Good morning, everyone. Thanks for joining us here at the Goldman Sachs Global Healthcare Conference. Good morning on our second day of the event for everyone who's joining us online as well. We're thrilled to have the team from ORIC here this morning, and we'll just get right into it. Maybe to start, there was some news last week, not from you guys, but from Fulcrum, which was an update that has obviously been top of mind given the mechanism of action overlap. Maybe you could speak to the Fulcrum update on pociredir and any potential implications for your program in prostate cancer rinzimetostat.
Yeah. Firstly, thanks for having us here at the conference. It's a great conference. We were just talking about the long flight across the country. At a high level, last week, Fulcrum announced the discontinuation of their PRC2 inhibitor, which they were studying in sickle cell disease. If you read the press release, the press release kind of states that the FDA's position was really based on three things. One is the risk-benefit profile for sickle cell disease, which is obviously very different than it is for oncology. Two was the previously disclosed malignancies they saw in their preclinical tox work. Third was the ongoing secondary malignancies that tazemetostat is seeing in various indications as well. People think that's a read-through to us. When we take a look at this, we think the implications are limited when we look at rinzimetostat.
Again, that's really for three reasons. One is that we've dosed over 100 patients, both as a monotherapy and in combination with AR inhibitors. We have not seen any instances of secondary malignancies based on the preclinical work we've done, which is a four-week tox and a 13-week tox in two species, which is a requirement for oncology, which is different from non-oncology. We have not seen any signs of malignancies as well. Third, I think most importantly is, as I said before, the risk profile for prostate cancer is very different than sickle cell disease. That's, I think, first and foremost. When you think about any drug, it does come down to the risk-benefit profile, taking into consideration therapeutic area, taking into consideration the overall patient population as well.
We also went on to say that over the last six months, obviously, we've had a number of interactions with the FDA as we imminently look to start our phase III study, and there's been no change to our base case plan. Now, as you can imagine, with the news on tazemetostat, which I think happened in the first quarter, secondary malignancies was a topic that came up as well, but there was no delay or anything in our timing. Lastly, last week, we did announce that we have completed the end of phase I meeting. The three objectives of that meeting were, first, was to finalize the protocol. The second was to confirm the dose selection that we picked for the phase III study, which is 400 mgs once a day of rinzimetostat in combination with darolutamide.
Third was to determine any other prerequisites that were required for the initiation of the phase III study. We did announce last week that the protocol is finalized, the dose is confirmed, and there's nothing else precluding us from starting that phase III study. We expect to start that study imminently. At the end of the day, I think our view is this all comes down to the risk-benefit profile of the drug. Even if you look at some of the prostate cancer drugs today, like docetaxel, some of the PARP inhibitors, some of the radioligands, there is some small percentage of patients that see these secondary malignancies. Again, it all just comes down to the risk-benefit profile, which again, oncology is very, very different than sickle cell disease.
Great. Maybe we could talk about a more relevant comp within the prostate cancer context, which is mevrometostat. Could you just speak to the mechanism of action differences and distinctions between rinzi and mevro?
Yeah. Going way back, I think PRC2 inhibitors, in general, have been studied in prostate cancer for a number of years. I think the number one issue's been the first-generation PRC2 inhibitors have been plagued with poor drug properties, poor in vivo potency, very, very short half-lives, call it one to two hours, and some of these also had CYP autoinduction, where you actually saw a decrease in exposure with repeat dosing. We think mevrometostat is called a second-gen PRC2 inhibitor. We think they've improved on a number of those. They've got good in vivo potency. They've increased the clinical half-life from about one and a half, let's call it five hours, and they don't appear to have this CYP autoinduction issue. As you can see, that has translated into a pretty profound benefit based on their randomized data they presented at ASCO GU in 2025.
What we bring to the table, I think, is we continue to have good in vivo efficacy. We have a clinical half-life of 20 hours, and we think that could be a key differentiator for us because with these epigenetic modifiers, what you want to do is cover system for 20, 24 hours, and we're able to do that with that. Pfizer's half-life being five, six hours does require BID dosing, so you do have this kind of peak to trough. Our view, and I think Pfizer's view as well, is that a lot of the on-target toxicities is Cmax driven, so we're able to prevent that with the once-a-day dosing.
