Ursula Matulonis, MD: Hello, my name’s Ursula Matulonis. I’m a medical oncologist at Dana-Farber, and it’s great to have everybody here today. It’s my pleasure and honor to be part of this “Leading Thoughts” program and be on with two of my great colleagues and friends, Dr. Ramez Eskander and Dr. Robert Coleman. Can you please introduce yourselves to the group?
Ramez Eskander, MD: Hey everyone. I’m Ramez Eskander. It’s a pleasure to be here. I am a gynecologic oncologist at the University of California San Diego, where I help lead our gynecologic cancer clinical trial program. Thankfully, I also have an opportunity as an associate clinical trial advisor for GOG Partners. I am thrilled to be here with you guys today. Thank you.
Dr. Matulonis: Rob?
Dr. Coleman: Thank you so much, Ursula. I’m Rob Coleman. I’m a gynecologic oncologist with US Oncology Network, here in sunny Houston. It’s always sunny, hot, and humid in Houston. I also serve as a codirector for GOG Partners, and I’m the chief medical officer for Vaniam Group. It’s great to be with you.
Dr. Matulonis: I think what we’re going to do in the next few minutes is give clinicians a high-level view of what we see as new agents coming down the road, coming down the pike, for our patients with relapsed endometrial cancer. [Much] has already changed, and Dr. Eskander has been a leader in that, [including] the movement of immunotherapy drugs, anti-PD-1 drugs, to the upfront setting, based on the presence of mismatch repair deficiency or not, or perhaps even regardless of that.
I think it is important [to remember], some patients are still going to unfortunately relapse, despite receiving that therapy, or have progressive disease, despite receiving platinum-based chemotherapy and an anti-PD-1 agent.
I would like to hear from you all. I think certainly some of the newer drugs that are moving through would include WEE1 inhibitors, CDK4/6 inhibitors, and different permutations of immuno-oncology agents, specifically combinations. We’ve already talked about antibody drug conjugates in another program. I think we’re going to sort of move those to the side. They are also very exciting, but I think we’re here to talk about other agents.
I’m going to start with you, Rob, if you have a particular favorite that you find exciting moving forward.
Dr. Coleman: I have lots of favorites. There are so many different [ways] we could go about this. I’d like to maybe start on the endocrine side, because we never really get a chance to talk about endocrine therapy very often in endometrial cancer. Yet that was our very first approved drug in endometrial cancer. This hormonal access, I think, has been important for us. We’ve kind of struggled to figure out where it should go. Now that we know a lot more about endocrine signaling in endometrial cancer, and now with the availability of other agents that we can combine with this, we’ve had some modest success with these combinations.
Two of the accesses I think that have been really interesting to follow have been this mTOR AKT PI3 kinase pathway, for which we now have combinations that are showing some efficacy, with individual targets that combine with endocrine therapy. Also, the CDK4/6 inhibitors. Even expansion of the CDK, the second kinase pathways, have been following and mirroring, to some extent, what we see in breast cancer.
I’m happy that we get a chance to actually talk about endocrine therapy, because it is quite effective. I think our struggles have been, “How do we demonstrate this in these independent roles in endometrial cancer patients?” There certainly is a cohort of patients with low-grade endocrine receptor-expressing endometrial cancer who would be good candidates for this kind of therapy. New trials are coming that are looking at the combination of CDK4/6 with anti-estrogen-based therapies. Several different options are out there. I kind of like that as a narrative, which we haven’t had a chance to talk about in the past.
Dr. Matulonis: I think that’s super important. There have been a number of trials now looking at the CDK4/6 inhibitor combinations in recurrent endometrial cancer. Some have been published, and some are ongoing. That’s for patients with estrogen receptor–positive endometrial cancers. Most of those are going to be low-grade endometrioid tumors that are p53 wild-type. At least, what we found in the abemaciclib/letrozole study, is that p53 mutated cancers did not respond as well. It’s really that estrogen receptor–positive p53 wild-type population.
Ramez – along that line of what Rob talked about in terms of signaling pathways – obviously when we sequence our patients and their cancers, we occasionally will find RAS mutations. That is not uncommon, certainly in endometrial cancer, specifically in endometrioid cancers. There are a number of different RAS inhibitors or other ways of inhibiting the RAS-MAP kinase pathway. Are there any agents that you’ve tested or seen results from that you’re excited about?
