Avutometinib/Abemaciclib/Fulvestrant Combo Is Active, Safe in CDK4/6 Inhibitor–Resistant HR+/HER2– Metastatic Breast Cancer

HR+ Breast Cancer | Image
Credit: © Sebastian Kaulitzki
– stock.adobe.com

The combination of avutometinib (VS-6766), abemaciclib (Verzenio), and fulvestrant (Faslodex) demonstrated a manageable safety profile and preliminary efficacy in patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer (HR+/HER2– MBC) resistant to CDK4/6 inhibitors, according to findings from a phase 1 trial (NCT05608252) presented at the 2025 AACR 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.

Phase 1 Study Design

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.

Baseline Patient Characteristics

The median age at enrollment was 60.5 years (range, 37-71), and all 16 patients were female. All patients identified as White. ECOG performance status was 0 in 93% of patients and 1 in 6.3%.

At initial diagnosis, 31.3% of patients had stage II disease, 25% had stage IV disease. The remainder were diagnosed at stage I (12.5%) or stage III (6.3%). A disease-free interval greater than 2 years from primary diagnosis was observed in 62.5% of patients, whereas 12.5% relapsed within 2 years. De novo metastatic disease was present in 25% of the cohort.

Visceral involvement was observed in 31.3% of patients, with liver metastases present in 18.8% and lung or pleural involvement in 12.5%.

All patients had prior exposure to CDK4/6 inhibitors, most commonly in the metastatic setting (93%). Palbociclib (Ibrance) was the most frequently used agent (68.8%), followed by ribociclib (Kisqali) and abemaciclib (19% each). The median duration on CDK4/6 inhibitor therapy was 18.8 months (range, 9.1-78), and 81.3% of patients had received at least 12 months of treatment with a CDK4/6 inhibitor.

Patients received a median of 2 prior lines of endocrine therapy in the metastatic setting (range, 1–5); prior fulvestrant was administered to 43.8% of patients. Use of selective estrogen receptor degraders (SERDs) was reported in 62.5%, and 31.3% had received prior therapy targeting the PI3K/AKT/mTOR pathway.

Chemotherapy or antibody-drug conjugate (ADC) exposure in the metastatic setting was limited, with 75% of patients receiving no prior cytotoxic agents. The remaining 25% had received either 1 or 2 prior lines of chemotherapy or an ADC.

Preliminary Efficacy Data

The median PFS was 3.6 months (95% CI, 2.1-not reached) at a median follow-up of 9.8 months. A waterfall plot of target lesion changes demonstrated measurable tumor shrinkage in a subset of patients, supporting biological activity of the regimen. Swimmer plots further illustrated treatment duration and best response across the cohort.

Pharmacokinetic (PK) profiles of avutometinib and abemaciclib on days 1 and 15 of cycle 1 indicated consistent drug exposure with no evidence of adverse interaction, and concentrations remained within the expected therapeutic range.

Reference

Waks AG, Seguí E, Li T, et al. A single-arm phase 1 trial of avutometinib, abemaciclib, and fulvestrant in CDK4/6 inhibitor–pretreated patients with HR+/HER2– metastatic breast cancer. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT108.