Karyopharm Therapeutics Inc. (KPTI) Earnings Call Transcript & Summary

Good morning. My name is Tom, and I will be your conference operator today. At this time, I would like to welcome everyone to Karyopharm Therapeutics' conference call to discuss its data from SIENDO study. [Operator Instructions] Be advised that this call is being recorded at the company's request. And I would now like to turn the call over to Elhan Webb, Senior Vice President, Investor Relations. Please go ahead.

Thank you, Tom, and thank you all for joining us today to the conference call to discuss our data from the SIENDO study. Today, I'm joined by Richard Paulson, President and CEO; Dr. Patricia Judson, SVP Medical Strategy; and Dr. Robert Coleman from U.S. Oncology Research. In addition, during our Q&A session, we will also be joined by Mike Mason, CFO; and Sohanya Cheng, Chief Commercial Officer. Detailed results from our Phase III SIENDO study was presented earlier today at the ESMO Virtual Plenaries session. The same data will be presented again at the SGO, Society for Gynecology and Oncology, on Saturday. The slide presentation of today's conference call is available under the Events and Presentations section of our website at karyopharm.com. Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995, as outlined on Slide 3. These include statements about our future expectations, clinical developments and regulatory matters and timelines, the potential success of our products and product candidates, including our expectations relating to the commercialization of XPOVIO and NEXPOVIO, financial projections, our plans and prospects. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC, and in other filings that we may make with the SEC in the future. Any forward-looking statements represent our views as of today only. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so, even if our deals change. Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today. I will now turn the call over to Richard. Please turn to Slide 4.

Thank you, Elhan, and good afternoon, everyone. I would first like to welcome Dr. Patricia Judson, our new Senior Vice President of Medical Strategy; and Elhan Webb, our new Senior Vice President of Investor Relations, who just presented to you. This is her first investor call since joining Karyopharm. Both are very interested in getting to know you and working with all of you in the near future. I'm excited to discuss our plans for a new study of selinexor in patients with advanced or recurrent p53 wild-type endometrial cancer. Patricia will present the results from our SIENDO study, which produced exciting hypothesis-generating data in patients with p53 wild-type endometrial cancer. I would like to acknowledge the exceptional work done by a lot of very dedicated individuals at both Karyopharm and at the SIENDO clinical trial sites. We are planning on engaging the same group again with our new study. And most importantly, I once again want to express our sincerest gratitude toward the patients and their families who participated in this study. Now before I turn the call over to Patricia, I'd like to step back and ground all of us in why our work in endometrial cancer is so important. Endometrial cancer is the most common gynecological cancer, with 66,000 new cases in the U.S. and over 130,000 new cases in Europe each year. For the majority of these women, the disease is caught early enough to be addressed surgically. However, each year, 14,000 women in the U.S. are diagnosed with Stage 4 for recurrent endometrial cancer and require chemotherapy. And of these, about 9,000 will respond to chemotherapy and could benefit from maintenance therapy. Nearly all patients who respond to frontline chemotherapy will develop a recurrence within a short period of time. And the standard of care following chemotherapy is watch and wait. The cancer generally recurs within 4 months following chemotherapy with no additional treatment. So we are eager to launch a new study solely focused on patients with p53 wild-type endometrial cancer, where selinexor may offer the greatest promise. Roughly half of all women with advanced or recurrent endometrial cancer have wild-type p53, and we are optimistic that our new study will demonstrate that this population can benefit from our work with the selective inhibition of nuclear export. We will act with urgency, recognizing that the mortality rate for endometrial cancer continues to rise. And unlike many other solid tumors, mortality for endometrial cancer increased 2% annually from 2008 to 2018. And with a 5-year survival of only 17% and median overall survival following chemotherapy of 18 months, there is clearly a need for maintenance therapy that can extend progression-free survival, although no best therapy exists today. Instead, the current standard of care is to simply watch and wait for the cancer to return and progress. It is easy to understand why this is an unsatisfying option for both patients and physicians. There's a clear and urgent need for us to do more. And with that, I will now turn the call over to Patricia. Patricia?

