Letrozole/Abemaciclib Generates Activity in ER+ Endometrial Cancer


Patients with hormone receptor-positive endometrial cancer had an objective response rate of 30%, including 8 confirmed responses, when treated with letrozole with abemaciclib.

Treatment with letrozole (Femara) plus abemaciclib (Verzenio) led to encouraging and durable evidence of activity in patients with recurrent estrogen receptor (ER)-positive recurrent endometrial cancer, according to findings from a phase 2 study (NCT03675893).1

Findings showed there to be 9 responses, 8 confirmed, for an objective response rate (ORR) of 30% (95% CI, 14.7-49.4). The median progression-free survival (PFS) was 9.1 months, PFS at 6 months was 55.6% (95% CI, 35.1-72), and median duration of response was 7.4 months.

For safety, the most common ≥ grade 3 treatment-related adverse events (AEs) included neutropenia (20%) and anemia (17%). No grade 5 AEs were reported.

“Previous studies of hormonal/endocrine therapy in endometrial cancer were associated with a median PFS of about 3 months. Although direct cross-study comparisons are hindered by study-specific differences in eligibility criteria, patient characteristics, samples sizes and statistical designs, the objective response rate of 30% and the median PFS of 9.1 months observed with letrozole/abemaciclib suggest that this regimen may be an effective alternative endocrine therapy approach for patients with recurrent endometrioid endometrial cancer,” Panagiotis A. Konstantinopoulos, MD, PhD, a physician and director of Translational Research, Gynecologic Oncology Program at Dana-Farber Cancer Institute, and associate professor of medicine at Harvard Medical School, told Targeted OncologyTM.

In the 2-stage, phase 2 study, investigators evaluated treatment with letrozole and abemaciclib in recurrent ER-positive endometrial cancer to determine if it is effective at slowing or stopping endometrial cancer cell growth.2

Eligibility criteria included patients aged 18 years and older with all endometrial cancer histologies who had measurable disease. There was no limit on prior therapies, and prior hormonal therapy was allowed. Other requirements included having an ECOG performance status of 0 or 1, and normal organ and bone marrow function.

Participants were given treatment with abemaciclib at the recommended phase 2 dose of 150 mg by mouth 2 times a day along with letrozole at 2.5 mg by mouth once daily.

Among those included in the study, 28 (93%) had endometrioid histology and 29 (97%) patients had received at least 1 previous chemotherapy regimen. The median follow-up was 12.5 months (95% CI, 8.4-18.9).

Primary end points were ORR by RECIST 1.1 and PFS rate at 6 months, and secondary end points were overall survival (OS) and treatment-related AEs.

At the data cutoff date of December 03, 2021, a total of 30 patients were initiated on protocol therapy, including 28 with endometrial cancer. Fifteen (50%) patients included in the study had prior hormonal therapy.1

Results from the study also showed that the median OS was 21.6 months (95% CI, 10.6- not evaluable.

Seventy percent of patients experienced diarrhea, but it was mostly grade 1 or 2 (n = 19). A total of 16 (53%) patients had ≥ 1 dose reduction of abemaciclib, including 7 because of diarrhea and 6 because of fatigue. Two (7%) patients discontinued therapy because of their AE. At the data cutoff date, 11 patients had died, 2 were lost to follow-up, and 17 were alive.

Regardless of grade, prior hormonal therapy, mismatch repair, and progesterone receptor status, patients had responses. According to exploratory tumor profiling, several mechanistically relevant candidate predictors of response, including CTNNB1, KRAS, and CDKN2A mutations, or absence of response (TP53 mutations), were seen and require independent validation.

“Responses were observed regardless of grade, receipt of prior hormonal therapy, or mismatch repair and progesterone receptor status. TP53 mutation status may be a biomarker of absence of response to this regimen. In other words, TP53-mutated tumors did not respond as well to letrozole/abemaciclib,” added Konstantinopoulos. “Next steps are to analyze the collected blood samples from this phase II study and specifically to look at circulating tumor DNA [ctDNA] in tumors to predict response to treatment, and to look at the kinetics of this ctDNA.”

  1. Konstantinopoulos PA, Lee EK, Xiong N, et al. A phase II, two-stage study of letrozole and abemaciclib in estrogen receptor-positive recurrent endometrial cancer. J Clin Oncol. 2023;41(3):599-608. doi:10.1200/JCO.22.00628
  2. Abemaciclib + letrozole +/- metformin in recurrent or persistent endometrial cancer. ClinicalTrials.gov. Accessed June 13, 2023. Accessed August 10, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03675893
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