Welcome all. I'm Flora Backus. I'm a gynecologic oncologist and professor in the Division of Gynecologic Oncology at The Ohio State University in Columbus, Ohio. And I'm honored to be one of the co-chairs of the IGCS Education Advances and Updates Workgroup and excited to provide this educational recording titled Towards Personalized Therapy in Endometrial Cancer, which is part-sponsored by Kareo Pharm. And I'm joined today by Dr. Vicky Macker. Dr. Macker, please introduce yourself. Hi, everyone. Vicky Macker here at Memorial Sloan Kettering Cancer Center in New York City. Really just honored to be here today with all of you. And thank you for joining me today. I'm really, really excited. And I think the title that we came up with really summarizes the current state of endometrial cancer, where we're going. We've heard a lot about immunotherapy in endometrial cancer, maintenance treatments, and we're going to talk about some more steps towards personalized medicine. So I'm really thrilled to hear your data and love to see a little of the backgrounds and then we'll chat a little bit. Great. Thank you so much. Sounds great. Can you see my slides? Yes. Okay, great. Well, thank you, Dr. Bacchus. I'm really thrilled to be here, as I said, and very excited to share our recent ASCO 2024 report on the long-term follow-up of Selenexer maintenance for patients with TP53 trial type advanced or recurrent endometrial cancer, a pre-specified subgroup analysis from the Phase III CNDOS study. As you alluded to, we know that the treatment options for patients with advanced or recurrent endometrial cancers are rapidly evolving and carboplatin paclitaxel and immune checkpoint inhibitor therapy is moving into the first-line setting. We also know that the greatest benefit of immune checkpoint inhibitors in combination with chemotherapy is really most seen in the MMR-deficient tumors and that a more modest benefit is appreciated in MMR-proficient tumors, which comprise approximately 80% of endometrial cancers. TP53 is a well-recognized prognostic marker for endometrial cancers. Greater than 50% of advanced or recurrent endometrial cancers are TP53 wild type, and approximately 40% to 55% are both TP53 wild type and MMR-proficient. Selenexer is a very novel, interesting drug. It's investigational, it is oral, and it inhibits something called exportin-1 or XPO-1. And when it does this, it prevents the XPO-1-mediated export of several tumor suppressor proteins, including wild type P53. At the primary analysis of the Phase III CNDOS study of Selenexer maintenance therapy in patients with advanced or recurrent endometrial cancer, the improvement in PFS for the intent to treat population was not clinically significant. However, a pre-specified exploratory analysis of the TP53 mutation status showed promising efficacy signal in patients with TP53 wild type endometrial cancer. The CNDO trial was a randomized, double-blind Phase III study evaluating Selenexer versus placebo as treatment maintenance for patients with Stage IV or first relapse of endometrial cancer. In this study, after receiving at least 12 weeks of platinum-based chemotherapy and having either a complete or partial response, eligible patients were randomized in a two-to-one fashion to receive Selenexer 80 milligrams orally weekly or placebo. The primary endpoint was investigator-assessed progression-free survival, and key exploratory endpoints included molecular subclassification by TP53 status and also MMR status. Now, molecular characterization on this study was done by next-generation sequencing, and if NGS was not available, then it was done by immunohistochemistry. And greater than 60% of patients had confirmed MMR-proficient status. The overall patient demographics I don't show but just wanted to discuss, and you should know that the baseline demographics and baseline characteristics of the TP53 wild type subgroup were similar in patients receiving Selenexer and placebo. In both cohorts, most patients with TP53 wild type endometrial cancer presented with endometrioid adenocarcinomas. Approximately half the patients had recurrent disease, and about 40% of patients had a complete response to their most recent chemotherapy. With that, we'll go into the results a little bit. So, in the TP53 wild type subgroup, long-term follow-up of almost 37 months showed a promising PFS benefit, where the Selenexer group had a median PFS of 28.4 months compared to 5.2 months in the placebo group. The hazard ratio here was 0.44, representing a 56% reduction in the risk of disease progression. In patients with TP53 wild type and MMR-proficient tumors with follow-up of 38 months, median PFS was 39.5 months with Selenexer versus 4.9 months with placebo with a hazard ratio of 0.36. And in patients with TP53 wild type and MMR-deficient tumors with follow-up of almost 33 months, median PFS was 13.1 months with Selenexer versus 3.7 months with placebo with a hazard ratio of 0.49. And although the overall survival data are still immature, we saw a very interesting trend of approximately 35 to 50% decrease in the risk of progression or death. And this was seen in the TP53 wild type, the TP53 wild type and MMR-proficient cohort, and the TP53 wild type MMR-deficient cohort. The most common treatment emergent adverse events in patients with Selenexer were nausea, vomiting, and diarrhea. And encouragingly, these adverse events were generally manageable. Overall, grade 3 or greater treatment emergent adverse events occurred in 20% of patients or less, with the most common being neutropenia, thrombocytopenia, and nausea. And importantly, only 17% of patients discontinued Selenexer treatment due to a treatment-related adverse event. So these results further support the EXPORT-EC042 study, which is a randomized phase 3 study of Selenexer maintenance therapy in patients with TP53 wild type advanced or recurrent endometrial cancer following response to prior systemic therapy. A total of 220 patients are planned. Patients must have known P53 wild type tumor status, and this will be established by next-generation sequencing. Eligible patients must have stage 4 or first