Good morning, and welcome to the Olema Oncology webcast. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentation. As a reminder, this conference is being recorded and a replay will be made available on the Olema website following the conclusion of the event. I'd now like to turn the call over to Geoffrey Mogilner , Vice President of Investor Relations and Communications at Olema Oncology. Geoffrey, please go ahead.
Thank you, and welcome to the Olema Oncology conference call to review the palazestrant-ribociclib combination clinical data that is being presented at the 2024 ESMO Breast Cancer Annual Congress in Berlin. Please note that during today's call, we will reference slides that are viewable during the webcast. These slides are also available on the investor section of our website, ir.olema.com. As we begin the call, I'd like to remind you that today's discussion will contain forward-looking statements that are subject to risks and uncertainties, including, without limitation, those discussed in our filings with the Securities and Exchange Commission. Actual results could differ materially from those forward-looking statements.
Please see slide two of the accompanying presentation, our press release issued this morning, and our periodic reports, including our most recent quarterly report on Form 10-Q and future filings filed with the SEC, for a description of important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. Furthermore, this presentation incorporates publicly available third-party data that we have not independently verified. There are risks inherent in conducting cross-trial comparisons, as noted on slide two.
We caution you that any comparisons with third-party data should not be viewed as a side-by-side comparison, and you should not rely on the completeness or accuracy of the presentation of the results of any third-party drug candidate due to differences in study design, how other companies quantify or qualify eligibility criteria, and how results are recorded, among other factors.
We encourage investors to independently review the data. With me today are Dr. Sean Bohen, Olema's President and Chief Executive Officer, and Shane Kovacs, our Chief Operating Officer. After our prepared remarks, we'll open the call for Q&A. Now, I'll turn the call over to Sean.
Thank you, Jeff. Hello, everyone, and good afternoon from Berlin. Today, we will share the interim results from our ongoing phase 1b/2 clinical study of palazestrant in combination with ribociclib, being presented at the ESMO Breast Cancer Annual Congress here in Berlin. We last presented data from this study at SABCS in December, with early data on 19 patients at a November 1 data cutoff date. We have since fully enrolled this 60-patient study and benefited from a great deal of interest on the part of investigators. In fact, this study is enrolled faster than any of our prior studies with palazestrant, which we believe reflects the enthusiasm both for palazestrant and for using what is today the CDK4/6 inhibitor of preference, ribociclib.
The data we are presenting today is as of a cutoff date of March 13 and includes 50 patients who have been on treatment for at least one cycle or four weeks. The patients were enrolled as of early February. We believe that this is the largest clinical data set to be presented of a next-generation endocrine agent in combination with ribociclib, and we are quite pleased with the early results.
The data show compelling combinability of the two drugs, with no clinically meaningful impact on the drug exposure of either therapy and an overall safety and tolerability profile that is consistent with the ribociclib label. In addition, our early efficacy results are very promising, with an 85% clinical benefit rate observed to date across all CBR-eligible patients. Our focus as a company is to transform the standard of care in women's oncology.
Palazestrant was designed to improve upon current treatment options for women diagnosed with advanced or metastatic ER-positive, HER2-negative breast cancer. Palazestrant is a CERAN, a complete estrogen receptor antagonist, which we believe is the primary mechanism of action that will best suppress the ER-mediated growth and proliferation signal in certain tumors. Palazestrant degrades as well as any SERD in development. However, ER degradation is an epiphenomenon of receptor trafficking, not the primary therapeutic mechanism.
Palazestrant completely blocks estrogen receptor signaling and thus far has shown attractive pharmacokinetics and exposure, favorable tolerability, robust tumor shrinkage, combinability with CDK4/6 inhibitors, and CNS penetration. We believe that the data generated to date are highly encouraging and present an opportunity for differentiation versus existing therapies and competitive molecules in development. The results presented here support the opportunity for a potential first-line pivotal trial in combination with ribociclib. Now, moving on to the data.
Here is a summary of the clinical development plan that we are currently pursuing to demonstrate that palazestrant is combinable with numerous targeted therapies. Today, our focus is to discuss the palazestrant ribociclib data. We are also generating data in combination with palbociclib and alpelisib and are initiating a clinical trial to study palazestrant in combination with everolimus.
