Letrozole-abemaciclib plus metformin shows promise in endometrial cancer treatment

Adding metformin to letrozole and abemaciclib does not cause serious safety concerns and may even encourage favourable responses among patients with oestrogen receptor (ER)-positive recurrent endometrial cancer (EC), according to a phase II study presented at SGO 2025.

Letrozole/abemaciclib combined with metformin also results in a much longer progression-free survival (PFS) than letrozole/abemaciclib alone. [SGO 2025, abstract LBA06]

In addition, patients with “no specific molecular profile (NSMP) tumours without RB1 and CCNE1 alterations derive the most benefit from this regimen,” said lead author Dr Panagiotis Konstantinopoulos from Dana-Farber Cancer Institute in Boston, Massachusetts, US.

Twenty-five patients received protocol therapy, with a median follow-up of 17 months. Of these, 18 (72 percent) received hormone therapy previously, with a median of two prior lines. Eight patients demonstrated an objective response: three complete responses (CRs) and five partial responses (PRs; objective response rate [ORR], 32 percent, 95 percent confidence interval [CI], 14.9‒53.5).

Stable disease was observed in 16 patients (64 percent) and progressive disease in one (4 percent). In Kaplan-Meier estimates, 69.7 percent had PFS in 6 months. The median PFS was beyond 19.3 months.

Neutropenia (n=6, 24 percent) and fatigue (n=4, 16 percent) were the most common grade ≥3 treatment-related toxicities. None of the patients ceased treatment due to toxicity.

Pharmacokinetics

In pharmacokinetic (PK) analyses, metformin plasma concentrations were almost threefold higher in letrozole/abemaciclib plus metformin versus metformin monotherapy.

No objective responses were noted among patients with TP53-mutated ECs in molecular profiling via Oncopanel targeted next-generation sequencing (NGS). Those with NSMP ECs with RB1 or CCNE1 alterations also showed no objective responses. The median PFS in these tumours was 3.0 months only.

On the other hand, objective responses were seen in patients with NSMP ECs without RB1 and CCNE1 alterations, with an ORR of 50 percent and PFS of 87.5 percent in 6 months. No mismatch repair deficient (MMRd) and POLE-mutated tumours were observed. Moreover, the researchers observed responses regardless of progesterone receptor (PrgR) expression.

“The addition of metformin to letrozole/abemaciclib is feasible and safe and appears to induce deeper responses and more prolonged PFS than letrozole/abemaciclib alone,” Konstantinopoulos said.

Participants

In this phase II study, Konstantinopoulos and his team identified patients with recurrent ER-positive (≥1-percent immunoreactive tumour nuclei) endometrioid EC, measurable disease, any number of prior therapies, any prior hormone therapy but no prior CDK4/6 inhibitor, and no current metformin use.

Eligible patients received abemaciclib 150 mg orally twice daily, metformin 500 mg once daily, and letrozole 2.5 mg once daily until progression or unacceptable toxicity. ORR and PFS rate at 6 months served as the primary endpoints.

“A safety lead-in was included, and the target accrual was 25 patients; if there were ≥6 objective responses or ≥9 patients without disease progression or death at 6 months, letrozole/abemaciclib [plus] metformin would be considered worthy of further investigation,” Konstantinopoulos said.

Correlative studies were also performed, including PK analyses of metformin alone and in combination with letrozole/abemaciclib, molecular profiling, and PrgR expression by immunohistochemistry.