Thank you, Richard. So I'm going to share with you the results from our prospective, double-blind, randomized Phase III SIENDO study of oral selinexor versus placebo as maintenance therapy after first-line chemotherapy for advanced or recurrent endometrial cancer. On Slide 6, you see the trial design. So the SIENDO Phase III trial investigated the efficacy of selinexor, 80 milligrams orally once weekly, versus placebo in treating Stage IV or first relapse of endometrial cancer after completing a platinum-taxane-based chemotherapy. The patients were randomized 2:1 to selinexor versus placebo. Patients were stratified based on Stage 4 versus recurrent disease at diagnosis, and stratified based on the response to chemotherapy, whether they had a partial response or a complete response. The primary endpoint was investigator-assessed progression-free survival, and secondary endpoints included overall survival, progression-free survival by blinded independent central review, patient-recorded outcomes and the others listed there. Predefined exploratory endpoints included progression-free survival by histologic subtypes and molecular classifications, including p53. The statistical assumptions were that 140 progression-free survival events were needed to provide an 80% power to detect a hazard ratio of 0.6, with a one-sided alpha of 0.025 and a 2:1 randomization ratio favoring selinexor. On Slide 7, we see the patient's baseline characteristics are well balanced between arms. The median age of patients in both groups was similar, selinexor 65.5 years versus placebo 64. More than half of the patients presented with a histology of endometrioid carcinoma, consistent with what we see in the real world. The next most common was serous carcinoma, making up another 1/3. More than half of patients in each arm had recurrent disease. In addition, 50% to 60% of the patients had only a partial response to their most recent chemotherapy. On the next slide, you see the results from the primary endpoint, which was investigator-assessed, median progression-free survival in the intent-to-treat population. For the selinexor arm, median PFS was 5.7 months versus 3.8 months for placebo, a difference of 1.9 months in the maintenance setting. This level of improvement in the maintenance setting is unlikely to support an sNDA approval. When visualizing the Kaplan-Meier curves, one notes that the curves separate at about 4 months and remain separate. The hazard ratio, based on the IRT data, was 0.76, with a one-sided p-value of 0.063. The hazard ratio, based on the audited eCRF data, is 0.70, with a one-sided p-value of 0.24. As seen in the right lower side of the slide, the eCRF hazard ratio and p-value is based on audited stratification factors. In 7 patients, the stratification factor of complete response versus partial response was entered incorrectly into the IRT by the site. When the errors were detected during monitoring, they were corrected by the site in the eCRF prior to database lock and prior to unblinding. Therefore, the eCRF data represents the correct complete response and partial response information on the patients. The statistical analysis was validated by the principal investigator, independent ENGOT statistician and approved by the independent Data Monitoring Committee. On the next slide, we see a preliminary analysis of the prespecified exploratory subgroup of histology. This shows that in patients with endometrioid endometrial cancer, there was a longer median PFS in the selinexor-treated patients, compared to placebo. Whereas in patients with serous cancer, we don't see a difference in the median PFS. These results are consistent with molecular profiling, as the vast majority of endometrioid patients are p53 wild-type, whereas patients with serous carcinoma are predominantly p53 mutants. On Slide 10, we have the preliminary analysis of a prespecified exploratory subgroup of patients with p53 wild-type endometrial cancer. There was a longer median PFS in patients treated with selinexor than patients receiving placebo, 13.7 months versus 3.7 months, a 10-month difference. This is exciting hypothesis-generating data from the study and, as we'll discuss later, it's the basis of our future study. On Slide 11, we review the tolerability of selinexor a s a maintenance therapy. Selinexor was generally well-tolerated in the SIENDO trial. The