Great. You started to allude to this, as you think about that differentiation, how would you expect to show up in clinical benefit, and what maybe tie that into what you've actually seen in the clinical data you've produced to date?
Yeah, that's a great segue. I think what we expect that to see is in the safety side of things, and I think we have seen that. As you know, we had a pretty comprehensive Q1 update. The objective of the Q1 update was really threefold, is one, to select the patient population that we were going to study the first phase III in, select the dose of rinzimetostat that we're going to move forward with, and thirdly, to determine which AR inhibitor are we going to pick for the first phase III study. As you know, we're studying both with apalutamide and with darolutamide. We did that. We selected a dose of 400 mg of rinzimetostat, and we've decided to go with darolutamide for the first phase III study.
If you look at that data update, I think first and foremost, the efficacy that we've shown primarily on the PFS, because that's ultimately the regulatory endpoint, it's highly competitive to what rinzimetostat has shown compared to mevrometostat. If you look at the landmark analysis at five months, and we're looking at five months because the average follow-up we had, the median follow-up, I should say, was five months. We had a landmark analysis about 84%, which is right on top of what Pfizer showed at five months, both as their ASCO GU data in 2025, I think it was about 80%, and then ASCO GU 2026, they showed about 84%. The differentiation really comes on the safety side. We were able to show that highly competitive efficacy with a differentiated safety profile.
If you look at the adverse events and safety events, us versus Pfizer, you can see both in the frequency and the severity of events were significantly less. If you look at Grade 3 treatment-related adverse events, we had mid-single digits, I think, depending on which data set you look at, the 875 BID in the fed or the 1250. In the fastest state, they had somewhere in the mid-30s to high 40s. We think safety, at the end of the day, will win out here. Obviously, you're dealing with older men that are on therapy for an extended period of time. I think that's the key differentiator so far what we've shown. Now, could that translate into longer PFS longer term? We'll have to run that out to see what that looks like.
Right. One of the things that's come up in our conversations subsequent to the data was this non-specific discontinuations in the phase I trial. Maybe you could just contextualize that for us and help us think about what you guys saw in your early phase I update relative to apples-to-apples comparisons versus mevro or other prostate cancer trials.
I think that's a good question. That's something that we've gotten a lot of questions about since our last data update. A couple things. We addressed that in a few ways. One, what we saw in our study is no different than what you typically see in other phase I studies for prostate cancer. Just to remind people, it is a phase I study. The primary endpoint is safety and PK. It's not an efficacy endpoint. I think that's one. When you look at other phase I studies in prostate cancer, there's been many that's been reported recently, including mevrometostat, and some of the other T-cell engagers, and other things like that. It's very common that you have early non-related discontinuation. I think that's one.
In these early phase I studies, you don't always have perfect clarity on exactly why there are discontinuations short of something definitive like a safety or an adverse event. Patients can discontinue for a variety of reasons. Often it's attributed to something like withdrawing consent or physician's decision. What's a little bit unique in prostate cancer studies, you also have the phenomenon of increasing PSA, and often patients can come off the study, especially in a phase I study where the endpoint safety can come off early, not for radiographic progression, but just to move on to other studies or other therapies. That's something that you typically see in phase I studies with prostate cancer, even though the prostate cancer guidelines discourage that. They encourage you to stay on treatment until radiographic progression, which is a key regulatory endpoint.
As we move forward, thinking about a phase III study, a lot of times that resolves itself, usually because the primary endpoint is something efficacy. In the case of mevrometostat, it's radiographic progression-free survival or overall survival. Patients, physicians are often blinded to PSA response to not have any bias in the study. You see that as typical in the way the progression of clinical studies for prostate cancer trials are conducted.
You've guided to providing another update from the program later this year. Maybe you could just talk about the scope of update that you're going to provide. What kind of things should we be expecting there?
