452P A phase Ib dose escalation study of binimetinib plus mFOLFIRI in patients with metastatic RAS mutated colorectal cancer

Abstract

Preclinical and early clinical evidence suggest that MEK inhibition (MEKi) acts synergistically when combined with cytotoxics in RAS mutated (mt) metastatic colorectal tumours (mCRC). We investigated the safety and clinical activity of MEKi, binimetinib, and mFOLFIRI in patients (pts) with RAS mt mCRC (NCT02613650). Eligibility criteria: Pts >18 years with RAS mt mCRC, ECOG 0-1, acceptable organ function, radiographic measurable disease, and progression or ineligibility to oxaliplatin. Pts were treated with binimetinib plus mFOLFIRI, in a dose-escalated standard 3+3 design, to determine the maximum tolerated dose (MTD) and report the dose-limiting toxicities (DLTs). A 6-day lead-in period with binimetinib alone was required prior to combination therapy. Binimetinib was dosed at two levels – 30mg BID and 45mg BID - and was given on days 1-12/14-day cycle po with mFOLFIRI every 14 days iv. After determination of MTD, an additional 12 patients will be enrolled in the dose expansion phase to assess preliminary efficacy. 13 pts were enrolled in the dose escalation phase: 7 pts on the first binimetinib dose level and 6 on the second. Median age was 56 yrs (44-71), 9 were male and 9 had received prior treatment with irinotecan. The mean number of prior therapies was 2 (1-6) and the median carcinoembryonic antigen (CEA) level on screening was 84.9 ng/mL (7.2-476.3). The most common grade 1-2 adverse effects (AEs) (N) included rash (10), nausea (9), diarrhoea (8), vomiting (7), fatigue (5) and mucositis (4). Grade 3 AEs included anaemia (1), rash (1), heart failure (1), and fatigue (1). One pt had grade 4 neutropenia related to mFOLFIRI. One pt had a DLT (decreased cardiac ejection fraction) on dose level 1 and 3 additional patients were added to dose level 1. Two pts discontinued the study due to grade 2 AEs (stomatitis and pruritus) and 2 withdrew consent. The mean number of cycles received was 8 (2-29). Best response included 1 partial response and 5 stable disease (all had received prior irinotecan and 3/6 had progressive disease on it). Four pts remained on the study for >6 months (32-67 weeks). The study is currently on the dose expansion phase after 6 pts were treated at MTD (dose level 2). This cohort will enroll only irinotecan refractory pts. MEKi plus mFOLFIRI is tolerable and showed preliminary efficacy in the dose escalation cohort in pts with RAS mt mCRC and prior exposure to irinotecan.