Phase 1 trial of avutometinib, abemaciclib and fulvestrant for HR+/HER2- metastatic breast cancer after progression on CDK4/6 inhibitor

The efficacy of CDK4/6 inhibitors (CDK4/6i) in HR-positive/HER2- negative metastatic breast cancer (HR+ HER2- mBC) is limited by resistance mechanisms, including MAPK pathway activation. A phase 1 trial at Dana-Farber Cancer Institute (Boston, MA) evaluated avutometinib (dual RAF/MEK inhibitor), abemaciclib and fulvestrant for patients with HR+ HER2- mBC after progression on CDK4/6i. The primary endpoint was the maximum tolerated dose (MTD). Sixteen patients were treated (median age 61 years; 88% visceral disease, 63% pior SERD). The MTD and recommended phase 2 dose (RP2D) were oral abemaciclib 100 mg twice daily, oral avutometinib 3.2 mg twice weekly, en intramuscular fulvestrant 500 mg every 28 days. Common treatment-related adverse events were creatine phosphokinase elevation (50%), neutropenia (50%), diarrhea (44%), and skin rash (44%). No grade 4 or 5 TRAEs occurred. Objective response rate was 13%, 24-week clinical benefit rate was 40%, and median progression-free survival was 3.6 months (95% CI 2.1-NR). The authors conclude that the regimen was well tolerated at the RP2D and showed preliminary clinical activity. A phase 2 trial is ongoing.