Yeah. We provided updated guidance in January of each year, which we do on a regular basis. At the time, we specifically intentionally called it a program update to give us full optionality or flexibility on what we provide there. That could be a number of things. That could be just an update on where we are at the first phase III study, which we refer to as Himalayas-1. It could be our thoughts on a second phase III study in prostate cancer, could be potentially a third, another study outside of prostate cancer, or could be some additional data update as well. Obviously, we're expecting the MEVPRO-1 data update as well. It could also be some color on the results of that study and anything we learned from that study as well. That's broad.
Obviously, we'll provide additional details at a later point.
Within that range of things you just said, one of them is data in the post-ARPI population, what do you think you need to have to be able to write a robust update such that it would be worth sharing in the second half of the year in terms of patient numbers, et cetera?
Yeah. Specifically on the post-AR inhibitor population, I think, one, we're obviously excited by the data we've shown so far. I think when you look at radiographic progression-free survival, it looks fairly consistent to what we've seen in the post-abiraterone setting. I think you ask a good question, what do we need to see to move that one forward? I think, one, we want to see a little bit more patients responding the same way that we have in our initial bolus of data. Two, I think a little bit longer duration is what we want to see. Again, as Dominic said, similar to the post-abiraterone patients, we had a median follow-up of about five months. The five-month PFS actually stands out pretty well compared to other therapies in the space at that landmark.
I think we want to see a few more months of duration to see if that holds, and I think that we would get pretty excited by that moving forward, since there is a significant unmet need there.
Remind us what the benchmarks are for RPFS at five months?
Yeah. It's relatively similar to the post-abiraterone setting, in that you see a lot of patients, either one in clinical studies or two in the real world getting AR switch. This would be the opposite. Instead of patients having received abiraterone and getting an AR inhibitor, this is the vice versa. They're getting an ARPI, the AR switch would be abiraterone. In that setting, there's been some recent phase III studies that reported data. You typically see an RPFS of about three months. The AR switching is typically shorter, patients do worse having seen an AR inhibitor switching to abiraterone. I think that's one. Chemotherapy is about the same, about seven to eight months. That is a five-month landmark PFS and a 60%, whereas we're tracking about 85%.
I think the other interesting benchmark there, it is a relatively small data set. It's a population that Pfizer has not been focused on with mevrometostat, but they did report phase I data in one of their earlier updates a couple of years ago in that setting. There they showed a five-month landmark PFS in the high 60s. Again, there's some separation there. Again, it's small data sets to compare, but I think what we're seeing so far is very encouraging.
Mm-hmm. Sorry, did I?
You covered it.
You got it. All right.
You got it.
Let's talk about the registrational study, Himalayas-1. Maybe first speak to the dose selection at 400 mg, are you confident with that selection? It sounds like you had these regulatory conversations that you've satisfied any sort of Project Optimus or other requirements.
I think we disclosed this on the Q1 update. We did complete an extensive exposure response analysis across a number of different measures, looking at the correlation to exposure to both the efficacy and safety, and the key takeaway there is that from an efficacy standpoint, there was no statistical difference in the dose. On the safety, there was, so that was a key driver. This is actually the ideal scenario of Project Optimus, right? You want to maintain the efficacy without pushing the dose too much from a safety standpoint. As you pointed out, we did complete the end of phase I study, and the FDA was satisfied with the completion and the way we approached Project Optimus. 400 is our dose going forward. We feel good about it, we'll have data in probably in early 2028 from the phase III study.
All right. One of the key strategic questions you answered with the update earlier this year was the decision on combination agent of darolutamide. Maybe you could talk about the advantages you saw partnering in that direction, both with respect to the drug and Bayer as a partner.
