Letrozole, abemaciclib and metformin in endometrial cancer: a non-randomized phase 2 trial
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.
Authors
- Elizabeth K. Lee (ORCID: https://orcid.org/0000-0001-7533-7853)
- Meghan Shea (ORCID: https://orcid.org/0000-0001-5262-1245)
- Hannah Sawyer
- Martin Hayes (ORCID: https://orcid.org/0000-0001-8998-9713)
- Jan H. Beumer (ORCID: https://orcid.org/0000-0002-8978-9401)
- Madeline Polak (ORCID: https://orcid.org/0000-0002-1331-3845)
- Carolyn Krasner
- Susana M. Campos (ORCID: https://orcid.org/0000-0001-9672-473X)
- Page Widick
- Ursula A. Matulonis (ORCID: https://orcid.org/0000-0002-3103-6992)
- Tien V. Le (ORCID: https://orcid.org/0000-0002-5798-5694)
- Cesar M. Castro (ORCID: https://orcid.org/0000-0002-1159-5658)
- Ningxuan Zhou (ORCID: https://orcid.org/0000-0002-7623-2276)
- Panagiotis A. Konstantinopoulos (ORCID: https://orcid.org/0000-0002-1032-1479)
- Rebecca L. Porter (ORCID: https://orcid.org/0000-0002-4848-1275)
- Sara Bouberhan (ORCID: https://orcid.org/0000-0002-0315-2152)
- Richard T. Penson (ORCID: https://orcid.org/0000-0002-8091-8588)
- Lani Koppermann
- Joyce Liu (ORCID: https://orcid.org/0009-0008-4667-6555)
- Su–Chun Cheng
- Alexi A. Wright
- Neil Horowitz
- Sarah Hindenach
Institutions
- Beth Israel Deaconess Medical Center (US)
- Johns Hopkins University (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- Sidney Kimmel Comprehensive Cancer Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-03
- DOI
- https://doi.org/10.1038/s41467-025-67087-8
- Citations
- 2
- Primary Topic
- Advanced Breast Cancer Therapies
- Type
- article
- Field-Weighted Citation Impact
- 3.04
Funders
- U.S. Department of Health and Human Services
- Breast Cancer Research Foundation
- Eli Lilly and Company
- National Cancer Institute