Study findings show the addition of metformin to letrozole and abemaciclib induces deeper responses and prolonged progression-free survival (PFS) vs letrozole and abemaciclib alone in patients with recurrent estrogen receptor (ER)-positive endometrial cancer, particularly among those with no specific molecular profile (NSMP) tumors without RB1 and CCNE1 alterations.

These data will be first presented by Panagiotis Konstantinopoulos, MD, Dana-Farber Cancer Institute, at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

A total of 25 patients received protocol therapy. All patients had recurrent ER-positive (≥1%) endometrial cancer, measurable disease, and received any number of prior therapies (median, 2 prior lines), including prior hormonal therapy (72%). Patients were treated with letrozole (2.5 mg daily), abemaciclib (150 mg twice daily), and metformin (500 mg daily) until disease progression or unacceptable toxicity.

The primary end points were objective response rate (ORR) and 6-month progression-free survival (PFS6).

At a median follow-up of 17 months, the ORR was 32% (95% confidence interval [CI], 14.9 to 53.5). Of these patients, 3 achieved a complete response (CRs) and 5 achieved a partial response (PR). At best response, 64% of patients achieved stable disease (SD), while 1 patient experienced disease progression. The Kaplan-Meier analysis estimated PFS6 was 69.7%, and median PFS exceeded 19.3 months.

In terms of safety, the most common grade 3 or higher treatment-related adverse events were neutropenia (24%) and fatigue (16%). No patients discontinued treatment due to toxicity.

Pharmacokinetic (PK) analyses revealed that metformin plasma concentrations were approximately 3-fold higher when combined with letrozole and abemaciclib compared to metformin monotherapy.

Molecular profiling identified no responses in TP53-mutated tumors or NSMP tumors with RB1 or CCNE1 alterations. Among patients with NSMP tumors lacking these alterations, the ORR was superior at 50% and an estimated PFS6 at 87.5%.

"Addition of metformin (at plasma concentrations sufficient to inhibit the PI3K pathway) to letrozole/abemaciclib is feasible and safe, and appears to induce deeper responses (including complete responses) and more prolonged PFS than letrozole/abemaciclib alone,” Dr Konstantinopoulos et al concluded.

They added, “NSMP tumors without RB1 and CCNE1 alterations derive the most benefit from this regimen."

Source:

Konstantinopoulos  P, Zhou N, et al. Phase 2 study of letrozole, abemaciclib, and metformin in estrogen receptor (ER)–positive recurrent endometrial cancer (EC). Presented at 2025 ASCO Annual Meeting. May 30-June 3, 2025; Chicago, IL. Abstract 2004.