Letrozole, abemaciclib and metformin in endometrial cancer

Rákkutatás · Endometrial cancer · TP53

Letrozole, abemaciclib and metformin met the prespecified objective response and PFS6 criteria to be considered worthy of further investigation in ER positive endometrioid EC.

Based on preclinical studies showing synergism with simultaneous inhibition of the estrogen receptor (ER), CDK4/6 and PI3K pathways and based on window of opportunity studies showing that metformin suppresses PI3K/mTOR signaling in endometrial cancer (EC), we conduct a non‑randomized phase 2 study of letrozole/abemaciclib/metformin in ER positive endometrioid EC (NCT03675893). Primary objectives include objective response rate (ORR) and rate of progression‑free survival (PFS) at 6 months (PFS6) while secondary objectives include PFS, overall survival, duration of response and toxicity. Twenty‑five patients initiate protocol therapy [letrozole 2.5 mg orally (PO) once a day (qd), abemaciclib 150 mg PO twice a day (bid) and metformin 500 mg PO qd]. ORR is 32% (3 complete and 5 partial responses, 95% CI 14.9‑53.5%), Kaplan Meier estimate of PFS6 is 69.8% (95% CI 46.9‑84.3%) and median PFS is 19.4 months (95% CI 5.7 months‑not estimable). No patients discontinue therapy because of toxicity. There are no objective responses among TP53 mutated ECs and among NSMP (no specific molecular profile) tumors with RB1 or CCNE1 alterations; CTNNB1 mutations correlate with clinical benefit. Pharmacokinetic analyses demonstrate that administration of letrozole and abemaciclib with metformin result in a more than 3‑fold increase in metformin exposure.

The combination shows promising activity and durable responses in a heterogeneous population of ER‑positive endometrioid endometrial cancer, suggesting a potentially effective endocrine strategy that warrants further investigation.

Bizonyítékszint: Korai humán adat. Kis vagy feltáró emberi adat.

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