On slide 6 are the baseline demographics for the first 50 patients enrolled. If you recall, in December, we presented a data cutoff of 19 patients, 14 of whom remained on treatment as of the November 1 cutoff date. We are showing data for 50 patients who have been on treatment for at least 4 weeks. To summarize prior treatment, 70% of the patients received a prior CDK4/6 inhibitor with endocrine therapy. And of note, 11 patients, or 22%, had two prior lines of CDK4/6 inhibitors.
So this is their third treatment with a CDK4/6 inhibitor. 58% of the patients had visceral disease and 62% had measurable disease. Finally, 27% of the patients had tumors with activating mutations in the ESR1 gene. So the cohort represents both ESR1 wild type and mutant tumors. The treatment emergent adverse events show that the incidence and severity of adverse events are comparable to the published experience of ribociclib, plus an aromatase inhibitor.
Importantly, there is no increase in the incidence or severity of grade three and four adverse events with the palazestrant ribociclib combination, given at the full label dose of 600 milligrams of ribociclib and the full recommended phase II dose of palazestrant at 120 milligrams. The combination of ribociclib plus palazestrant was well-tolerated with no dose-limiting toxicities.
The maximum tolerated dose was not reached, and no patients discontinued palazestrant due to a treatment-related adverse event. Two patients discontinued ribociclib due to an AE, but stayed on palazestrant. Of note, neutropenia and QTc prolongation were very much in line with what would be expected from ribociclib plus an endocrine agent.
Overall, and importantly, the safety and tolerability profile was consistent with what you would expect from the ribociclib prescribing information. The pharmacokinetics from the combination show that palazestrant has no effect on the steady-state exposure of ribociclib across all dose levels. There were no drug-drug interactions, and palazestrant did not affect the drug exposure of ribociclib at the 600-milligram dose, compared with published drug exposure for single-agent ribociclib. On slide nine, you can see that ribociclib had no clinically meaningful effect on palazestrant drug exposure.
Slide 10 shows the swimmer plot as of the cutoff date of March 13th for all 50 patients who have been on treatment for at least one full cycle, which is four weeks. As I mentioned, the study is now fully enrolled at 60 patients, and while the data are still maturing, we believe the early efficacy data are very promising.
We have observed five partial responses out of 23 response-eligible patients, two of which are confirmed PRs and three unconfirmed PRs awaiting confirmation with a subsequent scan. The clinical benefit rates are highly encouraging. Across all CBR-eligible patients, the CBR was 85%. For patients with an ESR1 activating mutation, the CBR was 83%, and for wild type patients, it was 86%. In patients who had previously received at least one prior line of CDK4/6 inhibitor treatment with endocrine therapy, the clinical benefit rate was 83%.
At the time of the data cutoff, the longest duration of treatment was 44 weeks, with 33 of the 50 patients remaining on treatment. The waterfall plot shows that antitumor activity was observed in both wild type and ESR1 mutant tumors. Of the 22 response evaluable patients with measurable disease, 50% had a reduction in the target lesion size as of the data cutoff date, including patients who previously received a CDK4/6 inhibitor.
Many of these patients remain on treatment with the opportunity for additional responses with subsequent scans. Slide 12 presents our early results in the context of other molecules in combination with CDK4/6 inhibitors, noting the prior caveats associated with cross-trial comparisons.
Here, we compare the clinical benefit rates from the MAINTAIN study of ribociclib plus fulvestrant or exemestane versus fulvestrant or exemestane alone, given after a prior CDK4/6 inhibitor, and the CBR of vepdegestrant, an oral SERD, with palbociclib, given after a prior CDK4/6 inhibitor. As you can see, the clinical benefit rate that is emerging from the palazestrant-ribociclib combination study shows highly promising signals of efficacy versus these benchmarks.
In fact, our CBR of 85% in a more heavily treated patient population compares quite favorably to the frontline trials with CDK4/6 inhibitor-naive patients that led to approval of the CDK4/6 inhibitor class. For example, in MONALEESA-2, which was ribociclib plus letrozole in a first-line patient population, the CBR was 80%. In PALOMA-2, palbociclib plus letrozole in a first-line patient population, the CBR was 85%....
