A phase II study of fulvestrant and abemaciclib in hormone receptor positive advanced or recurrent endometrial cancer.

5511 Background: Inhibition of the Cyclin D-Cyclin dependent kinase (CDK)4/6-INK4-retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Elevated CDK4 expression is observed in 34–77% of endometrioid endometrial cancers (ECs) and is an early event of neoplastic transformation. Responses to endocrine monotherapy in advanced or recurrent EC are suboptimal and short-lived. We hypothesized that CDK4/6 inhibition with abemaciclib combined with fulvestrant is a promising strategy to improve outcomes with endocrine therapy in patients (pts) with advanced or recurrent hormone receptor-positive EC. Methods: This was an investigator-initiated, open label, single arm phase II study in pts with advanced or recurrent EC. Eligibility criteria included age ≥18 years, estrogen receptor or progesterone receptor expression ≥ 1% by immunohistochemistry, measurable disease, ≤ 2 prior lines of chemotherapy, and ≤ 1 prior line of hormonal therapy. All histologies were eligible except carcinosarcoma. Mixed histologies required ≥ 95% endometrioid component. Pts received fulvestrant 500 mg intramuscularly monthly with an initial 2-week loading dose and abemaciclib 150 mg orally twice daily until disease progression or prohibitive toxicity. Primary endpoint was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1. Results: At data cutoff (October 7, 2023), 27 pts initiated protocol therapy and 25 pts were evaluable for efficacy. 24 pts (89%) had tumors with endometrioid histology. 9 pts (33%) had prior hormonal therapy and 26 pts (96%) had ≥1 prior line of chemotherapy. 11 pts achieved a partial response resulting in an ORR of 44% (90% CI, 27.0% to 62.1%). The median duration of response, among pts that experienced a response, was 15.6 months (90% CI, 7.2 – nonestimable (NE)). All responses were in grade 1 or 2 endometrioid ECs. 10 out of 11 responses (91%) were in pts with copy number low/no specific molecular profile ECs, while 1 response (9%) was in a patient with microsatellite instability-high EC. Median PFS was 9.0 months (90% CI 1.8 to 20.4) and median OS was 37.8 months (90% CI 16.3 to NE). Most common ≥ grade 3 treatment related adverse events were neutropenia (22%) and anemia (19%). Conclusions: The combination of abemaciclib and fulvestrant has promising activity with durable responses observed in pts with advanced or recurrent EC; a phase 3 trial is planned. Clinical trial information: NCT03643510 .