Future Outlook for Treatment of Endometrial Cancer

Transcript:

Ritu Salani, MD, MBA: Before we close, I want to ask each of you: I don’t know if we can predict 6 months from now, but where do you see the management of endometrial cancer in the next several years?

Bhavana Pothuri, MD: We’ve already changed the way we look at endometrial cancer. We’ve gone to a molecular paradigm, with 4 subtypes. We’re a little behind in the United States compared with Europe. We need to start by doing molecular testing on all patients when they’re diagnosed. That will help us as we determine treatments in the subsequent lines. We’re going to have different therapies for each subset. For dMMR [mismatch repair deficient] patients, we’re going to break that down even more into different Lynch [syndrome] types, methylated, and somatic. In the copy number low subgroup, we’re going to have hormonally driven therapies, like CDK4/6 inhibitors with letrozole. We’re going to have the selinexor maintenance therapies. In the copy number high, all these exciting ADCs [antibody-drug conjugates] come in. Some are going to be biomarker directed. Some of them are going to be for all patients. The HER2 [human epidermal growth factor receptor 2] ADCs are an exciting target, as are TROP2, FR-⍺. We’re going to see a nice way that we’re going to have in baskets. That’s where I see it.

Matthew A. Powell, MD: It’s a big year for endometrial cancer. We’ll probably see 4 more trials reporting in the next year. With DUO-E, AtTEnd, LEAP-001, and RUBY Part 2. There’s a lot of information that we’ll be discussing, and hopefully [there will be] profound benefits for our patients. I’ll echo what you said about ADCs. We’re looking a lot like ovarian cancer. We’re doing similar biomarker assessments. Biomarkers are now part of our staging for endometrial cancer, so FIGO [International Federation of Gynecology and Obstetrics] is going to ask us to radically change the way we stage endometrial cancer to take into account how the different subgroups perform. I didn’t want to call out the polymerase epsilon group, which is probably the least mentioned and least seen because it doesn’t usually need systemic therapy. How can we de-escalate care? How can we do less to patients and let them have the same survival and, hopefully, a better quality of life? We’re looking at that in the POLE group and the copy number low or NSMP [no specific molecular profile] group. For patients who are ER [estrogen receptor] positive, we’re leaving them alone even if they have a fairly substantial tumor, because they do so well.

Ritu Salani, MD, MBA: Great.

Shannon N. Westin, MD, MPH, FACOG: I’m excited about the standardization of utilizing the molecular testing in these patients, because it’s been a bit of a struggle in getting things like next-generation sequencing—and the additional cost—available to a lot of our patients. Building that into the staging is going to help us broadly apply that molecular testing. I’m enthusiastic about that. I love the idea of de-escalating.

Looking at what we’re doing in the second line and expanding our targeted therapy options for patients in the second line, my colleagues have all mentioned the ADCs. I’m 100% behind that. There are other agents that are also interesting. I’m a big fan of the WEE1 inhibitors. There’s activity there, but we have to find a way to give those drugs in a less toxic fashion. I hope we’re going to make strides with that over the next few years. There are a number of other exciting targets, like combining hormone therapy and things like that. That’s what I’m very enthusiastic about. But we’re hoping that all these things we’ve done in the front line will [lead to] fewer patients in the recurrent setting.

Ursula A. Matulonis, MD: I totally agree. As we learn more, we’re going to dig in to these different subtypes. And I was going to mention WEE1 as well.

Shannon N. Westin, MD, MPH, FACOG: Sorry.

Ursula A. Matulonis, MD: It’s OK. It’s like cyclin E amplification. There are definitely some efforts in endometrial serous cancer. We’ll see cyclin E1 amplification. In the estrogen receptor positive, those β-catenin are not as immunotherapy sensitive, [so we can] think about CDK4/6 inhibitor combinations and SERDs [selective estrogen receptor down-regulators]. Following some of the breast cancer literature, those drugs are active in ER-positive low-grade endometrial cancers. A challenge will be—this is where we’re going to work with our regulatory folks as we as we parcel down into different smaller subsets—do we run mandatory phase 3 trials? That’s going to be hard to do as patient numbers go down. It’s a little easier with ovarian cancer because the population is more heterogeneous, but endometrial cancer is going to be more challenging. It’s also necessitating international collaboration.

Shannon N. Westin, MD, MPH, FACOG: We’ve talked a little about different molecular pathways that are important in endometrial cancer. One we explored 10 years ago is the PI3-kinase AKT pathway. We struggled. We did a lot of single-agent studies because that’s what we knew, but we’re starting to see agents that target that pathway come back in. Everolimus and letrozole clearly have activity [and are] compendium listed. Taking that to the next level and using some of the newer drugs, GY028 combines ipatasertib—an AKT inhibitor—with progesterone agents. That could be well tolerated and hopefully will be very active. There are also opportunities to go back to the PI3-kinase, which we’d moved away from.

Ursula A. Matulonis, MD: That’s an extraordinarily common aberration in endometrial cancers. You’re absolutely correct. We did multiple trials of single-agent PI3-kinase inhibitors. None of them were positive, but maybe newer-generation ones will be more beneficial.

Ritu Salani, MD, MBA: I think all the upcoming ideas and landscape changes are going to be instrumental. Even though we started talking about the increasing incidence and mortality, hopefully we’re going to see a real impact from the therapies and treatments we’ve discussed. We’re not being complacent. We’re continuing to push forward, identify new need gaps, and address those as quickly and as thoroughly as possible as we can make those changes. Any last points before we close?

Shannon N. Westin, MD, MPH, FACOG: The future is bright. It’s very exciting. We have a lot of data to cover in 2 major gynecologic cancers. It’s super-exciting.

Ritu Salani, MD, MBA: I am so lucky to sit on this panel of experts. I want to thank each of you for a rich and informative discussion. To our viewing audience, we hope you found this OncLive® Peer Exchange to be useful and informative.

Transcript edited for clarity.