Journal Article

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

Campos, Susana, Cheng, Su-Chun, Horowitz, Neil, Liu, Joyce F., Shea, Meghan, Beumer, Jan H., Bouberhan, Sara, Polak, Madeline, Lee, Elizabeth K., Le, Tien V., Penson, Richard T., Matulonis, Ursula A., Koppermann, Lani, Castro, Cesar, Konstantinopoulos, Panagiotis A., Krasner, Carolyn, Zhou, Ningxuan, Wright, Alexi A., Widick, Page, Hayes, Martin, Hindenach, Sarah, Porter, Rebecca, Sawyer, Hannah

2025

Overview

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. Combined hormonal therapy and CDK4/6 inhibition face resistance challenges in endometrial cancer. Here, the authors present a phase 2, one-arm clinical trial, where metformin is combined with letrozole (hormonal therapy) and abemaciclib (a CDK4/6 inhibitor) reporting safety and efficacy in patients with endometrial cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 1-Phosphatidylinositol 3-kinase / 692/4028/67/1059/602 / 692/4028/67/1517/1931 / Adult / Aged / Aged, 80 and over / Aminopyridines - administration & dosage / Aminopyridines - adverse effects / Aminopyridines - therapeutic use / Anemia / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Benzimidazoles - administration & dosage / Benzimidazoles - adverse effects / Benzimidazoles - therapeutic use / Biomarkers / Cancer / Chemotherapy / Cyclin-dependent kinase 4 / Effectiveness / Endocrine therapy / Endometrial Neoplasms - drug therapy / Endometrial Neoplasms - genetics / Endometrial Neoplasms - metabolism / Endometrial Neoplasms - mortality / Endometrial Neoplasms - pathology / Endometrium / Estrogen receptors / Estrogens / Ethnicity / FDA approval / Female / Hispanic Americans / Humanities and Social Sciences / Humans / Insulin / Insulin-like growth factors / Kinases / Letrozole - administration & dosage / Letrozole - adverse effects / Letrozole - therapeutic use / Lymphatic system / Metformin / Metformin - administration & dosage / Metformin - adverse effects / Metformin - therapeutic use / Middle Aged / multidisciplinary / Neutrophils / Patients / Pharmacokinetics / Phosphorylation / Progression-Free Survival / Receptors, Estrogen - metabolism / Science / Science (multidisciplinary) / Survival / Synergism / Therapy / TOR protein / Toxicity / Treatment Outcome / Tumors / Uterine cancer