vast majority of AEs were grade 1 and 2. Grade 3 treatment-emergent adverse events were reported in 46% of patients overall. Grade 4 AEs were reported in only 2 patients, 1 patient with thrombocytopenia and 1 with hypotension. The difference in the rates of grade 3 AEs between selinexor and placebo were primarily attributable to the rates of asymptomatic cytopenias. None of the patients with grade 3 neutropenia had clinically significant infections or febrile neutropenia, and none of the patients with thrombocytopenia had significant bleeding events. Grade 3 non-hemologic AEs, seen here, were expected and treated with supportive care. There were no treatment-emergent adverse events leading to death, and no major organ toxicity reported with selinexor in the SIENDO study. On Slide 12, we see the rates of treatment-emergent adverse events leading to dose reduction, dose interruption and dose discontinuation. The discontinuation rate due to treatment-emergent adverse events is 10.5%, despite the fact that these treating physicians lacked experience with selinexor as the -- at the majority of the clinical sites. AEs were managed with supportive care, dose reductions and interruptions, keeping the rate of discontinuations relatively low. On Slide 13, we see the quality of life by patient-reported outcome. This shows that there's no statistically significant difference observed across the PRO assessments in global health, physical functioning, diarrhea or nausea and vomiting. There were, of course, numerical differences between the selinexor and placebo group, most prominently for nausea and vomiting, but these were not clinically significant. On the next slide, so the insights we've gleaned from the SIENDO study provide a clear path forward for the study of selinexor in the p53 wild-type advanced or recurrent endometrial cancer. We are excited about the 10-month improvement in median progression-free survival we saw in the preliminary analysis of the p53 wild-type subgroup, and we'll be studying this group further. So is there a biologic rationale for what we observed? p53 controls a multitude of regulatory signals. One of the most important is to identify cells with significant DNA damage and cause them to undergo apoptosis or programmed cell death. If p53 is not functioning, cells with damaged DNA, such as cancer cells, will continue to divide. p53 and other tumor-suppressor proteins must be in the cell nucleus in order to detect DNA damage. Cancer cells can abolish p53 function through inactivating mutations, resulting in p53 mutations, or by relocation of p53 from the nucleus to the cytoplasm, which is mediated by exportin 1, or XPO1. So XPO1 is a major nuclear export protein for tumor-suppressor proteins, including p53. When we inhibit XPO1, it resulted in an increase in nuclear levels and activation of tumor-suppressor proteins. So forced nuclear retention of p53 wild-type in the cell nucleus by the inhibition of XPO1 by selinexor allows p53 to carry out its tumor suppressor and other regulatory functions, which we believe is the mechanistic rationale for the data we've observed. We discussed the results of the SIENDO study, the hypothesis-generating data in p53 wild-type patients and the biologic rationale for why this may occur. We're now excited to be moving forward with a new Phase III randomized, placebo-controlled study in patients with p53 wild-type advanced recurrent endometrial cancer, and we are planning to initiate it later this year. We're working with ENGOT, or the European Network of Gynaecological Oncological Trials; the Gynecologic Oncology Group; and the FDA to finalize the study design and the statistical assumptions. We plan to use our existing trial sites, which will expedite enrollment. We anticipate studies start in the second half of 2022 and expect to report top-line results in the first half of 2024. So let's shift from the data to clinical perspective. I would like to welcome to the call, Dr. Robert Coleman. Dr. Coleman is a world-renowned gynecologic oncologist. He's contributed around 400 publications to our field. He is the past President of the Society of Gynecologic Oncologists, the current President of the International Gynecologic Cancer Society, and Co-Director of GOG Partners. He's the Chief Scientific Officer at U.S. Oncology, the largest community practice in the U.S. Welcome, Dr. Coleman.