Finally, in MONARCH-3, abemaciclib plus AI in a first-line patient population, the CBR was 78%. The first-line treatment landscape for CDK4/6 inhibitors has begun shifting fairly rapidly since the publication of the overall survival data, demonstrating a statistically significant and clinically meaningful OS benefit for ribociclib in each of the MONALEESA-2, 3, and 7 trials. Palbociclib in the PALOMA studies did not achieve significance for OS, and abemaciclib OS benefit was significant only in the context of the fulvestrant combination.
Ribociclib is currently the only category one CDK4/6 inhibitor recommended for use with either an aromatase inhibitor or fulvestrant per the NCCN guidelines. We believe that the favorable combinability profile that we have seen is critical to advance to phase III in the first-line setting, where palazestrant could be the only endocrine therapy to conduct a pivotal trial exclusively with the CDK4/6 inhibitor of choice, ribociclib.
We have successfully completed the clinical pharmacology studies for the palazestrant tablet formulation, as well as food effect and proton pump inhibitor studies. Slide 14 is an update on the results of our new tablet formulation for palazestrant and the upper GI tolerability profile of the tablets versus our prior capsule formulation.
We are seeing a significant improvement in upper GI tolerability with the tablet. The data we showed earlier for the palazestrant-ribociclib combination was using our prior capsule formulation, administered in the fasting state. Going forward, studies, including the ongoing OPERA-01 trial, will utilize palazestrant tablets, with patients able to take the tablets in the fed or fasting state. On slide 16, we show the trial design for the OPERA-01 phase III monotherapy pivotal trial. OPERA-01 is expected to enroll 510 second/third-line patients and is testing palazestrant versus standard of care endocrine therapy.
Our key inclusion criteria include evaluable disease, prior treatment with a CDK4/6 inhibitor, and a minimum of 6 months on the last endocrine therapy. One to two lines of prior endocrine therapy are permitted. The trial consists of two parts: a 3-arm dose selection part, followed by an assessment of the selected dose of palazestrant versus standard of care.
At this stage, we have multiple trial sites activated and are actively enrolling patients. As we have guided previously, we anticipate OPERA-01 top-line results in 2026. We will be presenting a trials and progress poster on OPERA-01 at the 2024 ASCO Annual Meeting in Chicago at the end of May. We believe that palazestrant displays a unique ability to combine with other targeted agents. We have demonstrated a favorable tolerability, PK, and efficacy profile in combination with full-dose palbociclib.
We are also pursuing clinical studies in combination with other targeted agents, including alpelisib, for patients with PIK3CA mutations, and we have added everolimus, an mTOR inhibitor. We will update you on our progress as we generate more data. We are very pleased with the advancement of palazestrant in the clinic, and we are optimistic about the potential of this molecule to truly transform the standard of care for women living with advanced or metastatic ER-positive, HER2-negative breast cancer.
With the data we are generating in our combination studies, in particular, in combination with ribociclib, we believe that we will be able to continue to advance our development program and create opportunities to access the first-line setting.
I also want to note that we have announced a development candidate nomination in our KAT6 inhibitor program, OP-3136, and we expect to file an IND application in late 2024. To conclude, the interim results that we are presenting today show that the combination of 120 milligrams of palazestrant plus ribociclib at the full dose of 600 milligrams is well tolerated, with no DLTs observed and demonstrating an incidence and severity of adverse events consistent with the expected safety profile of ribociclib plus an endocrine therapy.
We have promising efficacy data, including clinical benefit rates across CBR-eligible patients of 85% for all patients and 83% for patients who have received at least one prior line of CDK4/6 inhibitor therapy, as well as 5 partial responses to date among a heavily pretreated patient group.
We believe that Olema has a highly differentiated next-generation endocrine therapy with the potential to make a significant impact on the treatment of ER-positive, HER2-negative breast cancer. Palazestrant has demonstrated remarkable efficacy results in early-stage trials in the monotherapy setting, and we are optimistic that the results of the OPERA-01 phase III trial will enable an approvable path to the approximately $5 billion second third-line market.
Palazestrant has also shown that it is uniquely combinable with palbociclib and the current CDK4/6 inhibitor of choice, ribociclib, which enables the potential to access the $10 billion plus first-line market. We have a management team and a board of directors with deep experience, and we are well capitalized with approximately $249 million of cash as of the end of Q1.
