Welcome, everyone, to the J.P. Morgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at J.P. Morgan. I'm joined by my squad: Priyanka Grover, Malcolm Kuno, and Ratih Phin. Our next presenting company is ORIC, and presenting on behalf of the company, we have CEO Jacob Chacko. Jacob?
Thank you, Anupam. So it's my pleasure to talk to you today about ORIC Pharmaceuticals. I'll start out by the usual disclaimers with some forward-looking statements. You can read more about this in our SEC filings. So starting on slide three, ORIC stands for Overcoming Resistance in Cancer. That, in a nutshell, is the mission of the company. We're primarily focused on small molecule drug development in prostate cancer and lung cancer. We have two agents for us that are our lead molecules. One is a brain-penetrant drug for three different populations within lung cancer in three different populations that don't currently have either an approved or late-stage agent that is able to have that brain penetrance. I'll talk to you in more detail later in the presentation about why that's so important.
The second program is a PRC2 inhibitor that we're developing in metastatic castration-resistant prostate cancer in combination with multiple AR inhibitors. Those two programs have finished phase I single-agent dose escalation, are now in various monotherapy and combination studies with a goal that by the end of this year and early next year to have both of those programs in the pivotal studies. We've built the pipeline in a unique way, and that's through a combination of internal drug development. We have our own internal discovery and research capabilities, but we pair that up with targeted business development with a goal of ultimately having one IND candidate every 18 months. We've brought together an experienced management team that's worked together for years at a number of companies that have been name brands within the oncology space, so we've seen it and done it before.
And finally, the company has got a very strong cash position with a long runway, which obviously these days is quite important. You can see in the anticipated milestones that the next 18 months are going to be busy, busy, busy for us. So we've got seven different data milestones coming out in the next 18 months on those two lead programs. And that's obviously in anticipation of the pivotal programs starting for both of those programs, like I said, in the second half of this year for ORIC-114 and in early 2026 for ORIC-944. So on slide four, just a brief background on the team that we've brought together. As I mentioned, at ORIC, one of the things that's unique about the way that we've built the company is that we have both the internal discovery research capabilities to generate our own compounds in-house.
Those tend to be targets that are novel targets, first-in-class targets, first-in-class opportunities where our team has a novel biological insight, but we pair that up with strategic in-licensing, and that would be in instances where we find a target where it's a validated target that another company might have a more advanced approach or a better approach than what we've come up with internally, and so we're quite open to in-licensing compounds as well, so that's been a unique aspect of the way that we've built the pipeline. We then hand that off to our clinical development regulatory team that has largely hailed from Ignyta and Aragon, which are companies that are known for their development of both lung and prostate cancer therapies, and then finally, recently, we brought on our first commercial and medical affairs capabilities as well.
The pipeline, as I mentioned, is really headlined by the two programs, ORIC-114 in lung cancer and ORIC-944 in prostate cancer. ORIC-114 is going after three different targeted therapy populations within lung cancer, so namely EGFR exon 20, HER2 exon 20, and then atypical mutations in EGFR. Those three areas are areas that have really been underserved thus far. So among them in those areas, there is not an approved agent that has CNS activity. And the leading agents, as I mentioned, have not shown compelling CNS activity either. So we're developing this compound because it's quite potent on the order of single-digit nanomolar and low double-digit nanomolar across the variety of mutations in those three different populations. As I mentioned, we've completed single-agent dose escalation and now are in the expansion phase of the drug development there in a variety of monotherapy and combination indications.
ORIC-944 is our prostate cancer program. As I mentioned, that's in development in combination with two different AR inhibitors, namely apalutamide from J&J and darolutamide from Bayer. As you can see in the clinical collaborations column, we obviously, given the combination nature of some of these therapies, have struck collaborations with Johnson & Johnson and Bayer as well that have helped us with the development of those programs. We do have, as I mentioned, early discovery research programs and those capabilities internally. I won't have time to talk about those programs today, but we continue to work on novel first-in-class targets within both lung and prostate. So 2024 was a busy year. We did a lot, accomplished a lot. As you look at both ORIC-114 and ORIC-944, in both cases, we finished the single-agent dose escalation experiences. We picked provisional RP2Ds in the case of ORIC-114.
