Letrozole, abemaciclib and metformin in endometrial cancer: a non-randomized phase 2 trial

Area of Science:

• Oncology
• Pharmacology
• Genetics

Background:

• Preclinical studies suggest synergism between estrogen receptor (ER), CDK4/6, and PI3K pathway inhibition.
• Metformin demonstrates PI3K/mTOR signaling suppression in endometrial cancer (EC).

Purpose of the Study:

• To evaluate the efficacy and safety of a combination therapy including letrozole, abemaciclib, and metformin in ER-positive endometrioid EC.
• To determine the objective response rate (ORR) and progression-free survival at 6 months (PFS6) as primary endpoints.

Main Methods:

• A non-randomized phase 2 study (NCT03675893) involving 25 patients with ER-positive endometrioid EC.
• Patients received letrozole (2.5 mg/day), abemaciclib (150 mg twice/day), and metformin (500 mg/day).
• Assessed ORR, PFS6, overall survival, duration of response, and toxicity. Pharmacokinetic analyses were performed.

Main Results:

• ORR was 32% (3 complete, 5 partial responses).
• PFS6 was estimated at 69.8% with a median PFS of 19.4 months.
• No treatment discontinuations due to toxicity; CTNNB1 mutations correlated with clinical benefit. Metformin exposure increased >3-fold with co-administration.

Conclusions:

• The combination of letrozole, abemaciclib, and metformin shows promising activity in ER-positive endometrioid EC.
• Tumor molecular profiling, particularly CTNNB1 mutations, may predict response to this regimen.
• The combination is well-tolerated and enhances metformin exposure.