Kick off this next discussion with Revolution Medicines. With me today, I have Mark Goldsmith, CEO. Mark, welcome. Thanks for joining us.
Thanks for having me.
Mark, RASONQUE is on the market now. You reported earnings recently, and the product's off to a strong launch. As you're now 10 weeks into approval, what has surprised you most about the launch, if anything, and what does it tell you about who RASONQUE is reaching today?
Well, we expected a strong launch. I think the most satisfying part of it so far has been the reach in terms of prescribers. As we mentioned last week, some 2,700 individual prescribers in that first five-week period. That's a pretty strong number, and it says that physicians were ready for it, they were looking for it, relative to the number of prescribers from the expanded access program, it's a much larger group. So that, I think, is very satisfying for us. It says that we're off to a good start there. In terms of what sorts of patients, most of the patients on the drug at this point in time are previously treated, either second line or some fraction of them being third line. And there are some things around the edges, but most of the patients are, as we'd expect, the previously treated pancreatic cancer patients.
Okay. Any sense of how the real-world experience with RASONQUE compares to what you saw in the RASolute 302 study?
Of course, we don't have quantitative metrics. That sort of information we don't really collect. It's not a clinical trial. But anecdotally, our field force is in regular contact with physicians. They will certainly hear about anything significant, and the feedback we get from them quite consistently is that patients are having a good experience. We've done a lot of work to prepare prescribers. Every site, every new site gets a visit. They get materials, they get education of the entire care team, and we've tried to preempt issues that could come up if somebody's not familiar.
Our general experience, this was true in the phase III trial and it was true in the phase I/II trial as well, is that once a physician treats one or two patients with RASONQUE, they become familiar with what to expect. Many of them will get used to the idea of prophylaxing, particularly with regard to skin manifestations. That will tend to reduce it, either the incidence or the severity, and then what to do when something happens and so i t's just about education. I think our group has done a good job, and so far the feedback has been patients are very satisfied with what they're getting.
How are physicians using the flexibility of the label, especially the NCCN guideline listings, which go beyond these core second-line PDAC population?
Yeah, it's pretty early to tell at this point. I mean, we only have reported five weeks' worth of information, and we don't really get access to some of that. It's only what we're told about, since a prescription per se doesn't give the medical history of the patient. But generally speaking, I think again, we're talking about mostly previously treated metastatic pancreatic cancer, but we know that there are prescriptions for indications beyond that. We know certainly there are prescriptions for first-line patients. That's on label, so that's not really quite what you're asking. A small number. Most patients are previously treated at this point. I think that will probably grow, but I can't project exactly how that will grow.
We're aware that patients with non-metastatic disease, with locally- advanced disease, just by tradition, receive the same care as patients with metastatic disease. That's just common in pancreatic cancer. The same chemotherapies are used. When the NCCN decided to include that in its guidelines, that is locally advanced pancreatic cancer to receive RASONQUE, that's tradition in the field, so we weren't too surprised at that. I can't really give you any idea what fraction of patients at this point, but I think we can assume that those will go in the same direction as metastatic pancreatic cancer patients.
And then there is also prescription going for indications outside of pancreatic cancer. Lung cancer, non-small cell lung cancer, we know that there are patients who have received it. That is also in the NCCN guidelines. That's not based on the approval or the label. That's based on a New England Journal paper that we published just 10 weeks ago or so, that reported encouraging initial results from a single-arm trial and w e're also aware of indications that go beyond that as well.
How big of a driver do you expect the first-line label to become over time? What data do you have from the RAS and RAS in that particular setting that could help drive early use there?
Well, we're evaluating a variety of regimens in first line. The label itself is for monotherapy in first line, and it refers to for patients who are not candidates for multi-agent systemic chemotherapy, which is a fairly flexible definition, and the FDA clearly wanted doctors and their patients to make those decisions. So that can expand or contract. It's really up to doctors and patients to decide. My guess is that that will grow over time as doctors get used to using the drug, as patients report their outcomes to the medicine. My guess is that will grow. I don't think it will shrink, but it's very hard to project that today.
Yeah. And as investors and analysts building their models, you made some comments around some unique market dynamics early in the launch in the third quarter. Just remind us how you think that could impact the growth trajectory as we look forward.
Yeah, if I may, let me go back though to the previous question, then we could turn to that, and just point out my comments were about monotherapy, RASONQUE. We've also evaluated RASONQUE in combination with chemotherapy, which is something that pancreatic cancer docs asked us for. They said, "We don't want to give up chemotherapy in first line." Not all doctors said that, but many did. "So we'd like to see how does this monotherapy targeted agent add to chemotherapy, or how does chemotherapy add to that?"
