Phase Ib Study of Binimetinib with Paclitaxel in Patients with Platinum-Resistant Ovarian Cancer: Final Results, Potential Biomarkers, and Extreme Responders

Purpose: Epithelial ovarian cancer (EOC) is a molecularly diverse disease. Mitogen-activated protein kinase kinase (MEK) inhibition targets tumors harboring mitogen-activated protein kinase (MAPK) pathway alterations and enhances paclitaxel-induced apoptosis in EOC. This phase Ib study evaluated the MEK inhibitor binimetinib combined with paclitaxel in patients with platinum-resistant EOC. Experimental Design: Patients received intravenous (IV) weekly paclitaxel with oral binimetinib in three different administration schedules. Outcomes were assessed by RECIST and CGIC CA-125 response criteria. Tumor samples were analyzed using next-generation sequencing. Results: Thirty-four patients received ≥1 binimetinib dose. A 30-mg twice daily (BID) continuous or 45-mg BID intermittent binimetinib dose were deemed the recommended phase 2 doses (RP2Ds) in combination with 80 mg/m² IV weekly paclitaxel. Rate of grade 3/4 adverse events was 65%. The best overall response rate was 18%-1 complete (CR) and 4 partial responses (PRs)-among 28 patients with RECIST-measurable disease. Eleven patients achieved stable disease (SD), yielding a clinical benefit rate (CR+PR+SD) of 57%. Response rates, per both RECIST and CA-125 criteria, were highest in the 45-mg BID continuous cohort and lowest in the 45-mg BID intermittent cohort. All 4 evaluable patients with MAPK pathway-altered tumors experienced clinical benefit. Conclusions: The combination of binimetinib and IV weekly paclitaxel was tolerable in this patient population. The RP2D of binimetinib in combination with paclitaxel was 30 mg BID as a continuous or 45 mg BID as an intermittent dose. Although response rates were modest, a higher clinical benefit rate was seen in patients harboring alterations affecting the MAPK pathway.

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