Thank you. It's good to be here.

Yes. So I'd like to start by asking you about the patient population we're studying in SIENDO, patients with stage 4 and recurrent endometrial cancer. Can you please provide us some insights into the unmet needs of this patient population?

Yes. So I think it was mentioned in the opening comments that the -- across the United States, both men and women, that the mortality rates from cancer have been declining over the last 5 years, about 2% per year. There are only 6 cancers in women that have actually increased, and the top of that list is endometrial cancer. So despite the tremendous advances we've made in not only understanding the biology, we have not made measurable change in that [ miserable ] statistic, and so there is tremendous need to dig deeper and to understand what is going on with this particular cell type. And I think that the comments you made with these [indiscernible] rates as it relates to this trial is part of that story, understanding natural history and biology and how we can best approach them. So these core statistics for mortality rates, and I think what is underappreciated is the actual prevalence of this disease, which in this setting is actually increasing. We are really -- we have our work cut out for us to actually identify new therapies going forward.

Yes. It sounds like we have a lot of work and a lot of opportunity in this patient population. So why is maintenance therapy important? I mean can you speak to the treatment paradigm? So what's the benefit of treating with maintenance therapy rather than just giving a patient a treatment break and waiting for their cancer to....

Right. It's a great question. I feel like this is Groundhog Day. We've been talking about maintenance therapy in multiple different tumor types for years, decades. And I think it's probably best emphasized and characterized by the fact that patients who go into a watchful waiting, which unfortunately is what we have when we don't have effective therapies, is that these patients recur in a short period of time, even in the patients who have a complete response. So we treat these patients, whether they get a CAT scan or a PET scan or PET/CT, and there's nothing on there. And when we monitor those patients, they recur. So we obviously are missing, even if we operate and look for pathologic complete response, we still see recurrences happening in a very short period of time. So the need has been there for a very long time. And so we -- what we have been trying to do in the more recent years is to get smarter rather than just extending chemotherapy or using some non-targeted type of therapy to try to see if we can affect that long-term though, that natural history, and we've gotten smarter by using more targeted agents that are relevant to biology so that the resistance or the persistence levels that are maybe subclinical, or even if they're clinical, that we're able to affect the biology of those cells at that time, and that's why it's so important for us to understand the underlying biology that's driving that particular phenotype. So maintenance or a strategy, we use one at [ TFF ] and we use another therapy to come in and take this on.

Interesting. But I see maintenance therapy is probably preferential to a treatment breakdown, so it can prolong the response to chemotherapy and it can delay the time to subsequent, potentially more toxic therapies.

Yes, I think that's a key observation. We would like -- if we could effect longer and longer progression-free survival, it just provides us with better opportunities. I think that's a piece that gets missed in the whole story about oncology because we talk about intermediate endpoints that try to -- and they try to predict what's going to happen in the future. But the longer the patients live, the more opportunities they have. So the longer you live, the longer you live. And this is where -- why doing clinical research is so vital to changing paradigm for how we treat the disease. So our hope is that these maintenance strategies which are being introduced to try to extend an effective therapy and to keep the tumor from coming back provides us a platform to keep patients alive longer and potentially introduce the next new thing that might continue to extend them.

Yes, interesting. So when we talk about maintenance therapies, one of the things that's really important is to make sure that patients can tolerate them, that they're not really sick when they're on it. So I know that you participated in the SIENDO trial and your [ 70 ] sites participated. Can you provide us some insights regarding the safety and tolerability that you saw in these patients?

Yes. Boy, I tell you, it's a lot -- lots of attention on this. So the -- you're right, patients that are on a therapy that is intended to keep tumor from coming back probably do best if they can stay on the treatment. So tolerability is definitely a major component to understanding the -- actually the efficacy of the agent. So fortunately, a drug like this in our hands is, while it's new, it doesn't provide a different spectrum of toxicity that we haven't already dealt with and we have many examples of that. PARP inhibitors are probably the clearest example of that, where factors like nausea and myelosuppression were the most common side effects we saw. And actually, we did pretty well on this trial with respect to discontinuation rates because we actually saw higher rates when we first got introduced to PARP in a similar type of situation with -- in the ovarian cancer space. So this idea of being able to observe, learn as we treat this is a new experience for us, but being able to keep that discontinuation rate low with appropriate interventions was, I think, was a tribute to how well this actually is tolerated. I look at this as a tolerable regimen and one that does not bring to us new adverse events that we already haven't been exposed to.

Great. So yes, it's good to know that your sites were able to control the side effects of selinexor. So in the SIENDO trial, you met pre-specified exploratory subgroup of patients with p53 wild-type endometrial cancer. We saw an interesting hypothesis-generating data. What do you think about the data in the p53 wild-type subgroup?

Don't you love it when the mechanism's action aligns with the outcomes? I mean this is -- I mean so we've known about this for a long time. Actually, we've studied this preclinically as well. So we were very excited to see it's represented in the clinical trial. It fits. It's being able to maintain the presence of tumor-suppressive protein where it's supposed to do what it's supposed to do. I think it is a tremendous reflection on the mechanism. So it definitely hits the -- our -- what our hypothesis was for why this should work. And now we found patient population where it will work. So I'm very excited about this. We -- as I've said, we've studied this in the lab. This is exactly what we expected to see. I'm really excited about the next [ readout ], yes.

That's great. That's great. We're really excited too, which is why we're [ delining ] the Phase III trial in p53 wild-type patients. So my last question for you is regarding the treatment landscape. How do you see this changing over time?