And we reported a cohort of patients in first line who received RASONQUE combined with GNP, gemcitabine, nab-paclitaxel, so one of the two common regimens. And in that single arm study, patients did quite well in first line. So I think we have both monotherapy and chemo combination, and over time, those data will continue to evolve. Don't forget, they're also part of a randomized phase III trial called the RASolute 303 trial, which is moving along very well as well. So that's where we might also see increased uptake.
Okay.
You asked about a second topic. Could you remind me?
You mentioned on the earnings call some unique dynamics early in the launch.
Right. Yeah.
As we think about the trajectory going forward—
Yeah.
—how does that impact that?
Right. We wanted to make it clear to everybody that in interpreting that first five-week period, it's important to understand that there are several buckets of patients that add up to the aggregate results of the $198 million net sales during that five-week period. It's a strong number, but it's contributed to by these different categories. The first category are patients who were on the expanded access program, and so were already receiving free drug from Revolution Medicines, and then when it became a commercial product, transitioned over to commercial product.
Those patients likely have a profile that's different from the long-term profile that we'll see on RASONQUE. Those are patients who doctors who were part of the expanded access program tended to place their most advanced patients onto RASONQUE. It makes sense. Here's an experimental medicine. At that time, it wasn't yet approved. We had the strong data that we reported at ASCO, but it was not an approved drug and so t he first thing you do is go to your most advanced patients for whom you have the least to offer them.
The good news for those patients is many of them may well have benefited. The bad news is, once you're a third or fourth line patient pancreatic cancer, which is a remarkable thing anyway to get to third or fourth line, your prospects are not good, and likelihood of long-term benefit is lower. So those patients will tend to come off of drug sooner than patients who are earlier in their metastatic disease. So that's one bucket, and that will play itself out. Those patients all have transferred over onto commercial drug if they're continuing on RASONQUE. They are all now part of that commercial prescription base. But as they come off drug, there won't be a replacement set for those as there was. So that's one group.
A second group were patients who were advanced in their disease but had not yet gotten onto the expanded access program, and that could have been for a variety of reasons. Patients who were in hospice and chose not to be part of the expanded access program, or whose doctor didn't recommend them for it. Those patients, some of those came forward and said, "Well, I should be trying this. Here's a prescription I can get commercially. Why shouldn't I try this?" So they too would be advanced patients like the first bucket I mentioned, and those would get worked through the system over some period of time, but would not be a reoccurring group, or at least wouldn't be a large reoccurring group.
The third group are the core previously treated second-line pancreatic cancer patients, maybe recently diagnosed with second line, meaning that they progressed from first line, or they were non-metastatic and became metastatic. Those patients then are really the core of the label, and those are the patients who were studied in the 302 trial. So I think we'll see a transition from more advanced patients to more middle of the road kinds of patients. That's the bulk of the population, and that will affect durability and overall sales as a result of that.
Okay, great. And then you did receive a CHMP opinion recently as well, and so how do you approach the international launch if approved there?
Well, the European Union moved very quickly. The EMA, the European Medicines Agency, actually contacted us and asked us to participate in an expedited review program, I think it's called their Pathfinder Program. So we stepped up to that around the same time we were dealing with the FDA approval process, and they have moved it along. It's been a very accelerated review, and the CHMP issued an encouraging, a favorable opinion with a nice label. That has to be accepted by the European Commission. When they do that, it becomes an approved product in the European Union, but it still then isn't launched because then each market requires some bureaucracy, some handholding in order to get to an agreed-upon price and distribution model, and that's done on a country-by-country basis.
We're still a little bit of ways from those patients having access, but there is strong demand by the European Union, by the Japanese health authorities, and by others around the world who have contacted us trying to get access for their citizens. In terms of our preparation for that, this is the most novel component for us. We started out as a very U.S.-centric company, and I even had declared a few years ago that we wouldn't market any products ourselves outside the U.S. That was a genuine statement at the time based on our belief that we already had pretty ambitious goals as a company, and we thought it wasn't really credible that we could think of taking on the rest of the world.
We did shift in that view last year and initiated efforts to build out the capabilities outside of the U.S., and we now have a very strong organization. It's really got outstanding experienced leadership and growing components, starting with the priority EU countries, also in Japan, and several others around the world. So we do have infrastructure there, and we're ready when the EMA makes its decision. If it makes a favorable decision, we're ready to move. Of course, we don't have every corner covered, so in some cases, we may go to some sort of distribution or partnership model on a target country territory by territory basis.
