Journal: Nature communications
This phase II, single-arm study evaluated combined endocrine, CDK4/6, and metabolic pathway inhibition using letrozole, abemaciclib, and metformin in ER-positive endometrioid endometrial cancer (NCT03675893).
Design and treatment:
- Population: 25 patients with ER-positive endometrioid endometrial carcinoma.
- Regimen: letrozole 2.5 mg PO daily, abemaciclib 150 mg PO twice daily, metformin 500 mg PO daily.
- Primary endpoints: objective response rate (ORR) and 6‑month progression-free survival (PFS6).
- Secondary endpoints: PFS, overall survival, duration of response, toxicity.
Efficacy:
- ORR: 32% (3 complete responses, 5 partial responses; 95% CI 14.9–53.5%).
- PFS6 (Kaplan–Meier): 69.8% (95% CI 46.9–84.3%).
- Median PFS: 19.4 months (95% CI 5.7 months–not estimable).
Safety:
- Toxicity: No patients discontinued therapy due to toxicity.
Correlative/molecular findings:
- TP53 mutations: No objective responses were seen in tumors with TP53 mutations.
- NSMP tumors with RB1 or CCNE1 alterations: No objective responses.
- CTNNB1 mutations: Associated with clinical benefit.
- Pharmacokinetics: >3‑fold increase in metformin exposure when co-administered with letrozole and abemaciclib.
Overall: The triplet demonstrated meaningful activity with good tolerability in ER-positive endometrioid endometrial cancer, with emerging molecular predictors of benefit and resistance and a notable pharmacokinetic interaction increasing metformin exposure.