Immunotherapy has transformed patient outcomes for advanced/recurrent endometrial cancer, particularly for patients with deficient mismatch repair (dMMR) disease. In light of new data presented at the recent 2026 ASCO Annual Meeting, Charles A. Leath 3rd, MD, MSPH, FACS, FACOG, discusses the evolving role of chemoimmunotherapy, ongoing challenges in proficient mismatch repair (pMMR) disease, and emerging strategies aimed at improving efficacy while minimizing treatment-related toxicities.

Following these presentations, featured expert Charles A. Leath 3rd, MD, MSPH, FACS, FACOG, was interviewed by Conference Reporter Medical Director Noreen Iftikhar, MD. Clinical perspectives from Dr Leath on these findings are presented here.

At ASCO 2026, there were several interesting presentations on the expanding role of immunotherapy in advanced/recurrent endometrial cancer. Presentations from Ramez N. Eskander, MD (abstract 5502), and Matthew A. Powell, MD (abstract 5501), reported follow-up data from the phase 3 NRG-GY018 and RUBY clinical trials in patients with advanced/recurrent endometrial cancer, respectively. These trials investigated the safety and efficacy of chemoimmunotherapy combinations (ie, pembrolizumab plus carboplatin and paclitaxel [CP] and dostarlimab plus CP, respectively, both with immunotherapy maintenance) vs chemotherapy alone.

As Dr Eskander mentioned during his presentation, when the data from NRG-GY018 and RUBY were presented back-to-back at the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer, it was a very exciting time. And, over the last few years, we have continued to see reports from those studies, sorting out the magnitude of benefit in patients participating in those trials. Prior to the presentations of these 2 studies, we considered immunotherapy to be second-line therapy. Patients predominantly had surgery first, potentially followed by radiation, and their first systemic therapy was typically platinum- and taxane-based chemotherapy (eg, CP).

Historically, regarding immunotherapy for patients with dMMR tumors, we have the options of pembrolizumab or dostarlimab as single agents. For those with pMMR tumors, which is the majority of patients with endometrial cancer, we can use pembrolizumab and lenvatinib. All these immunotherapy agents have been evaluated in a comparative fashion against chemotherapy. In these comparisons, we saw activity that was better than that with traditional chemotherapies; however, we know that the activity is somewhat limited for patients with pMMR disease. Regardless, they are still considered the standard of care.

As Dr Powell and Dr Eskander both pointed out during their presentations, when we think about our patients with dMMR advanced/recurrent endometrial cancer, which is approximately 30% of patients in clinical practice, they tend to do better with a combination of chemotherapy and ICI therapy (eg, dostarlimab or pembrolizumab), followed by maintenance therapy. There is probably a group of these patients that I think the data suggest are likely cured by treatment with these agents. We are seeing better-than-expected outcomes, and it is very encouraging that these survival curves are really pretty flat and we are seeing limited additional events related to endometrial cancer.

We still have a ways to go for patients with pMMR tumors. There is certainly some benefit there, but it is not as pronounced as it is in those with dMMR tumors. That is ultimately what led us to participate in the phase 2 trial looking at second-line atezolizumab-plus-bevacizumab treatment in patients with either dMMR or pMMR advanced/recurrent endometrial cancer. At ASCO 2026, data from this trial were presented by Katherine C. Fuh, MD, PhD (abstract 2576). This was a multisite investigator-initiated trial that began back when pembrolizumab and lenvatinib were among the few immunotherapy options. The questions we had were: Could we use another ICI therapy (ie, atezolizumab) and another antiangiogenic therapy (ie, bevacizumab), and how might those agents be tolerated as compared with pembrolizumab and lenvatinib?

The phase 3 KEYNOTE-775 clinical trial looked at pembrolizumab and lenvatinib and was a positive study that established that this combination was an effective treatment for previously treated advanced endometrial cancer. Of these 2 agents, lenvatinib is a bit more challenging to use in clinical practice. Many of my patients may not have met the inclusion criteria for KEYNOTE-775, which is part of why we undertook this multisite investigator-initiated trial—to see whether we could use agents that are similar to those that are US Food and Drug Administration (FDA) approved in clinical practice but potentially better tolerated.

I think, as Dr Fuh noted in her presentation at ASCO 2026, that it does seem like this combination is active and can be a potential consideration. Certainly, based on these data, we do not have the ability to make definitive statements about whether this approach is better than other agents that have been evaluated in clinical practice. Overall, I do think that it is important to be aware of potential toxicities when we identify an active compound or combination and that we continue to look for ways to minimize those toxicities whenever possible.