A Phase IB Study of Binimetinib and Palbociclib in Molecularly Selected Advanced Triple-Negative Breast Cancer.

Purpose: Advanced, pretreated triple-negative breast cancer (TNBC) has a dismal prognosis and lacks effective options beyond standard cytotoxics. We previously showed, via phosphoproteomic screening, that cyclin-dependent kinase 6 (CDK6) and ERK hyperactivation are linked to adverse outcomes and represent actionable targets. This prompted us to evaluate palbociclib and binimetinib in advanced TNBC after one or two prior therapies.

Patients and methods: Patients with increased ERK and/or CDK6 activity were eligible. Treatment consisted in daily binimetinib (45 mg twice a day) plus palbociclib (100 mg daily, days 1-21) in 28-day cycles. Palbociclib escalation to 125 mg was allowed in cycle 2. The primary objective was to demonstrate a 2.5 month-long progression-free survival (PFS), a 50% increase over the reference PFS for cytotoxics (1.7 months). Whole-exome sequencing was performed in tumor samples of the efficacy population.

Results: Fifty-one patients were screened, of whom 50 were biomarker-positive. Twenty-four initiated treatment between June 2021 and July 2022. Toxicity was frequent, consisting mainly in fatigue, diarrhea, neutropenia, and ocular effects, requiring frequent dose interruptions or reductions. The primary objective was not met (median PFS 50 days). However, a bimodal PFS pattern emerged, with 13% of the patients achieving disease control lasting 4 to 13 months. Whole-exome sequencing revealed a distinct mutational landscape among long-term responders compared with early progressors.

Conclusions: In this biomarker-enriched TNBC population, the combination of palbociclib and binimetinib showed limited activity and notable toxicity. Whereas CDK6 and ERK hyperactivation confirmed their prognostic role, they did not predict treatment benefit. Exploratory genomic findings suggest the existence of a biologically distinct subset of patients with prolonged benefit, encouraging further investigation.

Significance: Previous studies showed that patients with early TNBC with increased CDK4/6 and ERK activity are at high risk of relapse. Preclinical data also suggest the benefit of combined inhibition of CDK4/6 and MEK, and novel therapies are needed for TNBC in the advanced disease setting. Despite the rationale and a biomarker-driven design, this combination was toxic and showed limited efficacy. This combination should not be further developed in this disease.