Combination Therapy for Recurrent Endometrial Cancer

Bradley J. Monk, MD, FACS, FACOG: Let’s transition and talk about the best treatment for second-line non–MSI [microsatellite instability]-high recurrent endometrial cancer. Katie Moore, you mentioned that pembrolizumab got accelerated approval for all MSI-high tumors, that that message is out there, that we’re using it, we’ve seen fantastic responses, sometimes over 50% in some cohorts. But most patients are not MSI-high. This has created a high unmet medical need, a need that we’ve been working on intently. Then ultimately, there was a study that led to accelerated approval again, but this time not in the MSI-high subgroup. Dave, tell us about this opportunity.

David M. O’Malley, MD: When we look at this group of patients, we have lenvatinib and pembrolizumab, which has, as I said, about a 37% response rate [RR]. The problem is the toxicity, which we’ve all alluded to. You’re talking about 70%, maybe even more, dose reductions, and about 90% if you include the interruptions. When we look at these patients, we get some amazing responses. In the waterfall plot of this original paper, basically everybody responded. That’s unheard of in second-, third-line endometrial cancer. We see this group of patients receive these opportunities. But we must get better at managing the toxicities.

Bradley J. Monk, MD, FACS, FACOG: Katie Moore, I’ve heard people say that if you get frontline carboplatin and paclitaxel in the adjuvant setting, and if it’s been, I don’t know, 6 or 12 months, because of some of these adverse events of the pembrolizumab, lenvatinib combination, that maybe you should go back to chemotherapy first. You talked about the expectation for GOG-209, that this was chemotherapy sensitive. What’s the expectation of retreatment let’s say with carboplatin and paclitaxel, so that we can make an assessment? Should we do that in the second line and relegate pembrolizumab, lenvatinib to third line, or do doxorubicin, something completely different?

Kathleen N. Moore, MD: Yes. That is the question. The answer is, we don’t know. We all guess. There is no defined platinum-free interval for endometrial cancer. Although people talk about it, it’s all made up data. There’s no 6- or 12-month interval that predicts re-response to platinum. It’s never been prospectively studied. The ongoing studies that we’re going to talk about at the end of this, do allow patients who had adjuvant paclitaxel, carboplatin, and they have variable periods, usually it’s a year,when they can come on these frontline metastatic studies. We will have those data coming. We’ll see if anybody responds. Is it like ovarian cancer? I bet not.

Bradley J. Monk, MD, FACS, FACOG: I bet not.

Kathleen N. Moore, MD: I don’t know if I should say I wish it were, but we kind of wish it were, where we could repeat use platinum. I don’t think we can. We’re going to learn it. That’s coming. But it does present this clinical dilemma where you have these patients who received adjuvant therapy on the GOG-258 regimen or whatever, and 2 years later, they recur. Do you go right to this lenvatinib, pembrolizumab combination, which has the highest response rates we’ve ever seen in second-line endometrial cancer? Or should you start with, and this is with MSS [microsatellite stable] of course, should you start with chemotherapy again and see if they re-respond?

Bradley J. Monk, MD, FACS, FACOG: Yes.

Kathleen N. Moore, MD: We don’t know.

Bradley J. Monk, MD, FACS, FACOG: Krish, you’ve been on all targeted therapies, all of you have,you’ve been an advocate of this anti-VEGF checkpoint combination in cervical cancer and also here. Tell us about the biology. Why would an anti-VEGF make IO [immuno-oncology] work in a cold tumor where it otherwise is not working?

Krishnansu S. Tewari, MD: Yes. It’s interesting. This is what’s exciting about it. Because we know that VEGF is immunosuppressive, especially in the tumor microenvironment. It’s this combination that allows for the tumor immune microenvironment to be reprogrammed, if you will. That’s where the synergy comes in. But we always say cross-trial comparisons are never good. But I like to cross tumors and stuff. If you look at PAOLA, you have patients who are HRD [homologous recombination deficiency] positive but they’re not necessarily BRCA mutated. But they need something else other than just the olaparib to work in the maintenance setting, so you add BEV [bevacizumab]. In this case, you have a microsatellite stable patient and they could benefit from pembrolizumab, but they need something else. That’s where the combination with anti-VEGF comes in.

Bradley J. Monk, MD, FACS, FACOG: I do that all the time. I try to look at other tumor types and get smarter and learn from my colleagues in ACC [adenoid cystic carcinoma], so atezolizumab, bevacizumab.

Krishnansu S. Tewari, MD: Yes.

Bradley J. Monk, MD, FACS, FACOG: But it didn’t work in ovarian cancer. Why, Katie Moore, why? It didn’t work in IMagyn050, presented at ESMO [the European Society for Medical Oncology annual meeting].

Krishnansu S. Tewari, MD: Yes. That’s why we don’t want this disease to be more like ovarian cancer….

Bradley J. Monk, MD, FACS, FACOG: Any comments on that, Katie? This is not an ovary discussion, but it’s weird, isn’t it?

Kathleen N. Moore, MD: I thought it was going to be positive. Ovary is just not these other tumors as much as want it to be. The synergy that was seen in HCC [hepatocellular carcinoma] and renal cell and increased T-cell trafficking and all the things that should have worked, and maybe they did happen, we don’t know. Maybe they did happen in the ovarian cancer tumors, but it didn’t matter. It probably comes down to lack of understanding of biomarkers. We have a lot to learn, but it didn’t work in ovary, unfortunately. But here it does work in endometrial cancer.

Bradley J. Monk, MD, FACS, FACOG: Krish, tell us about KEYNOTE-826.

Krishnansu S. Tewari, MD: Yes. It’s cervical cancer. It’s chemotherapy with or without bevacizumab, plus or minus pembrolizumab. It’s for the first line of recurrent metastatic cervix cancer. I’m hoping it’s going to be a positive trial. Like I said, we should know in 2021.

Bradley J. Monk, MD, FACS, FACOG: Yes. IMagyn050, we were hoping; it didn’t work. But we haven’t given up. KEYNOTE-826 is your regimen, Krish, GOG-240, chemotherapy, bevacizumab, first-line metastatic cervical, adding pembrolizumab to it.

Transcript Edited for Clarity