Dr. Eskander: I think this is an exciting time. I’ll back up just one second, because there’s one part of this conversation that I think is so relevant and important. Which is that we’ve talked a lot about the molecular characterization of endometrial cancer over the years. Of course, it started with The Cancer Genome Atlas (TCGA). It catalyzed the way that we thought about endometrial cancer management and drug development. We’ve made, certainly, a big leap with the mismatch repair–deficient population with immunotherapy. There’s room for improvement within the pMMR – the mismatch repair proficient population.
I think the comments that were made earlier are so critical, which is, we have to start thinking about these diseases in the context of their molecular aberrations, because that’s what drives excitement in the drug development space here. As you mentioned, to the comments earlier about the CDK4/6 hormonal therapy, it’s a TP53 wild-type, in conjunction with estrogen receptor–positive and progesterone receptor–positive patients who may benefit the most. But we won’t know that unless we ask our pathologists to look and tell us: Is this grade two endometrioid or grade three T53 mutator or TP53 wild-type?
What I am incredibly excited about, [and] this is a more general statement, but it’s our application of this identified molecular characterization, to help inform the development, rational development, in the design of the clinical trials that we have open and accruing right now.
Dr. Matulonis: I was going to say, you’re 100% right. So many thoughts are going through my mind. I mean, I think that’s absolutely correct. You’re absolutely right. I think what you find in sequencing of endometrial cancers compared to ovarian cancer is more of a plethora of mutations and sort of genetic aberrations.
I think the other question that’s going to come up is, “What do you target first? How do you see these therapies?” That’s going to be another sort of puzzle to figure out, as we develop different agents from what we think of as different buckets. But actually, those buckets may be interchangeable. HER2-overexpressed, RAS-mutated cancer that’s estrogen receptor positive – all these different kinds of aspects of the cancer are potentially targetable.
Dr. Coleman: It’s so important now that it’s entered into the International Federation of Gynecology and Obstetrics (FIGO) staging, right? It has its own prognostic implications that are driven, along with the other features that we see, with the stats of the disease when patients present.
Dr. Matulonis: Right. Exactly. Then again, also along that line of benefit with p53 wild-type versus p53-mutated cancers are the results of the trials testing selinexor, which is a nuclear export inhibitor – which is used in other cancers, but really for the first time is being used in endometrial cancer. Any thoughts about selinexor in endometrial cancer, Rob?
Dr. Coleman: I mean, this is kind of an interesting additional access, going back to what we were talking about with marrying the molecular characterization of this tumor. This particular drug, which is approved for and used in myeloma, banks on the fact that, if there is normal protein that’s being made, it’s preventing it from being exported into the cytoplasm to be degraded. The idea is that you’ll leave more normal protein around, so that it can do its function and its tumor suppressor function. This obviously was the focus of the SIENDO trial, which was looking at the use of this drug in patients who had finished their chemotherapy, to see if it could provide a benefit. Overall, the topline results did show that it had a signal that was present. We had hoped that the signal might be more robust.
When we looked into it further, and we were able to classify with respect to p53 alteration, we saw the wild-type again aligned with mechanism, which is what we’ve been focusing on in this discussion. When you align it with the mechanism, normal in p53 wild-type tumors, there was a very big difference between those arms. Again, it’s hypothesis-generating, which is exactly what we’re doing, following that hypothesis-generating exercise with a formal trial, and XPORT-EC-042 is that trial. We will hopefully be demonstrating this mechanism of action on p53 wild-type tumors, to demonstrate that we can prevent the time to recurrence for our patients.
Dr. Matulonis: It’ll be interesting to see this next iteration of results in the next-generation trial. I want to finish up with another type of endometrial cancer: endometrial serous carcinomas. More high-grade p53 mutated carcinosarcomas can certainly fit in there as well. WEE1 inhibitors certainly had initial promise with adavosertib and reasonable response rates. Adavosertib is a WEE1 inhibitor. Because these cancers display this concept of replication stress, a WEE1 inhibitor may have activity. Adavosertib, unfortunately, had significant side effects. Now there’s another agent, called ZN-c3, which we heard about at ASCO. We also heard about it at the Society of Gynecologic Oncology (SGO) Annual Meeting. Ramez, do you have comments about targeting p53-mutated cancers through these mechanisms, using WEE1 inhibitors or other agents that you think are of promise?