Yes, I answered this in my comments about [ the bahio ] getting smarter about attracting the biology. The landscape is changing fast in endometrial cancer. We didn't have -- it wasn't many years ago where our only approved therapy was a hormone, and we lived through that, both you and I did, treating patients with endometrial cancer. And now, our thousands of patients we spent with treating with chemotherapy and having really modest -- mostly negative improvement over a couple of decades. So this landscape has now changed because we've now -- we have a better idea of the underlying biology. We understand about [ micro satellite ] instability. We understand about how p53 can be dominated and characterized in the patient population. We know how cop number alterations are reflective of similar -- in many other tumor types that we're seeing and are hypermutable cases. So we have gotten much smarter about this biology. And so I think as time goes on, it's probably going to be more segmented like we see in lung cancer, where we have much more biomarker-directed therapies, and our hope is that this is going to be the one to add to that story.

Yes. Great. Well, thanks, Dr. Coleman. And we so appreciate your clinical knowledge in this space. So I'd like to turn it back to Richard.

Thanks, Patricia, and thank you, Dr. Coleman for sharing your perspectives on what it's like for clinicians to care for patients with advanced and recurrent endometrial cancer. As you mentioned and is clear to all of us that a maintenance therapy would be very beneficial to these patients. And we are working with the FDA on our new trial design, as Patricia talked to, plans to launch a new registration-enabling trial this year and deliver top-line data in the first half of 2024. And I know that these results cannot come soon enough for patients and for clinicians as they continue to work past watch and wait, as no maintenance therapy is currently available. So in closing, I would like to once again thank everyone who participated in the SIENDO study, either as an investigator or as a patient. We could have not gotten to this point without all of you. And with that, I would now like to ask the operator to open the call for the Q&A portion. Operator?

[Operator Instructions] And the first question comes from Maury Raycroft with Jefferies.

This is Farzin on for Maury. Can you provide more insight or details into the dose reductions and holidays in the trial, and if those patients performed any differently?

Sure, Farzin. Did I get your name correctly? Sorry.

Yes, Farzin.

Super. Thank you. Maybe I'll turn it to Patricia for that, and then we can also ask Dr. Coleman if he'd like to add to that after.

Yes. Thanks for the question. So the dose reduction schedule per protocol was that the 2 dose reductions were allowed. So patients were started on 80 milligrams, so they could go to 60 and then to 40. The vast majority of patients ended on 80 milligrams.

And Dr. Coleman, any additional...

Yes. I think that this is -- what's important is that we have the leeway to be able to address the side effects that come along the way. And so this is very common. What, I think, we witnessed is that there's a decent therapeutic window there that we can -- so we have flexibility to be able to address the side effects as they occur and it's effective. And the fact that the dosing level that most patients were on, that was actually what it started.

And then, can you talk more about the ITT population, the one you mentioned with the 7 patients? I think it was on Slide 8. So did this factor into your talks with the FDA? Or if they are wanting you to run a new Phase III based on that?

Yes. I think overall, when you look at the IRT or the eCRF data, again, as Patricia talked to, there were 7 patients that were identified and incorrectly classified and then were corrected in the eCRF tool. So as we look at that and we look forward, I think overall, the bottom line is, the Kaplan-Meier curves don't change. The PFS doesn't change. The key is that the 1.9 months improvement in the maintenance setting is really just not significant enough. And so what we're looking at is how do we move forward and do a trial in wild-type p53, which, as we talked to, was a prespecified exploratory group. They're an area that we need to add to in terms of our data, in terms of our trial. And maybe with that, I can ask, Dr. Coleman, if you'd like to expand on that at all?

Yes. I get pretty animated when people just look at mean -- the median of a survival curve. They're so dependent on morphology of the curve. So I know we all talk about it like it's like some gospel about reflection of the effect of treatment. But it really underscores what the value is. And I'll try to put this into some terms you might be able to understand. When I see a patient in clinic and I have not treated her yet, my decisions are based on what the probability is that, that event that I'm trying to avoid progression will be reduced. So I'm not looking at medians at that point in time. It's day 1. And so when I look at the effective therapy, I think about it in terms of what the risk reduction is or the average risk over the exposure, which is the hazard. So a hazard ratio of 0.71 or 0.705 means that there is a 30% reduction in the probability that an event will happen. It exists on day 1. It exists on day 2 and on day 7 and on day 45. So when the patient hasn't had an event, it doesn't -- it's different than looking at population data. And so I feel pretty strongly that the characterization of a 1.9-month difference between curves does not reflect the benefit of what's happening in the real world, which is what is affecting the patient at the patient level, not population. So to me, this is a significant reduction. We use other therapies with similar reductions already. But I understand that the observations were made. And I think if you want to use that as a benchmark, the 70% -- almost 65% reduction in the hazard in the probability of event in the p53 should be even more telling to you.