I think at the end of the day, we think both apalutamide and darolutamide are both great drugs. I think what we've said to date, there's really been no drastic difference between the two agents combining with apalutamide or with darolutamide. I think at the end of the day, and we know this, right? We know enzalutamide and apalutamide are CYP inducers, and when you're combining it with our drug as well as mevrometostat, you have this kind of CYP interaction, the CYP3A4, which decreases the dose or the exposure, I should say, of our drug and mevrometostat as well, which requires you to increase the dose, and I think that's why Pfizer is required to push their dose as well. That's a big difference, I think when you look at the difference between going with darolutamide and apalutamide. Again, we think they're both great drugs.
We just think from a differentiation standpoint, this further differentiates us from Pfizer in the first phase III study. Now to be clear, the decision to proceed with the first phase III study darolutamide does not preclude us from using a different AR inhibitor in the second phase III study in prostate cancer that we choose to go. I think that was a key driver. They're both great drugs, and if you ask a number of KOLs, I think they'd stack rank the three AR inhibitors. They'd say, the cleanest from an efficacy standpoint, I think most people would say, they're generally the same. I think from a safety standpoint, first they'd say darolutamide is the safest drug of the three, and if you look at some of the darolutamide, just to rehash history here, but enzalutamide was launched back in 2012.
Apalutamide came six, seven years later in 2018, and darolutamide came a year after that. Darolutamide's run rate, call it $3 billion-$3.5 billion, and they're growing at 50%-60%. They're one of the leaders in the space, and they're growing exponentially there. I think that's another factor we think about. Obviously, we want to hitch our wagon to the key driver there, and the further differentiation on safety here, we think the better it is for us for this indication.
Great. You mentioned that you've reached FDA alignment. I guess, what can you share about the parameters in the registrational program that you're going to start here in the near term?
I think, obviously, we don't go into intimate detail on our FDA interactions. At a high level, this study design is a 600-patient study, 300 in the treatment arm, 300 in the control arm. The dose we selected, as we said, is 400 of rinzimetostat plus the approved dose of darolutamide. The control arm will be a physician's choice of AR inhibitor or docetaxel. Again, the primary endpoint will be radiographic PFS. We're expecting to start that study imminently. We think it'll take about 15, 16 months to enroll that study, and we could have top-line data as early as early 2028.
Okay. What would you expect the mix of docetaxel versus AR inhibitor to be based on real-world utilization trends?
I think generally speaking, we'd say the range is close to 50/50, maybe it's 40/60 on the extremes. Depending on which KOL you speak to, there's definitely a preference that each KOL has on what they like to do, and some of that may be regional or their experience with the drug as well. I think that's generally real. If you look at Pfizer, I think they're generally assuming, it appears they're kind of assuming that similar split between AR inhibitor and docetaxel as well.
Right. All right. That's a great transition to MEVPRO-1 data, which is away from you all technically, is a big catalyst for the class this year. Maybe just remind us briefly of the trial design relative to the phase III that you guys are taking forward.
Just to remind everybody that, again, it's 600 patients. They're using 875 BID in the fed state of mevrometostat plus the approved dose of enzalutamide versus the control arm, which again, is physician's choice between docetaxel and enzalutamide. That study is powered to show a hazard ratio of about 0.66 or 0.65. They're assuming the control arm does 6.75. If you do rough math, it appears they're assuming around six months for enzalutamide and about seven-ish months for docetaxel. If you assume 50/50 split between the two agents, you get to this blend of 6.75 in the control arm. For the treatment arm, they're assuming 10.2.
Now, as you know, they showed about 14 months at ASCO GU in 2025 in their randomized data set. The more recent updated ASCO GU 2026, they showed about 14 months. They're assuming some level of degradation. We think that study is well-powered. We think that study has a good chance of being positive as well.
It's pretty common to assume some level of degradation from early studies into later studies in oncology. I guess, how would you guys think about that level of 14 months to 10 months in transition from a smaller study to a later-stage trial?
I think generally speaking, I'd say that's maybe a little bit on the conservative side based on we've seen multiple data sets that they presented where they've confirmed the 14 months. Again, we think it's an appropriately powered study. Even if they're able to show 10 months, I think 10 months in that setting is a big win for the class, for Pfizer, and then directly through to us. If you look at other agents in the space, Pluvicto, for example, in a pre-chemo patient population is probably close to 10 months. This, as you guys know, in this study design, you're looking at metastatic CRPC patients. These are patients that had failed abiraterone, and they could have seen up to one round of chemo as well. So in theory, these are more heavily pre-treated patients than the Pluvicto pre-chemo patient population.
