Dr Konstantinopoulos on Responses With Metformin Plus Letrozole/Abemaciclib in ER+ Endometriod Endometrial Cancer

“In total, there were 3 CRs [among 25] patients. Previously, in all CDK 4/6 inhibitor studies [in endometriod endometrial cancer], no CRs had been observed. This is the first time that we’ve seen CRs [with a CDK 4/6 inhibitor regimen in this patient population.]”

Panagiotis A. Konstantinopoulos, MD, PhD, director of the Mellen and Eisenson Family Center for BRCA and Related Genes, Director of Translational Research in the Division of Gynecologic Oncology and the Velma Eisenson Endowed Chair for Clinical and Translational Research at Dana-Farber Cancer Institute; as well as a professor of medicine at Harvard Medical School, discusses findings from the phase 2 RESOLVE study (NCT03675893) evaluating the combination of letrozole, abemaciclib (Verzenio), and metformin in patients with estrogen receptor (ER)–positive recurrent endometrioid endometrial cancer.

Results were presented at the 2025 SGO Annual Meeting on Women’s Cancer and showed that the addition of metformin to the combination of letrozole and abemaciclib was feasible, well tolerated, and associated with encouraging clinical activity in 25 patients with recurrent endometrioid endometrial cancer, Konstantinopoulos reported. Notably, the triplet regimen appeared to elicit deeper responses and more durable progression-free survival (PFS) than observed previously with letrozole and abemaciclib alone, he noted. At the time of data cutoff, the objective response rate was 32%, including 3 complete responses (CRs) and 5 partial responses, Konstantinopoulos detailed. These findings mark the first reported CRs in endometrial cancer treated with a CDK4/6 inhibitor–based regimen, which were not observed in earlier CDK4/6 inhibitor studies, he emphasized.

Additionally, 7 patients achieved stable disease (SD) lasting at least 6 months, and 9 patients experienced SD of less than 6 months’ duration, Konstantinopoulos continued, adding that 1 patient had progressive disease as best response. The median PFS exceeded 19.3 months at an estimated follow-up of 27 months. The patient with the longest follow-up experienced progression at 27 months. The 6-month PFS rate was 73.8% (95% CI, 50.7%-87.3%).

These updated findings compare favorably with previous results from a prior phase 2 study (NCT03675893) of letrozole plus abemaciclib without metformin in 30 patients with ER-positive recurrent endometrial cancer, in which the median PFS was 9.1 months (95% CI, 3.5 to 16.5), Konstantinopoulos noted. In other CDK4/6 inhibitor studies in endometrial cancer, the median PFS has typically ranged from 8 to 9 months, with shorter median follow-up durations, he concluded.

Disclosures: Konstantinopoulos reported participating in advisory boards with AstraZeneca, GSK, Merck, Immunogen, EMD Serono, Scorpion, Schrodinger, Nimbus, and Mural Oncology; participating in scientific steering committees with AstraZeneca; participating in data monitoring committees with Gilead; and receiving institutional funding as the principal investigator from AstraZeneca, Bayer, Eli Lilly and Company, GSK, Merck, Merck KGaA, and Pfizer.