Adding metformin to letrozole and abemaciclib (Verzenio) was tied to deep responses and prolonged progression-free survival (PFS) in some patients with recurrent estrogen receptor (ER)-positive endometrial cancer, per a phase II trial.
Of the 25 patients in the RESOLVE study, three achieved complete responses and five partial responses, for an objective response rate (ORR) of 32%. Sixteen other patients (64%) had stable disease, while one had progressive disease as best response, reported Panagiotis A. Konstantinopoulos, MD, PhD, of the Dana-Farber Cancer Institute in Boston.
At a median follow-up of 17 months, median PFS was estimated at beyond 19.3 months, with a 6-month PFS rate of 73.8% (95% CI 50.7-87.3), he said in a presentation at the Society of Gynecologic Oncology (SGO) annual meeting in Seattle.
"Addition of metformin to letrozole and abemaciclib is feasible and safe, and appears to induce deeper responses, including complete responses not reported with any of the previous CDK4/6 inhibitor studies in endometrial cancer, and more prolonged PFS than observed with letrozole-abemaciclib alone," Konstantinopoulos said.
Konstantinopoulos noted that preclinical studies have demonstrated synergism with simultaneous inhibition of the ER, CDK4/6, and PI3K pathways, and that "it is well known that metformin inhibits P13K signalling directly by activating AMPK [AMP-activated protein kinase], leading to inhibition of mTOR signalling, and indirectly by decreasing circulating insulin and IGF-1 levels, as well as by downstream signaling."
Thus, the researchers hypothesized adding PI3K inhibition with metformin could further enhance the activity of abemaciclib-letrozole in endometrial cancer.
Study patients had recurrent ER-positive (≥1% immunoreactive tumor nuclei) endometrioid endometrial cancer and measurable disease. They had undergone any number of prior therapies and any prior hormone therapy, but no prior CDK4/6 inhibitor therapy and no current metformin use. They received abemaciclib 150 mg twice daily, metformin 500 mg once daily, and letrozole 2.5 mg once daily until progression or unacceptable toxicity.
The most common grade ≥3 treatment-related toxicities were neutropenia (n=6, 24%), fatigue (n=4, 16%), and anemia (n=2, 8%). No patients discontinued therapy because of toxicity.
Konstantinopoulos reported that pharmacokinetic analyses showed that metformin plasma concentrations were three-fold higher when metformin was combined with letrozole-abemaciclib compared to metformin monotherapy, and that responses were observed regardless of progesterone expression.
He also reported that molecular profiling demonstrated that among the 25 patients, there were four TP53-mutated and 21 NSMP (no specific molecular profile) tumors. There were no objective responses among patients with TP53-mutated cancers and no objective responses among patients with NSMP cancers with RB1 or CCNE1 alterations.
SGO invited discussant Amanda L. Jackson, MD, of the University of Cincinnati, noted that multiple studies have suggested that metformin has a positive effect on PFS. A 2022 study by Konstantinopoulos and colleagues evaluating the doublet of letrozole and abemaciclib in ER-positive recurrent endometrial cancer showed an ORR of 30%, and a median PFS of 9.1 months with a 6-month PFS rate of 55.6%, she said.
Jackson pointed out that while the median PFS rate was 10 months longer with the addition of metformin in the current study, she cautioned that the groups in the two studies weren't the same, with the doublet study having 40% of patients with high-grade endometrial cancer compared to 16% in the study with metformin.
"So is this a good treatment for non-specific molecular profile cancers?" she said, and suggested "it's very optimistic."
While not effective in TP53, RB1, and CCNE1 mutations, "metformin seems cost effective and has minimal side effects, and is probably a great option," she stated.
author['full_name']
Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.
Disclosures
RESOLVE was funded by Dana-Farber Cancer Institute, The Lewin-Fund to Fight Women's Cancers, and Eli Lilly.
Konstantinopoulos discosed relationships with AstraZeneca, GSK, Merck, Immunogen, EMD, Serono, Scorpion, Schrodinger, Nimbus, Mural Oncology, Gilead, Bayer, Eli Lilly, and Pfizer.
Jackson disclosed relationships with Ethicon, Auris, AstraZeneca, OncLive, and Planned Parenthood.
Primary Source
Society of Gynecologic Cancer
Source Reference: Konstantinopolous P, et al "Phase II study of letrozole, abemaciclib and metform in estrogenn receptor-positive recurrent endometrial cancer" SGO 2025; Abstract LBA 96.