In the case of 114, it advanced into multiple expansion cohorts, which we're enrolling right now. The goal of those expansion cohorts is obviously to make go, no-go decisions for that program later this year, such that we can be in accelerated single-arm, accelerated approval trials by the second half of this year. For ORIC-944, the ultimate therapeutic potential there is in prostate cancer in combination with an AR inhibitor. In 2024, we finished our single-agent dose escalation experience. We proved the good drug properties of that compound and then have advanced that into combination drug development, which I'll talk more about shortly. We also raised money. That's the name of the game these days.
We put $125 million more on the balance sheet last year, extended our cash runway, such that we have a very strong balance sheet that enables us to advance these programs into the pivotal studies that I talked to you about. And then we also expanded our leadership team, namely in the areas of commercial and medical affairs, given the later-stage development of the company. So I'm going to start by spending a little bit of time on our brain-penetrant lung program, ORIC-114, which, as I mentioned, is being developed in three different populations within lung cancer. So as you look at the limitations of the compounds that have been either approved or in late-stage development in these three targeted therapy populations, they all have essentially two major limitations, one being the lack of CNS activity and the second being tolerability issues on the safety side.
So on CNS activity, like any other targeted therapy target within lung cancer, you see a high prevalence of patients who at initial presentation have CNS metastases. The important thing is, even for the patients that don't have CNS metastases at initial presentation, many, many patients, in fact, the majority of patients eventually progress in the brain. And so this is why it has become dogma now within the lung space to have drugs that are brain-penetrant in order to be able to treat and prevent those CNS metastases. Tolerability is a second major limitation of the drugs that have been developed for these particular targets. And that comes in two different flavors.
One is in the case of EGFR exon 20 compounds, you often have too high of activity against EGFR wild type, which leads to either tox in the form of GI tox like diarrhea or skin tox like rash. Now, we and the other next-gen inhibitors in this space have done a nice job of limiting the amount of EGFR wild type toxicity that is seen in the patients that we've treated. The ongoing tolerability issue for the other drugs in the space that is not an issue with ORIC 114 is off-target toxicity. As you look at the kinome trees, you will see what are known as dirty kinome trees, so essentially hitting targets that are off-target toxicities that lead to things like QTc prolongation, anemia, liver enzyme elevation.
In other words, toxicities that you also don't want to see aside from the EGFR wild type toxicities. With ORIC-114, we think that we've addressed these limitations. At least in the early phase I dose escalation, this data that we've presented thus far, we've already shown compelling systemic activity and intracranial activity in both EGFR exon 20 and HER2 exon 20. We've also demonstrated that CNS activity with confirmed CNS complete response and then again, a well-tolerated safety profile. As I mentioned, we're busy on the 114 side. We are currently enrolling three different cohorts in the second-line setting for those three populations. We are also in the process of initiating three cohorts for the first-line setting for those three indications, with a specific focus on EGFR atypicals, EGFR exon 20 monotherapy, and then actually a recently announced combination with subcutaneous amivantamab from Johnson & Johnson.
For this program alone, we expect six data readouts between now and middle of 2026. Those data readouts are the three second-line cohorts and the three first-line cohorts that I mentioned here on this page. So why does CNS activity matter? This has been a playbook that you've seen come time and time again, whether it's ALK, ROS, classical EGFR mutations. You see that the best-in-class therapy in each of those areas is a CNS active compound. The reason is because about 35% of patients at initial presentation have CNS metastases. As you get to later and later lines of therapy, that percentage grows to up to 50% or more of patients at initial presentation having CNS metastases.
The really interesting thing, though, is if you talk to clinicians and try to understand the importance of a brain-penetrating compound. It's not just the 35% of patients at initial presentation have CNS metastases. There's also a large chunk of patients who have metastases present but are not visible on imaging. So those are known as micrometastases. So they're there. You just don't realize they're there. And then there's finally a third group that maybe legitimately does not have CNS metastases at presentation, either visible or micrometastases at presentation, but will eventually develop CNS metastases if they're treated with a drug that is not brain-penetrant. Where this manifests itself is in the PFS.
So for example, by analogy, if you look at the ALK space, alectinib , which is by far the largest ALK inhibitor today that's prescribed to patients, obviously very successful in terms of what it's been able to do for patients, alectinib's ORR is not dramatically different than the first or the second approved ALK inhibitor. What's dramatically different is its PFS. And the reason is when you look at the PFS for these agents that are not brain-penetrant, you end up getting what you see here, which is an example that was shown by Takeda with mobocertinib, which was developed in EGFR exon 20, so one of the populations that is relevant to ORIC-114, where you see these dramatic differences in the PFS for patients with versus without brain metastases.