The next question comes from Brian Abrahams with RBC Capital Markets.

Discontinuation rates were obviously pretty low in the study. I was wondering if you had, though, any hypothesis for why you saw more AEs but milder AEs relative to the BOSTON population? Is that related to disease, population or dosing? If you could also talk a little bit more about the cadence of AEs, especially the GI adverse events. It seems pretty common, but were those very transient or did those persist? And did you see a similar AE profile in the p53 wild-type population? And then I have a quick follow-up.

Sure. So a few questions there packed together. Maybe on the one side, I was -- I mean obviously, as we all know, endometrial cancer and multiple myeloma are different cancers, also looking at combinations in the multiple myeloma area versus a single agent here. So I think we've got to kind of separate those 2. Maybe I'll let Patricia talk to the other questions, in terms of the AE profile and [indiscernible] patient populations.

Yes. I think that the -- as far as nausea and vomiting, the patients were required to have one antiemetic when the trial first started because it was an investigator-initiated trial. When it then became an industry trial, we mandated 2 antiemetics. So that helped improve the nausea and vomiting that we saw. We know -- we [ remedied ] up for 2 cycles. We know that most medications, as you go over time, patients tolerate it more. And whether that's because they just get used to the drug or whether that's because they're undergoing dose reductions or holds on the dose, and that makes a difference. And the AEs that we saw were almost all grade 1 and grade 2 and got better over time. The p53 population was no different than the overall population in what we saw for AEs.

Yes, and that would be what I would expect, actually, to -- it's good that it was reflected in the trial.

Got it. And maybe just as a quick follow-up. I think it was mentioned at the ESMO presentation that the overall survival data is not yet mature. Just wondering if you might be able to speak to any trends, at least qualitatively, that you might be seeing thus far on that front. And I think it was also mentioned that, that data would mature in the first half of next year. So just curious when and how you might plan to disclose that.

Yes. I think as that matures, we'll be able to share it either at an upcoming presentation or in a publication, but I'm sure it will be in a presentation.

The next question comes from Mike Ulz with Morgan Stanley.

Just one for me. In terms of the Phase III endometrial trial design that you're working to finalize with the FDA, is there a particular area of the design or a particular area where you're looking for feedback or you think the FDA might be focused? Or is the way to think about it more of just getting buy-in from the FDA prior to starting the study?

Yes. I think -- Patricia, do you want to talk to that?

Sure, sure. So we know it's going to be a prospective, randomized, double-blind trial. It's going to be randomized 1:1, but we're currently working on the study design. We're working -- we're meeting with the steering committee, and then we'll be meeting with the FDA, just for them to give us guidance on what they see as a path forward as well. Once we finalize the study design, we'll definitely let you all know.

The next question comes from Eric Joseph with JPMorgan.

In the p53 subgroup analysis, can you comment on how well balanced the composition of CRs versus PRs following chemo were between the 2 treatment groups? Is the curve separation shown on Slide 10 kind of -- how well maintained is that, when you isolate specifically within patients with achieved CR or patients which are PR? And then I have a follow-up.

Sure. Patricia, can you address that?

Yes. So the patients, in general, who had a partial response did a little bit better, slightly better, and the data will be published later, but did slightly better than the complete-response patients. But as you can see from that Kaplan-Meier curve, the curves drop initially quite quickly, and then they stay pretty stable. And the impact we see of those curves, that staying separate is really impactful for the patients.

Maybe -- I thought you made -- did you ask whether or not there was a difference in the CR and PR in that group versus the other population? Was that the focus of the question?

So in the base -- in the ITT population, you can see that it's pretty well balanced for patients that achieved CR versus PR following chemo, right? I'm wondering if that balance, that 60-40 balance, is reflected in the p53 subgroup analysis or whether they're sort of -- might be a little bit of a difference?

