<p>The treatment of advanced and recurrent endometrial cancer has a growing emphasis on targeted therapies. At the <strong>2025 ASCO Annual Meeting</strong>, researchers highlighted targeted therapies for patients with difficult-to-treat disease and provided insights into the prognostic value of the platinum-free interval (PFI).</p> <p><br></p> <p><em>Following these presentations, featured expert John K. Chan, MD, was interviewed by </em>Conference Reporter<em> Medical Director Lauren Weinand, MD. Clinical perspectives from Dr Chan on these findings are presented here.</em></p>

Mismatch repair–proficient (pMMR) endometrial cancer is more common, but, as we know, the treatment of this molecular subtype remains an unmet need, as pMMR tumors are typically less responsive to immunotherapy than MMR-deficient tumors. A phase 2 clinical trial presented by Keqiang Zhang, MD, at ASCO 2025 has significant implications because it found efficacy in pMMR endometrial cancer (abstract 5508). The trial combined the humanized anti–PD-L1 monoclonal antibody benmelstobart plus carboplatin/paclitaxel with or without anlotinib, an oral multitarget TKI with antiangiogenic activity, in 71 patients with advanced or recurrent endometrial cancer. The combination was associated with a high response rate with a notable progression-free survival benefit in patients with pMMR disease, suggesting that the combination potentially enhances immunotherapy response. However, this combination was linked to a significant rate of grade 3 or higher treatment-related toxicities; the most frequent were leukopenia, thrombocytopenia, and anemia. We need a larger phase 3 trial to confirm these early results.

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A study presented at ASCO 2025 by Panagiotis A. Konstantinopoulos, MD, PhD, looked at the combination of letrozole, abemaciclib, and metformin in 25 patients with recurrent ER+ endometrial cancer (abstract 5513). This abstract was interesting because ER+ endometrial cancer is quite common, but we have had only modest success using ER-targeted agents. The triplet combination was associated with an objective response rate of 32%; the 6-month estimated progression-free survival was 69.7%, and the regimen was well tolerated. Additionally, the subgroup of patients with no specific molecular profile disease without RB1 or CCNE1 alterations had a particular benefit. Interestingly, metformin plasma levels were approximately 3 times higher when combined with letrozole and abemaciclib vs metformin alone. I think that this regimen can have a potential benefit if we can validate these promising results in larger trials.

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Finally, I presented a large retrospective study at this year’s ASCO meeting that sought to determine whether the PFI is prognostic in endometrial cancer like it is in ovarian cancer (abstract 5609). The data set included 843 patients from the Flatiron Health electronic health care record database with advanced or recurrent endometrial cancer who had received platinum-based chemotherapy between 2013 and 2022, excluding those who had received ICIs. We were surprised to find that 68% of patients had a PFI of less than 6 months and only 14% had a PFI of 12 months or longer. Those who had a PFI of less than 6 months had a median overall survival of only 12.7 months after the start of second-line treatment, while those with a PFI of at least 12 months had a median overall survival of 30.5 months. In an adjusted multivariate analysis, patients with a PFI of 12 months or more had a significant reduction in the risk of death compared with patients with a PFI of less than 6 months.

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A PFI of at least 12 months is prognostic in advanced and recurrent uterine cancer, similar to ovarian cancer. The US Food and Drug Administration (FDA) approvals of several ICIs may help extend the PFI. A remaining question is: What does the PFI mean when patients progress on chemotherapy and ICIs? We hope to address this further as we gather more data on patients who have progressed after ICI therapy, especially since the FDA approvals were relatively recent.