Phase 2 trial of letrozole, abemaciclib, and metformin in ER-positive endometrioid endometrial cancer

Preclinical studies showed synergism with simultaneous inhibition of the estrogen receptor (ER), CDK4/6, and PI3K pathways, and window of opportunity studies showed that metformin suppresses PI3K/mTOR signaling in endometrial cancer (EC). A multicenter phase 2 trial in the USA evaluated the combination of letrozole-abemaciclib-metformin for ER-positive endometrioid EC. Twenty-five patients were included. The objective response rate was 32% (3 complete and 5 partial responses; 95% CI 14.9-53.3). Progression-free survival rate at 6 months was 69.8% (95% CI 46.9-84.3) and median PFS was 19.4 months (5.7-NE). No patients discontinued therapy due to toxicity. There were no objective responses among TP53 mutated ECs; CTNNB1 mutations correlated with clinical benefit. The authors conclude that the combination of letrozole-abemaciclib-metformin showed activity in ER-positive endometrioid EC.