I want to express my gratitude to the investigators and especially to the approximately 300 women to date who have been involved in our studies. We look forward to updating you on our progress as we advance our pipeline. We will now open the line for questions. Operator?
Thank you. To ask a question, you'll need to press star one, one on your telephone. To withdraw your question, please press star one, one again. Please wait for your name to be announced. Please stand by while we compile the Q&A roster. One moment for our first question, please. Our first question comes from the line of Anupam Rama with JP Morgan. Your line is now open.
Hey, guys, thanks so much for taking the question and congrats on the update. On the early CBR signal that you're seeing here with the ribo combo, is there anything to note on the baseline characteristics that might be driving the benefit, either by prior line of therapy or otherwise? Thanks so much.
Hi, Anupam. Good morning to you, and thank you for the question. We don't really see anything that you would find unexpected. If you look at, particularly at slide 10, we break out those patients and by their individual characteristics. And what you'll find is that, you know, the vast majority of them have had a prior CDK4/6 inhibitor. A number of them have had two prior CDK4/6 inhibitors. And in that group, there's a reasonable balance of ESR1 mutant versus wild type, though we're definitely seeing activity in both. So I don't think there's a particular imbalance in that initial group. As the data matures, I will say that you'll see that later enrollment had more CDK4/6 naive patients.
So I think, as we are able to update with greater follow-up on the cohort as a whole, including the 10 patients who aren't presented here, because they didn't enroll early enough, from the data cut-off to be included, you will see that there's an evolution of the characteristics, but I think this first set is pretty typical post CDK4/6, ESR1 mutant and wild type.
Great. Thanks so much for taking our question.
Thank you. One moment for our next question, please. Our next question comes from the line of Michael Yee with Jefferies. Your line is now open.
Hey, great, thanks, for the update, guys. Two-part question, on the swimmer plot data on slide 10, which I think is hugely helpful. Can you maybe just comment about how you were thinking about average follow-up, duration of the CBR? I know people like to try and calculate a PFS off of that, but that's often difficult because I think, not everybody has measurable disease. But it looks like average follow-up might be four to five months. I'm trying to think about the, you know, how a PFS curve might look.
So talk a little bit about what you're seeing there on that slide. And then, the second question is just, as you go forward, I know this study continues. How are you thinking about the start of the phase III , which you say is in planning? What would you do to pay for that? Do you need a partnership to pay for it? How do you think about getting that all-important study underway? Thank you.
Okay, Mike, thanks. Thanks for the great questions. I'll start with the first one. So duration of follow-up. Duration of follow-ups is less than, on average, less than four to five months, actually. One thing you got to remember is that, in terms of the total of 60 patients on the study, you've got 10 who aren't on here, because they had not had the opportunity to be on for four weeks, which is the tolerability evaluable period. That's when the CDK4/6 inhibitors show up with their primarily neutropenia. With ribociclib, you also see some QT prolongation. So they have even less follow-up than what you see here. And so actually, they really cannot calculate or estimate a PFS for this curve.
And the way you can see that is that we have so many arrows. We have so many patients who are ongoing on treatment, and you don't know how long that's gonna go until they actually do complete their treatment and ultimately progress, which we foresee could be quite some time. With regard to CBR, it's a landmark analysis, right? It's six months. So how long patients could go beyond that is unclear. Although I'll note that, you know, the patients that we calculated CBR from, you can see the 30 milligram patient who was a responder and was on for quite a long time, it's the one who discontinued, not for progression, but for other reasons. But otherwise, the patients remain on therapy. So hopefully that addresses that question.
There is, I should say, and you point this out, there's most certainly an opportunity to let this data mature, to be able to include those additional 10 patients and to update down the road on the maturation of the efficacy data. Regarding the start of phase III, the one thing that we really believe this enables is the initiation of regulatory interactions. So that's vitally important to go forward to phase III.
That is primarily a tolerability question, and I think that I don't think it's controversial that the tolerability at the full doses of ribociclib and palbociclib here is quite favorable. So that's a next step that's in planning. As you mentioned, we do need access to more capital in order to initiate and complete that trial.
The OPERA-01 trial, the second- and third-line monotherapy trial, is, you know, which readout in 2026 is something we could fund ourselves. So another thing that is helpful with this data is to be able to share it with potential partners, potential funders of that trial, and that the presentation today and tomorrow enables us to start that, and we will do that in earnest, as it's not surprising to you.