So it's in the ability of a brain-penetrating compound to close that gap in PFS between the patients with versus without brain metastases that you end up in the aggregate getting much longer durations with drugs that are brain-penetrant. So that's why we think that 114 is so critical in these three populations of interest. Now, why do these three populations of interest matter? One of the things that we the pendulum within small cap biotech tends to swing either hot or cold on targeted therapies. And lately, it feels like people tend to paint the targeted therapy area with a broad brush that the populations are "too small." As we look at the three target populations for ORIC 114, as I mentioned, EGFR exon 20, HER2 exon 20, and atypical EGFR mutations, each of those, each of them are between 2%-3% of non-small cell lung cancer.
You add up any two of those populations, and that's larger than ALK, non-small cell lung cancer. Obviously, long-term durability is going to be a key factor in the equation of what the long-term addressable market is in this space. But this is just to show you that from a commercial perspective, a relevance to patients' perspective, any one of these populations is actually larger than ROS, larger than RET. And as I said, you put a couple of them together and you're looking at a population that's larger than ALK lung. So this is why it matters to patients and why we care so deeply about the development of this program. So slide 11 shows you a schematic of the overall clinical development program for ORIC-114. In short, or in summary, we've completed the left-hand side of this slide, which is the phase I dose escalation.
We're currently in the middle part of this slide, which is the dose expansion. We've chosen two different doses for provisional RP2Ds, so 80 milligrams daily and 120 milligrams daily. To put those doses in context for you in the single-agent dose escalation experience, the first recent confirmed response we saw was at 40 milligrams daily. So the two RP2Ds going forward are 80 and 120 milligrams daily, which speaks to the wide therapeutic index of the compound and the good tolerability that we've seen thus far. The goal here is to continue enrolling those two different doses for each of the three cohorts for the next couple of quarters, and then by the middle to second half of this year, to have picked a selected go-forward dose for each of those three cohorts, doesn't have to be the same dose for each cohort, get that blessed by FDA.
And then depending on the strength of the efficacy signal that we see in each of the three cohorts, make go, no-go decisions for those. And from there, it would be the standard targeted therapy playbook, which is really starting second half this year, enroll single-agent accelerated arm cohorts that would enable NDA filings for accelerated approval, in the filings themselves taking place in the second half of 2027. We, in parallel, in a somewhat staggered fashion, would start first-line studies as well. And again, it all comes down to the strength of the signal of efficacy that we see later this year. So just as a reminder of what we've shown thus far, this is a highly synthesized summary of what we saw on the far right with ORIC-114 in the dose escalation experience.
You can see that we've enrolled a dramatically different population as part of the dose escalation experience than the drugs that have come before. So 86% of these patients had a prior exon 20 therapy inhibitor. I'm sorry, 81% had a prior exon 20 inhibitor. 86% had CNS metastases at baseline. That obviously dwarfs the percentages of those patients that you've seen enrolled by our competitor compounds where really you can count on one hand the number of patients that have been enrolled with a prior exon 20 inhibitor. And in general, you see about 30%-35% of the patients had prior CNS metastases at baseline. So obviously a much, much harder population. And even in that much harder population, we saw multiple examples of systemic activity, multiple examples of CNS activity. And in particular, as you see on slide 14, this is within EGFR exon 20.
This is a vignette that really captures the importance of ORIC-114. So this is a patient, a 55-year-old female with EGFR exon 20 mutated non-small cell lung cancer. Was treated with chemotherapy, progressed on chemotherapy. She then went on to amivantamab, which is the only agent that is now approved for EGFR exon 20 non-small cell lung cancer. Did quite well on amivantamab for almost a year, but then progressed in exactly the place that you think a patient would progress on a non-brain-penetrating compound, which is in the brain with four small lesions in the brain. She would not have qualified for any other trial in the space because she had already had a prior exon 20 inhibitor, and those patients were disallowed from those trials.
A second double whammy for her was that because her brain metastases had not been treated with surgery or radiation already, she also would not have qualified for any other trial in the space. So two different exclusion criteria that meant that her only option was to come on to the ORIC-114 trial. And with this patient, we saw a complete response in the lungs and a complete response in the brain. And at the time of the last data update, she was ongoing for nine months with the worst AE being a grade 2 mucositis and paronychia. So this is, again, a one-patient vignette, but really encapsulates exactly why we think that this drug is so important for its development in the lung space.
