Avutometinib, Abemaciclib, and Fulvestrant in Patients with HR+/HER2− Metastatic Breast Cancer Previously Treated with CDK4/6 Inhibitor: A Single-Arm Phase I Trial

Purpose: The efficacy of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in hormone receptor-positive/HER2-negative metastatic breast cancer is limited by resistance mechanisms, including mitogen-activated protein kinase (MAPK) pathway activation. We performed a phase I trial evaluating avutometinib, a dual rapidly accelerated fibrosarcoma/MAPK kinase (RAF/ MEK) inhibitor, combined with abemaciclib and fulvestrant. Patients and Methods: Eligible patients had prior progression on CDK4/6i; prior fulvestrant was allowed. The primary endpoint was the maximum tolerated dose (MTD). Planned dose levels were abemaciclib 50, 100, or 150 mg orally twice daily, with avutometinib 2.4, 3.2, or 4 mg orally twice weekly (3 weeks on/ 1 week off) plus fulvestrant 500 mg intramuscularly every 28 days. Secondary endpoints included safety, pharmacokinetics (PK), overall response rate (ORR), clinical benefit rate (CBR), and progression-free survival (PFS). Results: Sixteen patients were treated (median age 61; 88% visceral disease; 63% prior selective estrogen receptor degrader). The MTD and recommended phase II dose (RP2D) were abemaciclib 100 mg twice daily, avutometinib 3.2 mg twice weekly, and fulvestrant 500 mg intramuscularly every 28 days. Common treatment-related adverse events (TRAE) were creatine phosphokinase elevation (50%), neutropenia (50%), diarrhea (44%), and skin rash (44%). No grade 4 to 5 TRAEs occurred. ORR was 13% (2/15 patients with measurable disease), 24-week CBR 40% (6/15 patients with measurable disease), and median PFS 3.6 months (95% confidence interval, 2.1–not reached). PK was consistent with prior reports. Conclusions: The regimen was well tolerated at the RP2D, with no new safety signals, and showed preliminary clinical activity. A phase II trial is ongoing.