Thank you. One moment for our next question, please. Our next question comes from the line of Tyler Van Buren with TD Cowen. Your line is now open.
Hey, guys. Good morning. Thanks for the presentation. Great CVRs, great data. Have kind of two similar questions, but a twist on them. So I understand that the data are not yet mature, clearly, but as we think about the data maturing over the next year or so, what's the minimum median PFS threshold that you would like to see or achieve with this combination in this patient population? And the second question is, again, regarding the phase 3 palbociclib and ribo combination phase III trial, what else do you believe you need to see from these data as it matures, or what do you believe a potential partner needs to see? And would you rather do it with a partner?
Okay. Thank you, Tyler. You know, with regard to a median PFS, these patients are quite mixed, and particularly this early data set, they're post-CDK4/6, 25%, post two CDK4/6 inhibitors. So really, we believe the comparator in terms of how are we doing versus available treatment in that population is the MONALEESA trial. And obviously, CBR-wise, we are doing much better there. The PFS for the ribociclib fulvestrant arm there, reminding everyone that that was ribociclib after prior ribociclib plus fulvestrant versus fulvestrant after prior CDK4/6 inhibitor, and so the arm we referenced is ribociclib plus fulvestrant. The prior was mostly palbociclib because of the timing of when that trial was done.
Palbo was the dominant CDK 4/6 inhibitor, and so that was in the 5-month range. It was less than six months, so we think we're doing quite favorably in comparison to that. With regard to estimating PFS, otherwise, I think we have to look at the subsets of patients. We are getting some now, you know, first-line patients, CDK 4/6-naive patients on the trial. But again, those patients really don't have maturity, and we'll just have to see as we get to the end of it. PFS is obviously the approvable endpoint. The issue here is how can you be an AI in the context of ribociclib? And the PFS median there will be 2two years in the first-line setting. That's what they were approved upon.
By suppressing ESR1 activating mutation, we think we have a great opportunity to extend significantly upon that in that setting. With regard to, you know, what's needed to move forward, really, tolerability is what's needed to move forward, because our monotherapy activity is outstanding. In a heavily pretreated prior CDK4/6 patient population, we have a median of over seven months. So the drug is, we believe, compellingly active. And so, that's really the combination of tolerability of the combination and the monotherapy activity is what's needed. With regard to partnership, obviously non-dilutive access to capital is preferable to dilutive. There are a lot of ways to access this, and so we will be exhaustive in our efforts to access capital in order to do the first-line trial.
At this point, we're not losing any time, so, you know, we will be thoughtful and careful in how we approach potential partners, potential sources of funding. You know, I'm afraid I can't answer the question about what does a partner need to see. You would have to ask potential partners that question. I do think that what you're looking at is quite a compelling data set, recognizing that we already have a compelling data set to access the $5 billion monotherapy opportunity, $5 billion in the U.S., and then this, again, to get into the first line setting and displace the AI.
Thank you. One moment for our next question, please. Our next question comes from the line of Rich Law with Goldman Sachs. Your line is now open.
Hey, guys. Good morning, and congrats on the data. A couple questions from me. Can you discuss how the CBR was calculated? I think we saw, like, 11 patients past 24 weeks, and then I assume that there's two patients from the PR that were included in the CBR. But were those two patients confirmed or unconfirmed? And also, I think there's one patient in the CBR that discontinued on ribo. So maybe just a little bit about, like, these patients and how the CBR was calculated, and then a couple other questions too.
All right, you know, it's a complicated thing, Rich. Thank you for the question. So CBR is not a standardized outcome. For instance, it's not within the RECIST criteria. We use a relatively conservative definition of CBR. So, with regard specifically to your question about responses, some sponsors say if you've had a PR or a CR that is confirmed or stable disease for greater than six months, then you count as having had clinical benefit. We don't use that. You have to have had stable disease or better for at least six months or 24 weeks in order to count as CBR according to our definition. So the unconfirmed PRs are counted, provided that they remained with stable disease or better for at least 24 weeks.