Now, just yesterday, we announced a collaboration with J&J, which hopefully shows that it's not just us that thinks that this drug is important for development in the space. Johnson & Johnson, as I mentioned, has the only approved EGFR exon 20 inhibitor, which is amivantamab. Amivantamab is not brain-penetrant. And as many of you know, Johnson & Johnson has been exploring amivantamab in combination with lazertinib in two different populations. One is the Mariposa studies in classical EGFR mutations. And then they're also studying amivantamab plus lazertinib in atypical mutations. Now, lazertinib does not have potent EGFR exon 20 therapy activity. And so that's why Johnson & Johnson and ORIC decided to strike this collaboration where we're going to look at the combination of subcutaneous amivantamab with ORIC-114, specifically in EGFR exon 20.
The therapeutic rationale is well understood, which is with 114 being brain-penetrant, with amivantamab able to cover the resistance mutations like MET and C797S, and then with two exon 20 directed therapies able to get just broader and deeper coverage of the variety of exon 20 mutations. We think that this is worth studying in the clinic to see whether those two agents are combinable. This would obviously be really interesting if we see that they are in fact combinable because that would give us an interesting frontline strategy. One that, in contrast to essentially the two traditional frontline strategies today within EGFR exon 20, which is either monotherapy or combinations with chemo, this would afford us the opportunity to have actually a chemo-free combination where you pair ORIC-114 with amivantamab.
So on that last collaboration, I should have mentioned we intend to initiate this combination trial in the Q1 of this year with initial data in middle of 2026. I mentioned to you that we also had compelling activity in HER2 exon 20 at our last data update. Again, multiple different doses. We saw both systemic activity and intracranial activity. And then slide 17 summarizes for you a pretty robust clinical development plan, again, in both the second line and the first line in these three different populations. Ultimately, what this roadmap leads to, if all goes well, is accelerated approval filings in the second half of 2027 for the second line, hopefully one or more second line populations, and then full approval first line NDA filings in 2028. So obviously quite accelerated timelines, which is the case in this particular area within oncology.
I'm going to transition now to ORIC-944, which is our allosteric inhibitor of PRC2. One of the first things we often hear from investors, starting on slide 19, is that they're not familiar with PRC2. We always assure them they certainly are. They just know it by a different name. PRC2 is a complex that has three different subunits. The complex that's probably best known because there's an approved agent for it, or the part of the complex that's best known is EZH2. EZH2 is the catalytic subunit of PRC2. There's a drug called tezemetostat that was developed by Epizyme. That's now in the hands of Ipsen, which was developed in epithelial sarcoma and follicular lymphoma, which is an EZH2 inhibitor.
Now, the broader space of PRC2, whether that's EZH2 inhibitors or another subunit, EED inhibitors, have been limited by a number of different things, so namely drug properties. So what you tend to see in this space with these PRC2 inhibitors is poor in vitro potency, poor in vivo potency. You also have tended to see numerous drugs with short half-life on the order of two hours. You've seen properties like CYP autoinduction, where the drug literally induces the CYP enzymes, which then metabolize the drug. So you get lower exposures the higher you dose the drug. In other words, it's just sort of a litany of things that you don't want to see in the drug properties. And so this has really limited the development of PRC2 inhibitors, whether that's in prostate cancer or other indications.
With ORIC-944, we have a compound that we think has done quite nicely in terms of selectively targeting PRC2, again, through that EED subunit. It's very potent when you look at in vitro studies, very potent when you look at in vivo activity. Importantly, we've already shown in the clinic as a single agent that it has excellent drug properties. So a 20-hour clinical half-life, no CYP autoinduction. So essentially has just really seems to have solved some of the bad drug properties of prior compounds in PRC2. This compound, as I mentioned, is being developed in combination with an AR inhibitor, darolutamide from Bayer, and also in combination with an AR inhibitor, apalutamide from Johnson & Johnson. We just yesterday put out some preliminary combination data from that that I'll review with you today.
The goal here is to continue dose-finding work in combination with both of those AR inhibitors, such that by early 2026, we can start our own phase III pivotal program or programs for ORIC-944 in combo with one of those AR inhibitors. The target itself has been tremendously de-risked in prostate cancer by data that has been shared by Pfizer with a very similar compound in the exact same indication. And so that's why we have high confidence in the development of ORIC-944. Now, as I mentioned to you, the PRC2 complex, as you can see here on slide 20, has three different subunits. Most of the drugs in development thus far have targeted the catalytic subunit known as EZH2. There's been us and a few others that have targeted via allosteric inhibition going after the EED subunit.
