Phase Ib Study of Binimetinib with Paclitaxel in Patients with Platinum-Resistant Ovarian Cancer: Final Results, Potential Biomarkers, and Extreme Responders
Mené sur 34 patientes atteintes d'un cancer de l'ovaire résistant aux sels de platine, cet essi de phase Ib évalue la dose maximale tolérée, l'efficacité, du point de vue du taux de réponse globale et la toxicité d'un traitement combinant binimétinib, un inhibiteur de MEK dispensé par voie orale, et paclitaxel
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.
Clinical Cancer Research , résumé, 2017