And so some you will see - you know, it's interesting, and this is why we made the point about with greater follow-up, we may see more responses. You can see that some of our initial responses are occurring fairly late, after 16 weeks or even after 24 weeks. So that's a bit of why we say that. But with regard to the CBR, it's really about having stable disease or better. The reason we do that is we really don't think a short-lived, even if confirmed, response is a clinical benefit. We believe that in this patient population, heavily pretreated, six months on an oral therapy without having to switch to a more toxic therapy is a clinical benefit. Other than that, you have to have been able to be on the drug for one cycle.
You have to have been enrolled at a time where you could have had at least six months of follow-up, and those are really the main criteria. I think if that answered that question, I think you said you had more.
Yeah. So it sounded like the two PR patients were confirmed, and that's why they were included in CBR?
No, it doesn't matter whether you're confirmed or not to be included. In our CBR, you have to be 6 months, right? So if you, if, for instance, if you look at, the 120 dose, the second patient has an unconfirmed PR. It occurred late, it occurred at about 30 weeks, but that patient was well past 6 months with stable disease, so that patient counts toward the CBR. We don't use, the definition where if you've got a confirmed PR, but it didn't last at least 6 months, that we will count you. If you progress before 6 months, you are in the denominator, but not the numerator.
Okay, got it. This may be too early, but is there any efficacy difference between the capsule and the tablet?
Yeah, it is too early, actually. So first of all, I should point out to you here, we're dealing with capsules. So this study is capsules, actually capsules delivered to the patients on, in a fasted state, so on an empty stomach, essentially. So the. - w e are transitioning into the tablets, both in our ongoing studies and obviously OPERA-01 is all tablets going forward. That will be the launch formulation. We do not anticipate any efficacy difference. There is no pharmacological difference. They are bioequivalent. So there's no PK difference between the capsules and the capsules and the tablets, so we do not anticipate that there will be any efficacy difference.
We do, as we pointed out in the presentation, we are seeing an emerging tolerability difference, really just from the upper GI standpoint.
Okay, I see. Just last question for me. Based on the data and comparing it to the mono study, does it make sense to do a CDK4/6 phase III combo in the second or third line setting? Thank you.
Yeah, that's an interesting. Thanks, Rich. That's an interesting question. You know, it's an evolving landscape. So if you were to say we did well versus maintained, I think that's true. I think that is compelling, that ribo fulvestrant, our ribo palazestrant, seems to be considerably more active in patients who have had one or even two prior CDK4/6 inhibitors. The question that you have, though, is as you go into the future, how relevant is that? Since most of those patients received palbociclib as their first CDK4/6 inhibitor, and we're seeing the new starts, in particular, move toward ribociclib. So it's not really a ribo after ribo dataset.
We believe with the monotherapy activity that we have seen, post-CDK4/6 inhibitor, and a very favorable tolerability, we are committed to the OPERA-01 approach of using palazestrant as a monotherapy option in the second, third-line setting. That said, you can see our development program is exhaustively looking at the ability to combine with other targeted agents. CDK4/6 inhibitors, we really are looking at for the first-line setting, but other targeted agents that may be used in the second, third-line setting include, you know, alpelisib, PI3 kinase, and PIK3CA-mutated patients.
And then in patients where you don't have a mutation to identify, we're seeing that depending upon the geography and the practice pattern, everolimus is used relatively broadly, and we're combining with that as well.
Thank you. One moment for our next question, please. Our next question comes from the line of Sam Slutsky with LifeSci Capital. Your line is now open.
Hey, thanks for taking the questions, and, great work on today's update. So you've shown a few patient subgroups in this data set, such as ESR1 wild type and mutants, prior CDK4/6 exposed, two plus prior CDK4/6s, et cetera. To you, what are the most important patient groups in the study as you think about showing differentiation within the current landscape of oral SERD plus CDK4/6 combos?
Well, thanks, Sam. Thanks for the question. I think that for us, probably what we've said is the comparator data set, particularly for this update, is probably maintained, where you took patients who had had a prior CDK4/6 inhibitor with an AI. Most of those were Palbo, and then I should correct, most of the treatment arm was Ribo plus Fulvestrant. You could also get Exemestane, so that was another option in that arm, versus Fulvestrant or Exemestane. And then you saw this, you know, low forties CBR rate, and a median PFS in the five-month range in the Ribo-containing arm. And so I think for right now, with the patient group we have that's mature enough, that's the most relevant.
