Patients with endometrial cancer have more treatment options now than ever before; however, significant unmet needs remain. At the 2025 ASCO Annual Meeting, researchers presented data from several studies aimed at addressing these gaps, including with the use of novel targeted therapies such as ADCs.

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Following these presentations, featured expert Ramez N. Eskander, MD, was interviewed by Conference Reporter Medical Director Lauren Weinand, MD. Clinical perspectives from Dr Eskander on these findings are presented here.

The role of novel therapies, including ADCs, in the treatment of endometrial cancer was the focus of an educational session and several presentations at ASCO 2025. The presentation by Joyce F. Liu, MD, MPH, during the “State of the Art: Therapies Now and Around the Corner for Gynecologic Cancers” session was excellent and comprehensive. It looked at the treatment landscape for endometrial cancer, principally not only showing an understanding of where we were historically but also defining where treatment is moving. Dr Liu reviewed data from the NRG-GY018/KEYNOTE-868, RUBY/GOG-3031/ENGOT-EN6, DUO-E, and AtTEnd trials that informed the incorporation of immunotherapy for patients with advanced-stage metastatic and recurrent endometrial cancer. These data supported the US Food and Drug Administration (FDA) approval of chemotherapy in conjunction with immune checkpoint inhibition in advanced-stage metastatic and recurrent endometrial cancer in the mismatch repair–deficient (dMMR) and biomarker-negative, mismatch repair–proficient populations.

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Next, Dr Liu reviewed the biomarker data from some of these trials. Although the biomarker data appear discordant, this information is important in potentially helping to inform future scientific discovery. In the current state, we have insufficient evidence to use biomarkers such as PD-L1 and TP53 to inform treatment decisions.

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As noted by Dr Liu, efforts to move the paradigm of chemotherapy plus immunotherapy to earlier-stage, high-risk patients was evaluated in the KEYNOTE-B21 study (also known as ENGOT-en11/GOG-3053). Ultimately, this was a negative trial. However, a 70% reduction in the risk of disease progression was noted in the biomarker-positive, dMMR population. Clinicians can use this, in the context of the prior studies, as they are making decisions for a patient with dMMR disease, for example, who may have had positive lymph nodes that were completely resected based on KEYNOTE-B21’s magnitude of benefits.

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Dr Lui’s presentation also focused on where we might be going in the future. Recently, the DESTINY-PanTumor02 study showed very provocative efficacy with trastuzumab deruxtecan, an ADC that targets HER2 with a TOP1 inhibitor payload. Based on the totality of the results from the DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 trials, the FDA issued an accelerated approval for trastuzumab deruxtecan for patients with recurrent, pretreated HER2 3+ malignancies, which includes endometrial cancer. So, we now have an accelerated approval for an ADC that targets HER2 in endometrial cancer.

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In addition to the HER2 strategy, Dr Lui highlighted other targets, including B7-H4, TROP2, and folate receptor alpha (FR⍺). When we look at these ADCs, we are seeing response rates that are higher than what we saw with the control chemotherapy arm in a recurrent population, as detailed in Study 309–KEYNOTE-775. Thus, we have several active and ongoing clinical trials that are currently looking to examine these ADCs in those patients who progressed after previous chemotherapy and immunotherapy, but we anticipate that these treatments are going to move to earlier lines of therapy in the future. It is going to be a dynamic year for endometrial cancer care, as we have several active endometrial cancer clinical trials that may complete accrual or read out, potentially informing interim advancements for this disease.

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One of the more interesting studies in the endometrial cancer space from ASCO 2025 was on rinatabart sesutecan (Rina-S), an FR⍺-directed ADC, with data in the endometrial cancer cohort (abstract 3039). Ira Winer, MD, PhD, FACOG, and colleagues found that the overall response rate of Rina-S in the endometrial cancer cohort at the 100 mg/m² dose level was 50%. These are small numbers, but it is exciting to see yet another target in the endometrial cancer space with what appears to be preliminarily provocative efficacy, informing our eagerness to see this agent examined in the recurrent endometrial cancer space.

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Looking beyond ADCs, I reported on the trial design of a phase 1b/2 dose expansion study evaluating E7386, a drug targeting the Wnt/β-catenin signaling pathway shown to be relevant in endometrial cancer, in combination with lenvatinib (abstract TPS5632). What is interesting—although, again, small numbers—is that patients who had prior immunotherapy and chemotherapy but had not previously had lenvatinib had an objective response rate of 50% with the combination of E7386 plus lenvatinib. If they previously had lenvatinib, the objective response rate was approximately 33%, still both very interesting signals. The study is looking at 2 different doses of E7386 in combination with lenvatinib 14 mg. It is also helping us to understand the relevance of the combination because there is an arm of lenvatinib alone and an arm of physician’s choice of chemotherapy. We are excited to find out whether we are going to see a preliminary signal in the dose optimization strategy with this non-ADC combination of oral drugs, which is also very appealing for patients. I am really excited about the various therapeutic opportunities in this space.