Okay.
I think the other maybe small point to mention as well is Pfizer is using an improved dosing regimen and formulation in their phase III. They are switching from the 1,250 BID in a fasted state into their 875 fed. I think the data they've shown on that, obviously, one, way more tolerable than their original regimen that they used in their phase II randomized. Two, the data they presented earlier this year at ASCO GU, the efficacy seems like it's tracking a little bit better as well. The PSA response is a little bit better. The PFS hasn't been reached yet, and so there's actually potential for that it could exceed. In their earlier phase I study, they all showed 17.1 months.
I think as Dominic said, I think we believe if it is a positive study, that should be very commercially relevant when you look at the benchmarks. There are not many therapies in prostate cancer that have beaten the chemotherapy control arm. I think that's one really interesting thing, that that is the standard to actually beat. If they are able to do that would be fairly significant. The only other benchmark out there is Pluvicto that is doing very successful, competing well against docetaxel, that has an RPFS of about nine months. We think if Pfizer can post results in the 10 months is what they're assuming, with an oral therapy that's relatively generally well-tolerated, we think that would be very successful for the program and the class.
Great. Is there anything that you might take into consideration on seeing their data that could inform phase III at the margin in your own design?
That may be difficult. Obviously, we don't know when the MEVPRO-1 data will be released. I think the guidance is mid 2026 or second half 2026, which basically means the rest of the year. We're early June, we don't know when that's coming. As I said before, we're imminently starting the phase III study, it may be highly unlikely that we'd be able to read into that. The other thing I'd say is that Pfizer typically will present top-line data, just telling you if the study's positive and maybe a very little color around that. We won't know.
Yeah
the details about that as well. Realistically, it may be very difficult to get any color on what they've disclosed other than whether the study hits or not.
Okay. Maybe even just talk about a world in which obviously your base case is that it succeeds on efficacy and it looks reasonable from a profile perspective. Is there a world in which the trial disappoints, but you guys still feel confident in rinzimetostat, and what would that look like?
Yeah. We think about it in four buckets. One is there's a big win where they just knock it out of the park. Two is where they barely win. Three is where they barely miss, and four is where they really totally just miss.
Right.
Which I'd say four, based on the data that we've seen, based on the powering of their phase III study, we think is off the table. In the middle two, I think it's interesting because we really would need to understand why they barely made it or why they barely missed. Again, we think the key differentiator for us to date based on the data that we presented really comes in the form of safety, right? Better safety, you're going to get better compliance, you're going to maybe get longer duration as well. I think that's the key part. Now, again, when Pfizer presents that detailed information, we'll be telling. They obviously have three studies ongoing with MEVPRO-1, two, and three. We'll have to just see, obviously, what they present when they give this top-line data update.
Maybe you could talk about the market opportunity and this first indication that you've selected, and could you provide a high-level view of what you think the opportunity is there?
I think, one, just to start off, we think it's a very significant commercial opportunity. Again, we're going into patients that have previously failed an ARPi, specifically abiraterone. One thing to point out, if you look at the prescriptions in the U.S., abiraterone right now is tracking about 50% of prescriptions in the ARPi market. There's very significant abiraterone use in the U.S., global as well. We think there are a lot of patients that have failed abiraterone, roughly half the market. I think there's pretty good statistics out there that cite 35,000 to 40,000 metastatic prostate cancer patients. A majority of them have had seen a prior ARPi.
Potentially up to half of those would have seen abiraterone as their ARPi of choice. Again, one of the benefits with the PRC2 inhibitor, what we're starting to see with our data and the mevrometostat data, is you have the potential for really long duration of therapy with mevrometostat in the randomized phase II, a 14.3-month PFS. If you add those numbers together using typical pricing for an ARPI, you can easily get to a 3.5-plus year opportunity just in the U.S., just in the post-abiraterone setting. Again, if we were to move forward in a post AR inhibitor setting, that would be essentially about the same market size, again, just in the U.S. alone. It's a very substantial market opportunity with a very significant unmet need.