I think the other interesting thing here is to look at the ESR1 mutant versus wild type and see that there's no differentiation here. The reason for that is most likely that OP-1250 palazestrant is a CERAN. It's a complete estrogen receptor antagonist. So, many of the molecules in this space are in fact SERMs. They're partial agonists in the wild type setting, partial antagonists in the mutant setting. And so, very often you don't see wild type activity.
You may see some activity in the mutant setting, is which is what you see with elacestrant or Orserdu. And so I think that's the other interesting observation here, is to see that wild type activity. Now, going forward, as you get as you can see, we start to get more naive patients, CDK4/6 naive patients, I should say, rather.
And so then it'll be interesting as that data matures, we'll have to, we'll have to look at how much do we have, how do we look at those patients, and, and then what is the appropriate comparator there. Look, it's not a huge data set. These are prior CDK4/6, but we already cited for you what you would see, what, what was seen with CBR in the first line setting with the existing CDK4/6 inhibitors.
Got it. Okay, and then you touched on this before, but just I guess at this point, any really lingering questions that you're thinking on as the data matures a bit?
No. I mean, I think the question about, you know, where's the PFS and what's relevant subset that people are asking is a great question. There's only one way to answer that question, and that was particularly with all these ongoing patients, and that's time. And so we will definitely keep following this. We will look for an opportunity, you know, possibly later this year, certainly next year, if not later this year, to further update people on the efficacy story here.
Awesome. Thanks, everyone.
Thank you.
Thanks.
One moment for our next question. Our next question comes from the line of Yigal Nochomovitz with Citigroup. Your line is now open.
Hi, great. Thank you very much. Congratulations on this data set. I just wanted to go back very specifically to the definition of CBR. So as I understand it, if you look at the patient who had an unconfirmed PR at exactly eight weeks, but who's only on the therapy till about 10 weeks, that person is being counted because they're still on, and they at least have stable disease. And similarly, for the patient who had the confirmed PR at, I guess, around 15 weeks, who's on till about 17 weeks, that person as well is being considered as part of the CBR rate because they have at least stable disease as of that time and had the PR. I just wanna make sure I understand that correctly. Thank you.
Yeah, you got it. So first of all, if you have not had the opportunity to be on therapy for six months, you are not CBR eligible. Because that - we have to be able to evaluate. It's a landmark analysis, which is stable disease or better maintained for at least 24 weeks on treatment. So if you've had a PR, unconfirmed or confirmed, and you've only been on treatment for 20 weeks, you don't count toward the analysis. If you-
Okay.
If you make it out through 24 weeks, you will then count.
Right. That's why I was asking, because when you were asking-
Yeah.
In the prior question, there are 11 - there are only 11 patients. According to the summary spot, I see exactly 11 patients that have crossed the 24 mark, 24-week mark. So that would imply that that has to be the denominator. So I'm trying to ascertain as to -
No, that's not right. That's not right. No.
Oh.
No, no, that's for the numerator, right? The denominator is patients who could have gotten to six months, but didn't get there, right? Who radiographically progressed. We have to count those patients because it's not that they didn't have the opportunity to get six months of therapy, it's that their disease progressed in that period. So what you're talking about is numerator.
The denominator is patients who have had the opportunity to have had six months of therapy, have had at least one cycle of therapy, and then we look at whether they make it to six months. If they don't make it to six months because they have a radiographic progression, they go in the denominator, but not in the numerator because they didn't get clinical benefit.
Okay. All right, I'll have to take another look at that. And then the other question is on the, on the-- I'm just curious, you know, obviously, the, the, the overall survival data with ribo, you highlighted nicely and, and not seeing that with palbo. I'm just curious if you could sort of expand on, on the rationale for investing in the, the palbo combo, given that, given that, as well as abema, as I understand, that one's more for the adjuvant setting. Thanks.
Yeah. So, two things about, one's a historical observation about. But then I'll talk about the practical real world with the CDK4/6s right now, right? So the historical investment and the reason that the palbociclib combination came first is we didn't have the survival data when we did that. And like many sponsors, recall, we're the first one that's gonna do a ribo only, and maybe the only that's gonna do a ribo only, planning a first-line pivotal trial. We thought the CDK4/6 landscape was baked, that palbo was the leader. It was the first one. It had the market share at that time. Obviously, the maturation of the trials to survival flipped that in a very interesting way in favor of Kisqali, in favor of ribociclib.