relapse of their endometrial cancer and must have received at least 12 weeks of platinum-based chemotherapy with or without immunotherapy. And they must have had either a complete or partial response. Eligible patients will be randomized one-to-one to receive either oral Selenexer maintenance at 60 milligrams orally weekly or placebo. Now of note, the 60 milligram Q weekly dose was selected for manageable safety while attempting to maintain the efficacy that was demonstrated in the TP53 wild type population in the CNDO study. The primary endpoint of the study is investigator-assessed progression-free survival. Key secondary endpoint is overall survival. An important exploratory endpoint will include PFS assessment based on histological and molecular subtypes. And this important study is currently ongoing and actively enrolling, and we're really excited to see the results of the study hopefully being presented at a Congress in the near future. Thank you so much. Great. This is a really, really exciting overview and such exciting data. And I'll just start with a question about the last slide actually that you presented about the new export trials. So if you see the results in this long-term follow-up, people may wonder, like, if you have such good data, why do we still need to do another study in this patient population? Can you comment on that? I think that's a really great question. So I think it's important to remember that while the data from the CNDO study in the P53 wild type population was incredibly encouraging to see, we're still talking about small patient numbers. And it's really important to investigate this particular subgroup more closely and to really understand important things like efficacy, safety, duration of response, and also get a better understanding of the maintenance strategy. How long should patients be treated for? And I think some of these very important questions will be really clarified and will inform us as the study matures. Yeah, and so in the initial, in the CNDO study, patients would stay on treatment indefinitely, is that correct? They would stay on until progression or symptomatology, that's correct. Yeah, and so do you have an idea of how long most patients would stay on treatment? Yeah, that's a great question. You know, data regarding the average duration of treatment has not been provided because we still have patients that are on study, but I look forward to that data because I think it will be very informative. Yeah, and so we've seen, like, with the elaborate data, where we, I mean, this is a totally different population, I fully get that, but with the maintenance pembrolizumab, we continue with maintenance two years, with the starlamib three years, olaparib and ovarian cancer population, two years. Is there any thought of maybe having a limit, or do you believe that there can be a limit for this drug also, or is the biology different? You know, I think that we still have so much to learn about the activity of this drug in p53 wild-type endometrial cancers. I think we also need to really get a sharper understanding of toxicities over time. You know, are there toxicities that we're seeing, you know, in the acute setting that might differ from toxicity, you know, with long-term duration of such therapy? So I think there's still early days, again, really exciting, very intriguing data, deep responses, but I think we need more patient experience. We need a greater understanding of safety, tolerance, and also, you know, what happens as patients are on treatment for prolonged periods of time. All of these things, I'm hoping, will be clarified with the ongoing study, but many excellent questions, I think, you know, that are on everyone's mind. Yeah, no, I think that will be really great, and especially when you mention that there still are some patients staying on trial, that at least we won't have to wait. Well, yes, we'll have to wait for the final results, but we'll have some data emerging, at least, of how those patients do in the long run. Absolutely. Now, with these data coming out, do you have patients asking you about getting this drug? Like, why should I have to go on trial? I want this drug. Yeah, I mean, I think that there is a lot of interest on the parts, you know, of not only patients, but also clinicians. I think the data is so compelling. You know, those curves really speak for themselves. The toxicity profile has been predictable, and by and large, you know, we're able to manage these side effects, but, you know, the guidance that I give my colleagues, and certainly patients, is that though this data is very heartening, you know, to the points that have already been made, we really need greater patient experience, and this drug is still considered investigational in endometrial cancers. So, we just need to, you know, let the data evolve, and hopefully, the encouraging results that we saw with the Siendo study will be replicated in the X40-C042 trial, and this drug will be, you know, available for patients with this particular subtype of endometrial cancer. Yeah, great. So, we should look around, and where are there centers that offer this trial, I guess, and get our patients enrolled, and help you enroll to complete this quickly? Absolutely. That should be the mission. I fully support that, for sure. No, I think you make a good point, though. Like, we can't. We've seen some other trials where things didn't pan out in the confirmatory trials, so I'm very excited, but certainly keep a little caution is what I'm getting from you also. Absolutely. So, I have another question about, like, with Pembrolizumab now being approved for mismatch repair proficient recurrent endometrial cancer also, how do you see this evolving? I understand, of course, that this drug is not available yet, but say that if it is available, or maybe when you're making choices, like, should this patient go on the Pembrolizumab maintenance standard of care now, or should the patient go on a trial with the option to potentially get an XPO1 inhibitor? So, I think that this is such an important time in the world of endometrial cancer is because we finally