There is no difference in which of those subunits you target in terms of initial ability to inhibit the PRC2 complex. And we've looked at that through a variety of different elegant analyses, including RNA-seq that shows an R-squared value of 0.9 when you look at the gene signatures of the genes that are activated by either EZH2 versus EED. As I mentioned, the real issue in the space has just been poor drug properties. And that's plagued both the EZH2 inhibitors as well as the EED inhibitors. Now, why does this matter in prostate cancer? Slide 21 is a highly, highly simplified schematic for some very complex biology. But at a high level, what is happening is folks are well familiar with three different AR inhibitors: enzalutamide, apalutamide, and darolutamide, which collectively do about $11 billion of revenue in the prostate space.
Those drugs have done phenomenally well for patients. Patients have excellent clinical outcomes on those three drugs. But as people know, eventually patients become resistant to those drugs. What ends up happening is that the tumors evolve and they become AR-independent so that it no longer matters that you're using an AR inhibitor to treat the tumors. And so PRC2, what is thought is that by putting a PRC2 inhibitor in combo with an AR inhibitor, you're essentially able to push the tumor by virtue of the impact of PRC2 on a variety of different genes. You're able to push the tumor back into an AR-dependent state. And so that's why it's thought that there would be synergy in combining a PRC2 inhibitor with an AR inhibitor. Now, that synergy has been tested in the clinic by some prior compounds. It's failed in the clinic.
Frankly, the reason for those failures, we believe, is because of the poor drug properties of those compounds. As you look at a compound from Constellation on the left side of the page here on slide 22, also tezemetostat, which I mentioned is approved in two different heme indications, but was also studied in prostate. Both of those compounds were studied in prostate in combo with AR inhibitors. Both of those compounds, as you can see from this schematic here, have poor cellular potency, have poor in vivo activity, have even worse drug properties in the form of, like I said, two-hour half-life and CYP autoinduction. Literally, as I mentioned, in the case of one of those drugs, Epizyme put out data that showed with tezemetostat that as they dosed higher, they got lower exposure. That's obviously a suboptimal clinical experiment.
Now, Pfizer has a compound that they've been talking a lot about for the last year and a half. It's called mevrometostat. It's an EZH2 inhibitor, which, like I said, seems to have improved upon a number of the different drug properties of the first-gen compound. So with mevrometostat, you have a compound that is highly potent, that has good in vivo activity, that has a lack of CYP autoinduction, so seems to be better on that front, has a somewhat improved half-life that we estimate to be about four to five hours. So in a number of different respects, has improved upon the first-gen PRC2 compounds.
The profile you see on the far right is for ORIC-944, which is every bit as potent on cellular potency and in vivo activity as Pfizer's compound, but in addition, has a lack of CYP autoinduction, has a 20-hour clinical half-life as opposed to the four or five-hour clinical half-life for Pfizer's compound, has less interpatient variability than Pfizer's compound, so namely, on a number of different metrics, looks as good or better than Pfizer's compound.
Now, the reason I'm talking so much about Pfizer's compound is because Pfizer has put out, at least in a phase I data set, the most convincing clinical data set that shows the real promise of combining a PRC2 inhibitor with an AR inhibitor, where in two different prostate populations, they were able to demonstrate a PFS that was anywhere from three and a half to four times as long as the PFS you would expect from enzalutamide alone in that population. Preclinically, we have done experiments that seem to replicate those clinical results. So as you look here on slide 23, you can see that in this treatment refractory model, darolutamide, which does fantastically clinically, but this is a treatment refractory model, darolutamide looks a lot like the vehicle.
In the case of the orange line, which is mevrometostat, that's Pfizer's compound plus darolutamide, you can see a much longer PFS in these animal models. And then obviously, as you might expect from the better drug properties I alluded to earlier for ORIC-944, you see even better results with ORIC-944. And so we moved this compound into single-agent dose escalation, which we completed in the middle of last year. Really, the purpose of that single-agent dose escalation was to establish the better drug properties of ORIC-944. As I mentioned to you and as you see summarized on slide 25, with ORIC-944, you see a 20-hour clinical half-life. There is no CYP autoinduction. We get very low interpatient variability.
