A phase IB study of binimetinib and palbociclib in molecularly selected advanced triple-negative breast cancer.

Purpose: Advanced, pre-treated TNBC has a dismal prognosis and lacks effective options beyond standard cytotoxics. We previously showed, via phosphoproteomic screening, that 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 BID) plus palbociclib (100 mg daily, days 1-21) in 28-day cycles. Palbociclib escalation to 125 was allowed in cycle 2. The primary objective was to demonstrate a 2.5 month-long PFS, a 50% increase over the reference PFS for cytotoxics (1.7 months). Whole-exome sequence (WES) was performed in tumor samples of the efficacy population.

Results: Fifty-one patients were screened, 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 4-13 months. WES revealed a distinct mutational landscape among long-term responders compared to early progressors.

Conclusions: In this biomarker-enriched TNBC population, the combination of palbociclib and binimetinib showed limited activity and notable toxicity. While 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.