Avutometinib Combo Shows Activity, Safety for HR+/HER2- Breast Cancer
The combination of avutometinib (VS-6766), abemaciclib (Verzenio), and fulvestrant (Faslodex) showed a manageable safety profile and early signs of efficacy in patients with hormone receptor (HR) – positive, HER2-negative metastatic breast cancer whose disease progressed despite prior treatment with CDK4/6 inhibitors, according to findings from a phase 1 trial (NCT05608252) presented at the 2025 American Association of Clinical Research Annual Meeting.
The maximum tolerated dose (MTD) was determined using a Bayesian Optimal Interval design; dose-limiting toxicities (DLTs) were reported in 3 of 4 patients at the highest dose level. No DLTs were observed among the 9 patients treated at the intermediate dose level. The recommended phase 2 dosing regimen was established as abemaciclib at 100 mg orally twice daily, avutometinib at 3.2 mg orally twice weekly, and fulvestrant at 500 mg intramuscularly every 28 days.
Treatment-related adverse effects (TRAEs) were predominantly grade 1 or 2; no grade 4 or 5 effects were observed. The most frequent TRAEs in the safety population (n = 16) included increased creatine phosphokinase (CPK) levels (50%), neutropenia (50%), diarrhea (44%), fatigue (44%), anemia (25%), and rash (19%). Grade 3 TRAEs were limited to increased CPK levels (19%), neutropenia (6%), diarrhea (6%), rash (19%), and mucositis (13%).
Regarding efficacy, the confirmed ORR per RECIST 1.1 was 13.3% (n = 2/15), which included 1 complete response and 1 partial response. Stable disease was observed in 46.7% of patients, and the clinical benefit rate at week 24 was 26.7%. Progressive disease occurred in 6 patients (40%), and 1 patient was not evaluable.
“The combination of avutometinib, abemaciclib, and fulvestrant showed a manageable safety profile and preliminary efficacy in HR+/HER2- metastatic breast cancer resistant to CDK4/6 inhibitors,” lead study author Adrienne G. Waks, MD, of Dana-Farber Cancer Institute in Boston Massachusetts, and colleagues wrote in a poster presentation of the data.
The phase 1 study enrolled patients with HR–positive, HER2-negative metastatic breast cancer who experienced disease progression on a prior CDK4/6 inhibitor. Enrollment was limited to patients with measurable or evaluable disease, and prior treatment with fulvestrant was permitted but not mandatory.
Planned dose levels included avutometinib at 2.4 mg, 3.2 mg, and 4.0 mg orally twice weekly on a 3-weeks-on/1-week-off schedule; abemaciclib at 50 mg, 100 mg, or 150 mg orally twice daily; and fulvestrant at 500 mg intramuscularly once every 28 days.
Seventeen patients were registered to the study, of whom 16 received at least one dose of study treatment and were evaluable for safety. One patient was replaced following withdrawal prior to DLT assessment.
Primary end points focused on identifying the MTD of the combination. Secondary end points included safety, pharmacokinetic analyses, ORR, CBR, and progression-free survival (PFS) per RECIST 1.1 criteria.