It sounds like your expectation is you would share this market. How do you think about share?
Again, as Matt said, we think that TAM is $3.5 billion in the U.S. if you just do some rough math based on number of patients and duration, and using some average price. When you look at the ex-U.S. market, if you look at prostate cancer, it's probably 90% or 100% of the U.S. market. Overall, we think worldwide, that could be close to a $7 billion opportunity. When we think of market share, we look at it two ways. One is you have the perfect analogy with darolutamide, right? You have a drug that came out seven years after enzalutamide. The only difference is really on the safety front, and that's doing $3.5 billion, and that's growing 50% per year.
The other thing is we've done, actually Matt and our head of commercial have done an independent market research with a party, and based on that market research, if you just put the profiles of our drug versus mevro, and the only differentiation is safety, we should take that market share. Safety does matter here is the point, and we think that could be huge differentiator, especially as you move up into early lines of therapy, like castrate-sensitive prostate cancer, where patients are not on drug for months, but they're on drugs for four years or so.
Maybe we can pivot for the last couple minutes here to the EGFR program. It's specifically designed for potency against exon 20 and atypical mutations, and that drug is enozertinib, and I know there's a new name, but this one's easier for me to say. Let's start with how the agent is theoretically differentiated versus the range of other EGFR program.
We call it enosertinib, is the new name.
Wow.
Yeah, pre-clinically, the molecule, I think a couple things, was designed specifically for exon 20. Prospectively screened and designed for that. I think that's one differentiator. That is not true for most of the EGFR exon 20 inhibitors today. Two, also prospectively designed to be brain penetrant. We thought that that is a key feature pre-clinically that was missing in the marketplace. I think there's been a number of companies, a number of therapies that have been going after EGFR exon 20 for a while. We always felt the landscape was missing a truly good brain penetrant drug, which is extremely relevant in lung cancer.
As you see from studies and other prevalence reports that at least a third of patients will actually present with baseline brain mets at diagnosis or the time they enter clinical studies, and a majority of them will actually progress with brain lesions over the course of their therapy. What we've seen with other targeted therapies for the other oncogenic drivers is that you really need a brain penetrant drug to be very successful, to have very long duration of therapy. We think that that is the key differentiator. That was early pre-clinical data and how it was designed. We have presented clinical data now where we're actually seeing that. Those were the things that we really wanted to see in the clinic.
I think, one, that we look at the potency and selectivity, which is what it was designed for, and we're actually seeing that in the clinic. From a safety perspective, some EGFR toxicities where we see none of the off targets that other therapies have, such as cardiotoxicity and QTc prolongation, CPK elevations, liver enzyme elevations, things like that. We haven't seen any of that. I think that's one, very good. Two, we're enrolling extremely heavily pretreated patient population. We're allowing extremely broad enrollment criteria for CNS criteria. One of the distinguishing features is that we allow patients to come into our study with so-called active brain metastases. They do not have to have been treated. They can come with full active CNS metastases. That's very different from other studies that will restrict patients from having brain metastases at all.
Some studies allow it, but they have to be treated with things like radiation. That's key. What we have seen from our early data, we're actually seeing really dramatic responses in those patients. We think, again, that is the differentiating feature that we have presented so far. We think that that will translate into long duration of therapy that has the potential to do that. We're excited to continue to update folks with the progress of that program.
Great. You did share an update in December, you, I think, anticipate sharing another update mid-year this year. Maybe you could talk about the data to date and the scope of the update we could expect.
Sure. I can cover the data, then I think Dom can point you to what to expect going forward. I think a couple of things that we've shared is we are really prioritizing first-line patients. We initially started enrolling patients that were previously treated. Now we're really focused on the first-line patients, both in the EGFR exon 20 side and the atypical side. What we've seen just from a high level so far, I think the efficacy in terms of initial ORR seems to be as good, if not better than what other therapies have reported, in both in terms of EGFR exon 20 atypicals. The safety profile as well looks as good or better than anything else, I think we feel extremely excited by that.