In other words, we really checked the boxes on a number of different drug properties that we wanted to see out of ORIC-944 as a single agent. We also identified 600 milligrams daily as the optimal go-forward dose, at least based on the single-agent experience. That was what we then took forward into combination dosing, which began in the middle of 2024. Slide 26 is some new data we shared just yesterday, which was the culmination of the single-agent dosing experience with ORIC-944. As I mentioned to you, this shows you that the vast majority of AEs were grade one, grade two AEs, and really what we see is on-target PRC2-related side effects, which is namely heme tox, GI tox, and some fatigue. I mentioned we took forward 600 milligrams daily into our combination dosing. This started in the middle of 2024.
You can see here a trial schematic on slide 27. There are three phenomenal AR inhibitors. Pfizer owns one of them, enzalutamide, and that's what they're combining with their EZH2 inhibitor, mevrometostat. The other two phenomenal AR inhibitors are darolutamide from Bayer and apalutamide from Johnson & Johnson. And so last year, we struck collaborations with both Bayer and Johnson & Johnson for them to give us free drug and a heck of a lot of input into our trial designs. They obviously see the strategic rationale here of combining an AR inhibitor with a PRC2 inhibitor, given what Pfizer has already shown. We're now doing our dose-finding work in those two different combinations. We're actually looking at two different populations within the prostate space. So one is a population that's already had prior abiraterone as part of their treatment history.
And then a second population, which is any prior AR inhibitor, so even patients who've already progressed on either enzalutamide, apalutamide, or darolutamide. The goal is that we will continue the dose-finding work. We anticipate that sometime in Q2 this year, we'll have our selected provisional RP2Ds for those combinations with apalutamide and darolutamide. We'll then spend the rest of this year enrolling more patients at those two provisional RP2Ds to satisfy FDA Project Optimus requirements, such that by the end of this year, we would have selected one go-forward RP2D. We'd also have selected one go-forward AR combo inhibitor for our combinations. And then by early 2026, have started our own phase III program for this.
Now, given how much our competitor has been talking about their program, we've been getting a lot of questions about when folks can see PFS data from our ORIC-944 combinations with these AR inhibitors. We try to tell people to be patient. These combination dosings started in middle of 2024, so we're only about two quarters in. And so long story short, we're not going to have mature PFS data of our own until probably later this year at the earliest. Otherwise, it'd be first half next year, just given the long PFSs that you expect to see here. Now, in lieu of that, what we've tried to do here on slide 28 is give people at least a little indication of what seems like encouraging clinical activity right out of the gates for ORIC-944 in combination with apalutamide.
So by the middle of December, we had completed the first two dosing cohorts of ORIC-944 at 600 milligrams and at 800 milligrams in combination with apalutamide. What you see here is best percentage change in PSA response, which, as folks know, is a proxy that people use in the prostate space to try to assess early clinical activity. And as you can see here, of those six patients across those two different dosing cohorts, three patients achieved a PSA 50. In fact, two of those were PSA 90s. Now, a couple of caveats here, first, right off the bat. One is we continue to believe here that the right regulatory endpoint is radiographic PFS. That's the regulatory endpoint for every prostate cancer drug that's been approved. And we continue to believe that that's the regulatory endpoint for us as well in the long term.
But in terms of looking at just early clinical activity, this is obviously highly encouraging seeing these kind of PSA responses. All of these patients, as I urge you to look at the prior therapies at the bottom of the page, all of them have had prior abiraterone and progressed. Four of the six patients had prior chemotherapy, obviously a number of other investigational and approved therapies as well that these patients had seen. And so in light of that, seeing this depth and breadth of PSA responses is quite encouraging. Now, the caveats are, obviously, this is NF6. We'll see if this holds up in larger patient samples. And again, like I said, our PFS is ultimately the regulatory endpoint. The question you should be asking yourself is, what would apalutamide alone be able to do in this setting? And this is well documented across hundreds of patients.
For patients that have already progressed on abiraterone, if you give them apalutamide, you would expect that approximately one in every 20 of those patients would have a PSA 90 response, and then you'd expect one in every five of those patients would have a PSA 50 response, so obviously, small N, but we're already seeing quite encouraging activity in this combination. Now, the darolutamide cohort, we have completed one cohort with darolutamide. We're enrolling the second cohort right now, but as you see there on the page, on the bottom of slide 28, thus far, the preliminary clinical activity in the darolutamide combination is consistent with what you're seeing here with ORIC-944 and apalutamide, so we're encouraged, and we'll continue to develop this program. We'll continue to look at the dose finding over the next few months.