So I think our palbo development is done. We're following up the O02 trial. We showed very good combinability at full doses, very nice evidence of activity, and so we're quite comfortable with that. What's the value of that? I think it's a couple things to think about.
One is, Kisqali is not available everywhere in the world. It's not approved in Japan. So being able to show that you can combine well with palbociclib, not reducing the dose of either agent, which is unique, is valuable. It's interesting how the adjuvant—it's unclear yet how the adjuvant landscape will play out, right? The NATALEE data was positive. That's not yet approved for Kisqali.
I do think before we launch, we would want to generate some Verzenio combination data to show that again, we are favorably combinable in case for some reason someone wanted to use that CDK4/6 inhibitor. I don't think it's a priority for us right now. Really, ribociclib combo is our priority.
Okay, thank you very much.
Thank you.
You're welcome.
One moment for our next question. Our next question comes from the line of Emily Bodnar with H.C. Wainwright. Your line is now open.
Hi, good morning. Thanks for taking the questions, and congrats on the positive data. I'm curious if you can kind of provide rationale or reasoning on why you think you're seeing such a high benefit in the CDK4/6 pretreated patients. Is it kind of being driven by ribo or fulvestrant, or is it really just a synergy of both? And, what was the breakdown of prior CDK4/6 inhibitor use in the study so far?
Yeah. Okay, two things. So let me do the last one. You know, we have that data for prior CDK4/6. We aren't presenting it here. I can't remember if it's in the poster or not. I just... You can take a look at the poster's on the website, by the way. I should tell everybody that the actual poster is on our website. It is palbociclib dominant for the first one. You won't be surprised by that, that these are patients who would have started their first-line therapy a while ago. Again, it's not a huge data set to start parsing by prior CDK4/6, but I think it is potentially an interesting question down the road. Why greater activity? I mean, first of all, our monotherapy activity was quite compelling, right?
So when you look at our CBR in the monotherapy setting, post CDK4/6 inhibitor, you get a situation where we're already doing very well versus the comparators, even something like maintenance, which is ribo plus fulvestrant or exemestane. I think you have a combination of that monotherapy activity in both wild type patients and mutant patients. So unlike the SERMs, we're showing that there's activity in both those patient populations. So I think that helps to drive. And then I definitely ribociclib is contributing something here. You know, the ribo/fulvestrant combo, while it was not terribly compelling with a bit over 5 months median PFS, it definitely showed greater PFS than the fulvestrant or exemestane alone. So I think that the ribo is contributing as well.
Okay, thanks. Makes sense. And, could you comment on, I guess, any timing for when you might initiate regulatory discussions? Thanks.
Yeah, we can't yet. I mean, I think that's the kind of thing that you do and then talk about. I think what we're seeing here is that we're - w ell, obviously two things. One is we, with Novartis, expanded this trial from 30 to 60 patients. The purpose of that, very simply, was to remove any risk about database size in initiating regulatory conversations. That enrolled very quickly. They've all been enrolled since the end of Q1. Obviously, with the March 13th data cut, enrollment being faster at the end, we still have 10 of the patients who didn't make it here for being eligible for presentation. But obviously, we think that we, over the coming months, will have a mature enough data set to be able to initiate those interactions.
Okay, thanks for taking the question.
Thank you. As a reminder, that's star one one to ask your question. I'm currently showing no further questions at this time. I'd like to hand the conference back to Dr. Sean Bohen for closing remarks.
Thank you all very much for joining us for this data presentation on the palazestrant ribociclib combination study, phase 1b/2. I think what we've seen here is very compelling full dose tolerability with the combination. And while it is early, I think as well compelling efficacy data, particularly in the CBR rate that we're seeing with this combination. We look forward, of course, to updating further on this data set with greater maturity and with more patients enrolled, but able to mature for treatment. Obviously, we'll use this data set to try to move forward with regulatory interactions and as well enabling the first line trial in combination with ribociclib.
We continue to progress the OPERA-01 monotherapy second, third line trial, and look forward to updating that in the future with the primary readout contemplated for 2026. With that, we're making great progress. We also look forward down the road to updating on our KAT6 inhibitor, OP-3136, with non-clinical data to come in the second half of the year. With that, I thank you all, and I wish you a good day and a good week.
This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.