麻豆传媒

Almost a third of patients with recurrent estrogen receptor (ER)-positive endometrial cancer responded to the combination of letrozole and abemaciclib (Verzenio) in a small phase II study.

Nine of 30 patients responded to the aromatase inhibitor (AI)-CDK4/6 inhibitor combination, all with endometrioid adenocarcinoma. An additional 13 patients had stable disease, and median progression-free survival (PFS) for the cohort was 9.1 months.

Responses occurred regardless of tumor grade, prior hormonal therapy, mismatch repair status, and progesterone receptor status, reported Panagiotis A. Konstantinopoulos, MD, PhD, of Dana-Farber Cancer Institute in Boston, and colleagues, in the .

"A clinically important finding of our study was that activity of letrozole/abemaciclib was demonstrated in patiens who had previously received hormonal therapy including prior AI tamoxifen, and progestin monotherapy as well as patients who had previously received letrozole/everolimus (Afinitor) and megestrol/tamoxifen combinations," they stated. "These responses suggest that letrozole/abemaciclib may not be cross-resistant with other hormonal approaches and may represent a viable salvage endocrine therapy regimen for patients with ER-positive endometrioid EC [endometrial cancer]."

The findings added to those of a small randomized trial of letrozole and palbociclib (Ibrance), showing almost a three-fold increase in PFS with the addition of the CDK4/6 inhibitor to letrozole (8.3 vs 3.0 months). Although letrozole has limited activity in recurrent endometrial cancer, a good rationale exists for a CDK4/6 inhibitor as evidence has suggested that resistance to endocrine therapy is associated with continued dependence on cyclin D1 and CDK4/6, according to a critique of the trial.

Konstantinopoulos and colleagues noted that more than 80% of FIGO grade 1/2 and 50% of FIGO grade 3 endometrioid endometrial cancers express estrogen receptors. Though hormonal/endocrine therapy is an option for those patients, responses tend to be modest and short lived.

Given the convergence of multiple signaling pathways in the CCND1/CDK46 complex, the investigators hypothesized that CDK4/6 inhibition would have additive or synergistic activity with an AI. Such combinations already have FDA-approved indications for treating advanced/metastatic HR+ breast cancer.

"Importantly, CDK4/6 inhibitor combinations may be particularly attractive in EC, given the rarity of RB1 alterations ... that would otherwise cause de novo resistance to CDK4/6 blockade," they noted.

Investigators enrolled patients with recurrent/metastatic and/or resistant endometrial cancer with no available standard therapies. The trial was conducted in two stages. During the first stage, patients with any endometrial cancer histology were eligible, and enrollment was capped at 16 patients. If the combination achieved at least two objective responses or at least 2 patients were progression-free, the trial continued to the second stage, which limited enrollment to patients with endometrioid endometrial cancer or endometrial carcinosarcoma with an endometrioid component.

All patients in both stages of the trial were required to have ER-positive endometrial cancer. Overall, 28 of 30 patients had endometrioid endometrial cancer and 29 of 30 had received at least one prior chemotherapy regimen. Half of the patients had received prior hormonal therapy.

The trial had a composite primary objective, comprising objective response rate (ORR) and PFS at 6 months (PFS6). If the trial achieved an ORR of 20% or a PFS6 of 30%, further study of the combination therapy would be warranted.

The trial met the objective for continued investigation, demonstrating an ORR of 30% and a PFS6 of 55.6%. Median duration of response was 7.4 months. Responses occurred in four of 15 patients with prior hormonal therapy, five of 15 without prior hormonal therapy, five of 11 patients with FIGO grade 1,2, two of seven FIGO grade 2, and two of 10 FIGO grade 3.

Additionally, 12 patients had stable disease as best response, including five (all with endometrioid histology) who had stable disease for 6 months or longer. About two-thirds of the patients had some degree of tumor reduction. Median overall survival was 21.6 months.

The most common grade ≥3 treatment-related adverse events were neutropenia in 20% of patients and anemia in 17%.

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