Then stay tuned for the next data update for this program in the Q4 of this year or first half next year. So with that, I think you probably have heard a lot on these two different programs. There's a lot of clinical activity going on, a lot of data readouts coming out in the next 18 months, seven different data readouts in the next 18 months. The company is well funded with a long cash runway, but we're quite excited about these two different programs. Anupam, let me open it up for questions.
Yep. Thanks, Jacob. We have a few minutes for questions. Just want to remind folks if they want to raise their hand, I'll call on you. Someone's already submitted a portal question, so I can ask that, but you guys can too, or you can just email me.
I just want to start on one question of my own, which is on the phase Ib PSA response data that you shared just a few minutes ago. It's probably just a function of small numbers, and I know you're still dose escalating, but it did look like there's a little bit of an inverse dose response. Anything to comment there, or is it just a lot of small numbers?
Small numbers.
Got it. Okay. The questions from the audience. So the portal question is, this is related to ORIC-114. Where will the clinical trial results in the second-line treatment for second-line be presented at AACR or ASCO?
We have not historically specified where we plan to do it. I think that the most specificity we can give right now is it'll take place in the first half of this year.
And then given amivantamab itself has shown some toxicities, what are the expectations regarding safety when you use in combination, considering the safety profile observed in prior ORIC-114 studies?
Yeah. So that's the whole point of doing the investigational work of 114 with amivantamab. You're not going to know whether it's tolerable to combine two different EGFR-20 directed therapies until you try that out in the clinic. Obviously, Johnson & Johnson has showed with their combo with amivantamab and lazertinib in the Mariposa trials in classical EGFR mutations, and separately, amivantamab combined with lazertinib in atypical mutations that they can achieve a tolerable profile. And so we hope that the same is true here, but we won't know until we test that in the clinic.
If for some reason it looks like there's too much toxicity for the two in combination, then obviously we can default to one of the two traditional paths, which is either our first-line strategy being a monotherapy of 114 versus chemo or a combination with chemo versus chemo, which is exactly what all the other programs in the space have done.
Another pivotal question is, what are you looking for competitors in 2025 in the exon 20 space? And I'll throw one in as well, which is maybe speak to the CNS penetration.
We'd love for competitors to show some CNS penetration, I guess, is one thing, but I don't anticipate seeing that. There's going to be a lot of updates this year in the EGFR exon 20 space and the atypical space with a number of different competitors showing first-line data sets, also hopefully showing some durability data.
I think that'll hopefully help clarify what we and others need to shoot for in terms of competitive benchmarks.
Any questions from the audience?
Yes. When are you going to be in a position to share data in atypical mutations and what are your expectations there relative to the efficacy you've seen in exon 20?
Yeah. So we're going to share data in EGFR exon 20 and HER2 exon 20 in the second line in the first half this year. For atypical mutations, which we got started later than those other two cohorts, we anticipate sharing second-line data in the second half this year. I think the competitive benchmarks are still being written on the atypical side, just given what we saw last year was somewhat preliminary.
But in general, it looks like atypicals and EGFR mutations in the second line are vectoring to roughly the same place, which is somewhere in the 35+% range of ORRs, at least in the second line. I think what you saw last year was some, maybe I'll say somewhat inconclusive data sets in atypicals where at certain doses you might have seen good efficacy, but too much toxicity. And other doses you saw with some competitor compounds, not enough efficacy with a more tolerable profile. So I think those benchmarks are still being written, but I think they're roughly the same for those two populations. HER2 exon 20 is a different story. I think we tend to see slightly higher response rates for HER2 exon 20, even in the second line, so on the order of 50% or greater in HER2 exon 20.
That's probably a function of the fact that HER2 exon 20 tends to be a slightly more homogeneous population. So when we use these terms, HER2 exon 20 obviously encompasses multiple different mutations, but there's one in particular that is the majority of HER2 exon 20 mutations. That's not the case with EGFR exon 20 or atypical mutations, where it's actually, there's maybe three or four that are about half the population, but then a long tail of other mutations that make up those populations.
Any final questions from the audience? Nope. All right. Thank you so much, Jacob.
Thank you.