But those also are situations where we could, over time, decide to take over responsibility directly ourselves if we felt that our portfolio was getting large enough that it would be justified in some of these smaller markets, b ut we're prepared, we're ready. An enormous amount of work has gone on, really quite an impressive group, and we're ready to deal with it the moment we have the opportunity.
Okay. Obviously, there's a big focus on label expansion opportunities beyond the initially approved indication. So, expansion into a broader frontline PDAC setting is one thing that a lot of investors care about. The RASolute 303 study, I know it's recently completed enrolling in the U.S. I think enrollment ex-U.S. is still ongoing. So how do you think physicians and patients will weigh the RASONQUE monotherapy versus the gem/nab-paclitaxel combination at the end of the day?
Yeah, it's a great question. One of our principles has been not to make choices for doctors too early. There's a certain amount of hubris if you do that. It means that you already know the results of the trial before you've done it if you're that selective, so we try not to show that hubris and t hat 303 trial is an example of that. It's a three-arm trial comparing standard chemotherapy in first line versus either monotherapy RASONQUE or the combination of RASONQUE plus GnP.
We think that's really the right design. That's the ideal design. That may be difficult to do again after this trial reads out because it may well set new standards that then essentially eliminate chemotherapy as a preferred option. So it might become very hard to enroll patients in a chemotherapy-controlled study, b ut it's underway, it's gone well, it's enrolled very quickly. As you mentioned, in the U.S., we've completed enrollment. We basically capped enrollment in the U.S., if you want to think of it that way. We had set aside a certain number of slots. The rest of the enrollment is outside the U.S., and it's going very well, so t hat will come to completion.
The problem is we don't know what the results are until we do the experiment. We know the single-arm data that we've reported publicly. It's available on our website. We reported it at a medical conference, monotherapy and combination with GnP and t hose data both suggested favorable trends relative to standard of care chemotherapy. How they compare to each other is a very difficult thing to say from a cross-trial point of view. There's a lot of betting going on around how that's going to perform, and I think most people bet that chemotherapy plus monotherapy plus RASONQUE will be superior. That's a reasonable bet. How could two things be worse than one?
Most likely, but w e don't really know. At the end of the day, what we're trying to do is to create for patients and their physicians options so they can make their decisions rather than being in a regimen where there's just one choice, this is what you have to do. Different patients may have different preferences. Patients who have better performance status, who are healthier, have a more positive outlook, they may say, "Doc, give me the chemo. I want the— whatever's the toughest regimen that you can give me, give it to me because I've got the greatest chance of shrinking my tumor."
And others, an 82-year-old, may say, "I can't take that. Otherwise, I'd be in hospice care." Not to exaggerate, but those could be two examples. So I think having two options where RASONQUE becomes the backbone of therapy and chemotherapy becomes an optional component. And for anybody who paid attention to us a couple of years ago, we proposed this idea that RASONQUE should become the standard and chemotherapy might be added to RASONQUE. It's a little bit upside down for the way therapies have been developed in the past, where you start with the historical treatment and make that the core, and then you add to it. We've sort of flipped that around.
I think it makes sense in pancreatic cancer, where the driver is RAS. So why wouldn't you start by putting the brakes on RAS, and then everything else can come after that? But that's all TBD. We'll see what the data show, and I think doctors' practices and patients' preferences will be determined by the data and by their own circumstances.
Yeah. Some people were wondering, just given that RASONQUE is on the market now, second line plus, whether post-progression crossover from RASolute 303 could impact the overall survival readout for that study. It seems like that's less of a concern given the studies enrolled now in the U.S., but how do you feel about that?
Yeah, it's possible. That's one of the downsides of RASONQUE being successful, is that people want to have it, and therefore it's hard to insist that people not take it. I think if somebody progresses on chemotherapy in the control arm of a clinical trial and there's a drug that's available, they should go take it. I mean, I don't think we can discourage people from taking the medicine that they should receive. So there will be some crossover. At this point, having enrolled the U.S. as quickly as we did, largely before it was approved, I think we'll be able to get away with that.
Outside the U.S., it's not yet approved, and when it is approved, there's still some time lag to getting negotiations done on a country-by-country basis. So I think we're going to manage through this. We anticipated this all along and scaled the trial in the right way to deal with the statistics. It will be harder to do future trials, and it will certainly be harder for anybody else running a trial as well. So that's sort of our goal, is to raise the bar. And in the future, people will probably have to compare to RASONQUE as opposed to chemotherapy, which is a good thing for patients.