Then I think the one thing that is extremely differentiated is what we've seen on the CNS side. Again, in both of those patient populations, that's the first-line EGFR exon 20 and the atypicals, we enrolled patients with active CNS mets. Patients had measurable CNS mets, and in both of those populations, we had 100% CNS ORR in those patients with measurable disease. That has been something that has not been reported yet. We think, again, that one speaks to the differentiation, and I think leaves us hopeful that we'll see a long-term duration of benefit there. Other companies that have reported data, especially in the exon 20 side, most of them actually do not see a benefit in patients with CNS metastases, which is why a lot of times those are excluded from clinical studies.
We're seeing activity in patients that aren't even allowed to be enrolled in other studies. We saw a couple updates at ASCO. There's a company, Dizal, reported data with sunvozertinib. They had extremely restrictive CNS criteria, when you look at the data, they actually had no benefit in patients that actually had CNS metastases, even though they were required to be treated. That was the third study. We've seen that with others as well, is that there's just no benefit with some of the other therapies out there if patients have any sort of history with CNS disease.
I'll take the second part. We have a pretty comprehensive update in the second half of the year. This will be at the 80 mg dose, which is kind of the recommended dose we're going forward with. In first-line EGFR exon 20 as a monotherapy, we'll have 20 to 25 patients worth of data. In first-line EGFR atypical, we'll have another 20 to 25 patients of data, and then we'll have about 20 patients or so in exon 20 first line with combination with amivantamab as well. It's a pretty comprehensive update we'd expect to see there. It's obviously systemic response rate, CNS response rate, safety tolerability, and a look on durability as well. When we think about the benchmarks in each of those respective areas, we think more or less it's that 60% plus from a systemic response rate.
Okay. Maybe briefly, you could touch on what you see as the market opportunity or the size of the market in this population, particularly given the competitive landscape.
Sure. Yeah. I think when we think about this space, it's a smaller opportunity in terms of patients-wise than prostate cancer, but there is the potential for really long duration of treatment. What's been pretty well characterized is both of the EGFR populations we're targeting. Exon 20 people typically cite about 2%, maybe a little bit higher of lung cancer, and that will get you several thousand patients in the U.S., about 4,000 patients. The atypical side seems to be a little bit bigger. I think it's commonly cited about 3% of lung cancer. That, again, that will get you kind of another 6,000 patients. With about 10,000 patients, the potential for long duration of therapy, typical drug pricing, you can easily get to multi-billion dollars, just in the U.S. for both of those as a TAM.
The one thing that's a little bit different with targeted therapies in our view is you really want to have a best-in-class therapy. It is rare that you see markets kind of split evenly in targeted therapies. Again, we want to have a best-in-class profile. If that is true, that's a very substantial commercial opportunity for both of those populations we're targeting. Again, if you add both of them together, it's about 5% of lung cancer. That is kind of in the ballpark of an ALK market, and we've seen that market globally is about $4 billion-$5 billion, split between kind of the two leading therapies there.
Okay. Maybe in our final minute here, you could talk about cash runway and the clinical activities that are embedded in that guidance.
Yeah. We ended the first quarter with $420 million in cash and investments. That gives us cash runway into the second half of 2028. That does assume, obviously, the phase III study for rinzimetostat, the Himalayas-1 that we're starting imminently. That also assumes us starting a phase III study for enosertinib in early 2027. That's fully burdened in there. I think the other key takeaway is, as I said before, we're expecting top-line data from the first phase III study with rinzi in early 2028. We've got cash runway well past that going into the second half of 2028. We're well capitalized at this point in time.
Beautiful. Well, it was great having you. Thanks for the conversation today, and thanks to everyone who joined us. With that, we can turn it off.
Thanks.
I don't know what-
Thank you
my brain.
Great job.