ASCO Conference Coverage

Letrozole, Abemaciclib, and Metformin Combination in Recurrent Endometrial Cancer

Miranda Manier, BA

Key Highlights

  • The study showed an objective response rate of 32% and a progression-free survival rate at 6 months of 69.7%.
  • The combination treatment of letrozole, abemaciclib, and metformin appeared safe, with no patients discontinuing therapy because of toxicity.
  • Molecular analyses identified a subgroup of tumors that had an objective response rate of 50% and a progression-free survival rate at 6 months of 87.5%.
  • Metformin plasma concentrations were approximately three times higher when combined with letrozole and abemaciclib compared with metformin alone.

A phase 2 study presented at the 2025 American Society of Clinical Oncology Annual Meeting investigated a novel combination of letrozole, abemaciclib, and metformin in patients with estrogen receptor–positive recurrent endometrial cancer. The trial included 25 patients who received this combination therapy, with initial findings indicating promising signs of activity. A notable proportion of patients achieved measurable tumor responses and disease stabilization, and progression-free survival rates suggested a potential benefit over prior regimens, particularly within specific molecular subtypes.

Preclinical data have shown that targeting multiple pathways involved in ER-positive EC—including the estrogen receptor, cyclin-dependent kinase 4/6 (CDK4/6), and phosphoinositide 3-kinase (PI3K) signaling—can yield synergistic effects. Metformin has been shown to suppress PI3K signaling both directly, through AMP-activated protein kinase (AMPK) activation, and indirectly, via downregulation of insulin and IGF-1 signaling. These insights prompted this clinical study to evaluate whether adding metformin to letrozole and abemaciclib could enhance outcomes in ER-positive recurrent EC, a setting with limited treatment options and variable responses to standard hormonal and chemotherapeutic regimens.

Eligible patients had recurrent ER-positive endometrioid EC, measurable disease, and had received any number of prior therapies, including hormonal therapy but no prior CDK4/6 inhibitors. Patients received abemaciclib (150 mg PO bid), metformin (500 mg PO qd), and letrozole (2.5 mg PO qd) until progression or unacceptable toxicity. The primary endpoints were the objective response rate (ORR) and the progression-free survival (PFS) rate at 6 months. Secondary objectives included pharmacokinetic (PK) analyses, molecular profiling with targeted next-generation sequencing, and progesterone receptor (PrgR) expression assessment by immunohistochemistry. The study included a safety lead-in and a target accrual of 25 patients. If six or more objective responses or nine or more patients without progression or death at 6 months were observed, the regimen would be deemed worthy of further investigation.

At a median follow-up of 17 months, the study enrolled 25 patients with a median of two prior lines of therapy; 72% had received prior hormonal therapy. The combination yielded an ORR of 32% (95% CI, 14.9%-53.5%), including three complete responses and five partial responses. Sixteen patients (64%) experienced stable disease, while only one patient (4%) had progressive disease as best response. The median PFS had not yet been reached but extended beyond 19.3 months. Grade 3 or higher treatment-related toxicities included neutropenia (24%) and fatigue (16%), but no patient discontinued therapy because of toxicity. PK analyses revealed that metformin plasma concentrations were approximately threefold higher when combined with letrozole and abemaciclib than with metformin monotherapy. Molecular analyses indicated that no objective responses occurred in tumors with TP53 mutations or in NSMP ECs with RB1 or CCNE1 alterations, where median PFS was only 3.8 months. In contrast, NSMP tumors without these alterations had an ORR of 50% and PFS6 of 87.5%. Objective responses were observed regardless of PrgR expression.

“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,” the authors concluded.

Reference:
Konstantinopoulos PA, Zhou N, Penson RT, et al. Phase 2 study of letrozole, abemaciclib, and metformin in estrogen receptor–positive recurrent endometrial cancer. Presented at: 2025 American Society of Clinical Oncology (ASCO) Annual Meeting; 2025 May 30–June 3; Chicago, IL. https://www.asco.org/annual-meeting