Metformin Plus Letrozole and Abemaciclib Induces CRs in ER+ Recurrent Endometrial Cancer

Metformin in combination with letrozole (Femara) and abemaciclib (Verzenio) was tolerable and induced prolonged responses in patients with estrogen receptor (ER)–positive recurrent endometrial cancer, according to data from the phase 2 RESOLVE study (NCT03675893) presented during the 2025 ASCO Annual Meeting.1

Findings from the study showed that patients who received the combination (n = 25) achieved an overall response rate (ORR) of 32%, including a complete response (CR) rate of 12%. At a median follow-up of 18.7 months, the median progression-free survival (PFS) was 19.4 months, and the Kaplan-Meier estimated 6-month PFS rate was 69.8% (95% CI, 46.9%-84.3%).

“The addition of metformin to letrozole and abemaciclib is feasible and tolerable and appears to induce deeper and more prolonged responses, including CRs, than letrozole and abemaciclib alone,” Panagiotis A. Konstantinopoulos, MD, PhD, said during the presentation. “Data not [presented] today showed that responses were observed regardless of progesterone receptor expression or prior receipt of hormonal therapy.”

Konstantinopoulos is the director of the Mellen and Eisenson Family Center for BRCA and Related Genes, director of Translational Research in the Division of Gynecologic Oncology, and the Velma Eisenson Endowed Chair for Clinical and Translational Research at Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

What Was the Design of the RESOLVE Study, and What Were the and Baseline Characteristics of the Patients Enrolled?

RESOLVE enrolled adult patients with recurrent ER-positive endometrial cancer, which was defined as ER positivity in at least 1% of nuclei per immunohistochemistry.1,2 Patients also needed to have endometrioid histology, measurable disease per RECIST 1.1 criteria, and an ECOG performance status of 0 or 1. There was no limit on the number of prior therapies, and treatment with any prior hormonal therapy was permitted. Treatment with prior CDK4/6 inhibitors and current metformin use were not allowed.

Patients received 1 week of lead-in dosing with metformin monotherapy at 500 mg once daily.1 Following a pharmacokinetic analysis of metformin, patients received letrozole at 2.5 mg daily, abemaciclib at 150 mg twice daily, and metformin at 500 mg once daily. Treatment continued until disease progression or unacceptable toxicity.

The primary end points were ORR and 6-month PFS rate. Secondary end points included PFS, overall survival, and safety. The study authors also conducted correlative studies to assess the pharmacokinetics of metformin, molecular profiling, and progesterone receptor expression.

At baseline, the median age was 64.2 years (range, 49.7-84.2). Most patients were White (80%), had grade 1 disease (52%), and had undergone prior hormonal therapy (72%). The median number of prior systemic therapies was 2 (range, 0-8).

What Was the Safety Profile of the Combination and the Subgroup Efficacy Data?

In terms of safety, no patients discontinued study treatment due to toxicity. Common grade 1 treatment-related adverse effects (TRAEs) included diarrhea (52%), decreased platelet count (40%), and fatigue (28%). Grade 3 or higher TRAEs included decreased neutrophil count (24%), fatigue (16%), anemia (8%), and increased aspartate aminotransferase levels (8%).

Findings from a molecular profiling analysis showed that no patients with TP53-mutated disease (n = 4) or disease with no specific molecular profile (NSMP) with CCNE1 or RB alterations (n = 5) achieved a response. The ORR among patients with endometrial cancer with NSMP without CCNE1 and RB alterations (n = 18) was 50%, with a CR rate of 18.8%.

“Tumor profiling revealed several mechanistically relevant candidate predictors of response, or absence of response, which require independent validation,” Konstantinopoulos said during his conclusion.

Disclosures: Konstantinopoulos reported having consulting or advisory roles with AADi, Alkermes, Artios, AstraZeneca, Bayer, Gilead Sciences, Immunogen, Kadmon, Merck, Mersana, Mural Oncology, Nimbus Therapeutics, Novartis, Pfizer/EMD Serono, Repare Therapeutics, Scorpion Therapeutics, Tesaro, and Vertex; as well as receiving research funding from AstraZeneca, Bayer, Bristol-Myers Squibb/Sanofi, Lilly, Merck, Merck Serono, Novartis, Pfizer, and Tesaro.

References

1. Konstantinopoulos PA, Zhou N, Penson RT, et al. Phase 2 study of letrozole, abemaciclib, and metformin in estrogen receptor (ER)–positive recurrent endometrial cancer (EC). J Clin Oncol. 2025;43(suppl 16):5513. doi:10.1200/JCO.2025.43.16_suppl.5513
2. RESOLVE: abemaciclib + letrozole +/​- metformin, zotatifin, or gedatolisib in endometrial or low-grade serous ovarian cancer. ClinicalTrials.gov. Updated June 15, 2025. Accessed September 15, 2025. https://www.clinicaltrials.gov/study/NCT03675893