No, it's the same. It was 44% or 43% CR and 44% in the placebo and then 56% -- or 57% and 56%. So most -- is the same fraction in both of those cohorts. So yes, so it isn't influenced by a discrepancy in the CRs that were in each of the 2 randomized populations.

Yes. We didn't show that data today, but it is in the ESMO presentation that was presented earlier today.

Okay. Got it. Got it. And I guess some of the feedback that we had post the top-line results for that, in practice, patients that achieve best-responsive partial response after chemo might actually be candidates for second-line therapy. I'm curious from Dr. Coleman, your take on whether that treatment strategy or algorithm is broadly reflected in practice? And if so, whether selinexor -- how you think about it, contrasting its promise relative to [ limbimo ]/pembrolizumab, perhaps, approved in the second-line setting?

Yes. So yes. So the first part of that is, what do we do with these patients when we get a response but we don't get a complete response? And unfortunately, that's the case most of the time. For these patients, by the time they get through 6, sometimes 7 cycles of chemotherapy, just can't take more. And we really don't have an effective option. It also isn't really a great strategy to then switch chemo to a different agent. We just -- the patients need a break. And so what we do is we monitor them. That's why it was in the guidelines. So it's really a difficult place for us to be in. But in general, we will take a break. And as you saw in the placebo arm of this trial that -- and this is reflected in most of our trials -- that by the time of the first assessment, we start to see these patients to recur. So it's really a tough clinical situation for us. And so we -- most at least of the way I treat patients is to have definitive evidence of progression before I launch into another line of therapy.

Maybe one last follow-up, if I could. And I don't think it's commented on here. Any evidence of deepening responses for patients that achieved best-responsive partial remission prior to chemo -- sorry, following chemo and then prior to selinexor?

So we did see that the patients who had a PR had a better response to the chemotherapy. So we would anticipate that means that their disease is regressing with the treatment of selinexor.

That makes sense. Yes, you're already at the floor with the CRs. Of course. Okay. Great. Appreciate it.

The next question comes from Jonathan Chang with SVB Leerink.

This is Dustin on for Jonathan. I just wanted to ask if you could discuss your perspective and maybe from Dr. Coleman as well, respective on the ongoing IO combination studies in frontline endometrial and how that might factor into the XPOVIO endometrial cancer strategy?

Yes, Patricia, do you want to lead with that and then we can turn to Dr. Coleman?

Yes, absolutely. As you know, there's 2 approved agents, second line, in the dMMR/MSI high population, so dostarlimab and pembrolizumab. And then obviously, pembro and lenvatinib is improved in second line for patients who have microsatellite-stable tumor. We have a lot of trials ongoing, looking at using these agents upfront, either in combination with chemotherapy or the LEAP trial, which is looking at pembrolizumab and lenvatinib. We anticipate that the trials will be positive in the MSI population. I think the pembro-lenvatinib, personally, as a GYN oncologist, I think it's going to be a little difficult to beat chemotherapy in that population outside of the MSI high population. And then for the other trials, DUO-O and -- DUO-E rather and RUBY, we'll have to wait for their data to come out.

Yes. I think that you're raising a great point, and that's how do we likely characterize these cohorts. And I think what we're going to find is that there's going to be some overlap, there's going to be some non-overlap. And so I think we're going to be able to pick our way through the therapies. I mean as a clinician, I'm hopeful that everything is positive, you kidding me? We need treatment for these patients. And if we can align the best treatment with the tumor biology, then I am all in. And so I think that's where this is going to go. We're going to get smarter about this. And obviously, future trials will look at combinations and other things that we might be able to do to increase those activities to a broader patient population.

Yes. I think it's a great comment to close on. Because really, when you look at the excitement for patients, excitement for clinicians around all the different options, we think about, obviously, the other area of renal multiple myeloma, where there's a lot of different opportunities with combinations and permutations. And so I think seeing that we're getting into that and have the opportunity in endometrial cancer and that we have the opportunity to really establish combos, to establish treatment lines, to enhance maintenance to support patients, I think is exciting for patients. And that's why we're focused on moving forward rapidly, as we said, in the p53 wild-type population and working to bring this too up to patients as rapidly as we can. With that, I'd like to thank Dr. Coleman. I'd like to thank everybody for joining us, and we'll close the call because there's no more questions.

Thank you.

Thanks, everyone.

The conference has now concluded. Thank you for attending today's presentation, and you may now disconnect.