON) inhibitors, the leading bispecific, and put them together. It makes very good sense to do. We're glad that's now underway. It's underway and we're still dose optimizing daraxonrasib, we're just not in a position to declare definitively what we'll do and when we'll do it.
We're at an interesting potentially transition moment with these bispecifics coming along and potentially threatening pembrolizumab as ultimately as a standard of care. When do we make the switchover? Zoldonrasib is a little bit of a different situation because zoldonrasib is so well-tolerated, we could combine it with other things, and we just don't see any issues associated with it at all. There's not really much dose optimization to go with, to deal with. We just decided to move forward with pembrolizumab and the KEYNOTE-189 regimen. Yes, two different strategies. They're both tailored to the specifics of the situation.
The other lung cancer disclosure you had the other day was that you could have the fully enrolled second line plus cohort for the G12, for zoldonrasib.
Yes. Yeah.
There is a... Unlike pancreatic cancer, in lung cancer, there is a history of targeted therapies with accelerated approvals...
Yes
on single arm data.
Yeah.
Is that a pathway that is viable with that cohort?
Yeah. I mean, we expanded that because we saw compelling results with zoldonrasib, and have continued to see compelling results. So we decided to expand that cohort to make it of a size that we could draw real conclusions from and potentially give the FDA the opportunity to consider that as well. That enrollment has gone well. Zoldonrasib is a highly attractive compound, as I mentioned, for investigators and patients, and we'll see what happens there.
I think based on the commercial performance of the G12C inhibitors and some other launches in later line lung cancer.
Yeah
I think a lot of investors have grown kind of skeptical of what the actual commercial opportunity is in later line lung cancer. Do you agree with that it's more modest, or do you think people are missing something?
I think there are characteristics of those early compounds. you know, they had, they were breakthrough compounds. no disrespect to them. They opened up a field, but they delivered ultimately, you know, the median PFS in second line, previously treated lung cancers in the ballpark of five and half months. It's just not a whopping difference, compared to chemotherapy, and I think people are disappointed for that. I think we've seen significant improvement with later generations of RAS inhibitors. We're most familiar with the RAS(ON) inhibitors that we've created, and we feel confident that they can deliver real impact compared to inadequate standards of care like docetaxel.
Okay. you're promising CRC data. you know, how much should investors expect? There's a lot of different combinations that are happening.
Yeah.
In your CRC work.
Yeah.
How much should investors expect this update to be, you know, "Hey, we're seeing some interesting signals, but there's still a fair amount of optimization in figuring out how this fits together," versus a more complete picture of the, "This is the path forward"?
I can't provide much guidance about that. I mean, we generally try not to tease about things. We've indicated we think that we're going to be able to see a path forward in colorectal cancer, we'll share that information when we have it, and then you can make a judgment about what the answer to your question is.
Okay. Unfortunately, we're over time. We're gonna have to cut it off there. Thanks a lot, Mark, for joining us, as well as everybody in the room and on the webcast.
Thank you very much.