get to sit down and have these really important, germane conversations, right, about the biology of drugs, the data as it segregates by molecular phenotypes. So, essentially, what I would do if faced with trial versus chemo plus Pembro for an MMR-proficient patient is really distill the data down, right? So, I think patients need to be informed. They need to be educated so they can make informed decisions. And so, it's a detailed conversation. But certainly, off clinical trial, I do offer my MMR-proficient patients chemotherapy plus Pembrolizumab. But I think that this is also a very exciting alternative therapy. The great thing about the ongoing X4-DC042 trial is that it allows patients with chemotherapy and IO therapy, which I think, you know, is a very important strategy. So, I think when the data emerges, we're going to need to understand the degree of benefit, understand the toxicity profile, and then we'll really need to think about, you know, how to inform patient management. You know, what will the algorithm be? I think it's a little premature. We need to see the data, and I think that will really be informative. And just to clarify, you mentioned that patients are allowed to have had chemotherapy with immunotherapy previously to, for example, to go on the confirmatory trial. That would be in a different line then. Is that, am I understanding that correctly? Yes. So, patients, you know, could have had one line with chemotherapy plus IO and still be eligible for this trial as a maintenance strategy as part of the X4-DC trial. That's correct. Unlike the CANDOR trial, which did not allow, you know, patients that had prior immunotherapy. Wonderful. Yeah, that would help too, and definitely how we're going to sequence things. And talking about sequencing, we mentioned Pembrolizumab, the immunotherapy with chemotherapy and then maintenance. But then that patient who has previously received chemotherapy already and may not have received immunotherapy, but now we seen some data evolving with chemotherapy versus lymphadenepembrolizumab, chemotherapy with immunotherapy, or this chemotherapy followed by cellonexer. Where do we go? So, again, I think that these are such amazing times. I think we're absolutely moving, you know, to an era of personalized, you know, cancer therapeutics for our patients. And I think it comes down to a detailed conversation where you also have to take into consideration the patient, their comorbidities, toxicity from prior chemotherapy. And also, you know, I think it's important to remember that endometrial cancer is not ovarian cancer and that often these patients, when they've had prior chemotherapy, are more chemotherapy resistant. So, these are things that I think about in addition, obviously, to the molecular phenotype. So, I think just broad strokes, if a patient has had chemotherapy and has recurrent disease, you know, I think about these aspects and may consider in an MMR-proficient patient lymphadenepembrolizumab because I do worry about the chemotherapy resistance piece of this. In a deficient patient, I would consider immunotherapy. But obviously, first and foremost, regardless of subtype, I would consider clinical trial. And I think that for cellonexer, again, I think cellonexer will have an important place in the management of endometrial cancers that are TP53 wild type. But we really owe this ongoing study our respect and should allow the data to mature and reach fruition. And I think it will be very impactful when that day comes. Yeah, I'm so glad you bring that up. And also, the toxicity piece, because absolutely, I think we all have those patients with terrible neuropathy or that absolutely don't want to see hair loss again. And I think, I mean, you were intimately involved with the LEAP-001 data also. But even though it was a negative study, in my mind, there's still populations there when we look at it, especially those patients who've had prior chemotherapy, where this option is not just off the table, it's still an important regimen. Would you agree with that? I wholeheartedly agree and support the sentiments, you know, your sentiments. I think that there's so much learning that still is to be had from the LEAP-001 trial. I think that as the investigators really look at molecular subtypes, there will likely be, you know, types of endometrial cancers that do derive benefit. And you've made a very important point about the benefit of the regimen patients that had prior chemotherapy. So I think this is such an exciting time in that we're not shackled to palliative chemotherapy and just a few options for our patients. We actually have the opportunity to be thoughtful and an opportunity to avail novel therapies, very intriguing clinical trials of which the X4-EC-4-2 trial is obviously one of them. So it's really a tremendous time in that we're going to be able to offer a number of exciting opportunities for our patients with regards to clinical trials, but also now just an incredible number of therapies that I think are going to be available in the near future. Yeah, I think it's so exciting what you just brought up and said, like, it's not just palliative chemotherapy. And I know at least from me counseling my patients, it has absolutely changed how I counsel them. And, you know, we're seeing these long-term survivors and maybe they'll never need anything else. And it's a little early to say that these patients are cured, but they're doing well for a long period of time. And it is absolutely, it is an exciting time. And I was really, really honored to have you take the time to talk to us today about these very exciting data. You're such an expert and thank you for all the work that you've done for, well, regarding for the field of gynecologic oncology, but especially for patients with endometrial cancer, really made great progress. And I'm very thankful for you sharing again, your knowledge and CurioPharm for supporting this recording. Wish you continued health and safety. Thank you for having me. Thank you for tuning in.

Dr. Flora Backus

Dr. Vicky Macker

Endometrial Cancer

Selenexor Maintenance Therapy

Clinical Trials