Yeah. So there's been a lot of discussion how the KRAS G12D subset of pancreatic cancer could play out. It's the biggest subset, I believe. 40% of patients are G12D positive, and obviously you do have studies ongoing with zoldonrasib as well. The patient population obviously overlaps with the daraxonrasib populations. How do you expect that segment to play out over time as you think about the different options that are maybe available for patients?
Yeah. I really wish we knew the answer to that question. It is hard to see around the corner. I think, again, it will be somewhat data-driven. There is a natural assumption that if you have a mutant selective inhibitor, that will just be automatically superior to a RAS multi-selective inhibitor. I do not know that that is true. It is possible, but it may not be true. RASONQUE is quite a compelling compound mechanistically. It makes a lot of sense, and the data are very strongly supportive of it.
The main advantage of a mutant selective inhibitor may be its safety, its tolerability profile. It is not so much safety, more tolerability profile, b ut that is a compound-by-compound characteristic. That is really not a class-specific effect and i f you look at whether it is G12C selective inhibitors or G12D selective inhibitors, there is a whole range of AE profiles associated with those, even though they are mutant selective, so they should be, in principle, very clean, but they are not, because every compound has off-target side effects. So, it is not completely obvious to me that a mutant selective inhibitor will end up being superior in all cases or in any cases. It could be and so w e have made a bet across all the options.
We really haven't chosen, and that is part of our story. Part of the concept behind RevMed is to let the science tell us the answer to the questions. And we do have zoldonrasib, which right now is thought of as being, I will quote David Hong, who has reported it as the safest drug he has ever tested. I do not know if that is true. I do not know if other people have that experience. But certainly, broadly speaking, the investigator experience with zoldonrasib is that it is hard to distinguish it from placebo, so much so that we are running randomized controlled trials where we actually are giving a placebo pill versus zoldonrasib, and the patient does not know which drug they are receiving, which is very unusual in oncology.
So, that is a characteristic of zoldonrasib. It is not a characteristic of many of the other G12D selective inhibitors that carry with it GI profile and other side effects, hematologic or otherwise. So, I think it is going to be compound by compound. Everything is going to just have to compete on its own, and what people end up using and in what sequence they end up using them is still a TBD. I would also mention, in pancreatic cancer, in first line, most patients do not know what their genotype is, what their RAS genotype or their tumor genotype in general.
And while we encourage testing and we are supporters of testing, the reality is it is hard when somebody comes in with first-line metastatic disease, they are very sick, often very sick, and doctors want to start treating them. They love chemotherapy, not because it is so effective, but because you do not have to ask what the genotype is. You can just start treating a patient. Three days later, they can be treated. With RASONQUE, you can start that day. Take an oral pill. No matter what genotype you have, it is likely that you will benefit. So, I think the push to have mutant selectivity in the first line of pancreatic cancer is not very compelling.
In lung cancer, where 30% of lung cancer is caused by a RAS mutation, it is necessary to have genotype. Otherwise, you might be giving RASONQUE to 2/3 of patients who have wild-type RAS, which would make less sense in lung cancer. Fortunately, in lung cancer, 85% of patients know their genotype very early in their disease. So I think this will play out differently across all these different disease types, and we have got something for everything, and we are trying all sorts of combinations. Of course, we are also running a clinical trial where we combine zoldonrasib plus daraxonrasib, two RAS(ON) inhibitors given to the same patient, and that has interesting promise as well as a chemo-free regimen.
Yeah. In colorectal, you just announced a new study in frontline patients. How has your strategy shaped up in colorectal?
Yeah. Colorectal is a much more difficult disease. It has multiple genetic defects, multiple individual cancer clones. When you are treating that, you are really treating a patient who has multiple diseases at once. That is one way to think about it and i t is very hard to cover all of those. It requires multi-combination regimens. The first regimen that we are moving forward with, based on the results of our preliminary work, are a combination of zoldonrasib, a very well-tolerated drug, with standard first-line chemotherapy, and with cetuximab, a well-accepted anti-EGFR antibody often used in later lines. That triplet combination is now being studied in a randomized phase III trial called the RASonate 312 trial.
I know you guided to providing a broader update with underlying data on colorectal cancer. What should investors expect from that upcoming discussion?
Yeah. I think what we committed to, not so much a broader update, but support based on the data that we have so far and more details about that RASonate 312 trial design, we will provide that in the first half of the coming year and I would just emphasize the 312 trial is the first of what we think will be many phase III trials coming out of Revolution Medicines in colorectal cancer as we build our understanding, our knowledge, and the right regimens.
Great. Well, with that, I have to wrap up, but thank you, Mark. We appreciate the time this morning.
Thanks a lot. Nice to see you.
Thanks.