Dr. Eskander: There’s strong scientific rationale for us to try to target WEE1 inhibition, for the reasons you mentioned a moment ago, which is this replication stress with p53 mutation. The G1/S checkpoint is not as robust. You’re really reliant on that G2/M, and WEE1 inhibition can disrupt that. You drive the cell through this careless replication, and you get cell death. The issue that we’ve faced, as alluded to, is tolerability. Meaning that we have to have an efficacious drug, of course, but we have to make sure patients can stay on treatment, if they’re benefiting from it. With WEE1 inhibition, it has been a bit difficult to titrate the medication in a way that ensures that we have an effective drug that is also tolerable.
Currently, there is a resurgence of being more creative with drug delivery, figuring out how are we going to dose these medications and being more thoughtful about dose optimization and initial trial design to drive efficacy and tolerability. With Zentalis’s azenosertib, the ZN-c3 drug, the hope is that we see an evolution in the clinical trial design, both as a single agent but also potentially in a combinatorial strategy, although again, that’s been hard because of tolerability. Can we drive dosing in a way that allows us to see efficacy, while maintaining a tolerable agent in clinical practice? Because we understand that here, disease control is a priority, because these are pretreated patients. We hope that they’re going to be on it for a long period of time. I remain very excited about the opportunity for WEE1 inhibition. I think we are going to become smarter about how we develop the trials and how we design the delivery of these agents and the dose schedules. In so doing, we’ll hopefully be able to see an efficacy signal in these patient populations.
I think, going back to the comment you initially asked me, Ursula, about the RAS opportunities too: Shannon N. Westin, MD, from MD Anderson presented the olaparib/selumetinib study at SGO. In Dr. Westin’s data, this combination of a PARP inhibitor with selumetinib appeared to be most efficacious in the RAS-mutated endometrial cancer cohort. There was an ovarian cohort too, but it was the endometrial that we’re focusing on here. We want inhibition and absolute target. We’re looking at p53 mutated. We’re enriching for these to drive enrollment on these trials, which is key. They have biomarker-directed rational design and dose optimization and ultimately hopefully show a benefit and a U.S. Food and Drug Administration (FDA) approval for patients.
Dr. Matulonis: Really good points. I think the RAS mutations that we see in our gynecological cancer patients are not the G12C, where there’s approved drugs. It’s 12V, it’s 12D, it’s NRAS occasionally. Obviously, that’s an unmet need. I think another unmet need is trying to figure out better ways of treating our patients with endometrial serous cancer because the incidences of those cancers are going up. There’s an impact of race, where Black women have a higher risk of developing endometrial serous cancers and also have a higher mortality associated with these cancers. There are definitely unmet needs for these cancers and lots of work to do. Any last comments from you, Rob?
Dr. Coleman: The last thing I would say is just maybe to highlight a little bit more on the DNA damage and the cell cycle control mechanisms. We talked about WEE1, obviously, there. We also now have started to see some interest in using other components of DNA damage repair. We talked about PARP, but ATR is also coming in there. And of course, Ramez, you’re working also with the tumors that have ARID1A loss and ACH2.
It’s been so exciting to talk about endometrial cancer like this, because for years, we couldn’t get anybody interested in studying endometrial cancer. We have all these actionable targets now, and borrowing from our experiences across all solid tumors, opportunities to explore these drugs in this disease. It’s been just really a rebirth of new opportunities for our patients.
Dr. Matulonis: Thank you, Rob. Ramez, any last comments?
Dr. Eskander: I echo those statements. I think we could talk for an hour about this, if not more. As Rob was speaking, I’m thinking, “Oh yeah, and TROP2, now we’re targeting.”
Dr. Coleman: Exactly. Exactly.
Dr. Eskander: Oh, yeah.
Dr. Matulonis: That’s right.
Dr. Eskander: As this conversation evolves, I think you see it in each of our comments and our dialogue, there’s great enthusiasm. There is an excitement, I think, in this space, that hasn’t existed for a long time. I couldn’t be happier for our patients, where opportunities that are effective and hope in the face of recurrent disease is key. I think we’re at a great time.
Dr. Coleman: Absolutely.
Dr. Matulonis: Well, thank you so much, both of you, and have a great rest of the summer. Thank you so much.
Dr. Eskander: Thank you.
Dr. Coleman: Thank you. Thanks for having us.
This transcript has been lightly edited for clarity.
