Abstract CT515: A phase I/IB trial of binimetinib in combination with erlotinib in NSCLC harboring KRAS or EGFR mutation

Purpose: Oncogenic driver mutations in either KRAS or EGFR are present in up to 40-50% of NSCLC, share activation of the MAPK/ERK pathway and may be amenable to combination therapy to prevent negative feedback activation. In a phase I/IB trial, we tested the oral MEK 1/2 inhibitor, binimetinib, with EGFR-TKI, erlotinib, to establish MTD and evaluate safety of combination in patients with NSCLC harboring KRAS or EGFR mutations. Patients and Methods: Patients with advanced/metastatic NSCLC with at least 1 prior line of treatment (unless with activating EGFR mutation which could be treatment-naïve) were enrolled. The Phase I dose-escalation portion used a 3+3 design to determine the RP2D. Phase IB expansion enrolled patients with either KRAS- or EGFR-mutant NSCLC using the RP2D determined in Phase I. The primary objective was to evaluate the safety of binimetinib plus erlotinib in both phases. Tumor assessments were performed every two 28-day cycles. Blood samples were collected for pharmacokinetic analyses and tumor sampling was assessed to explore the biomarkers that could predict response or resistance to the binimetinib and erlotinib combination. Statistical analyses were performed via SAS 9.4. Results: 43 patients were enrolled (dose-escalation = 23; expansion = 20). Median age: 67 years (range 32-80); Females: 20 (47%); ECOG performance status 1: 37 (86%); never/former/current smokers: 10/27/6 (23%/63%/14%); and median 2 prior lines of treatment (range 0 - 5). 17 patients (40%) harbored EGFR mutation (10 exon 19 del, 6 L858R substitution, 1 G719D) and 22 (51%) harbored KRAS mutation (10 G12C, 11 other). The RP2D was erlotinib 100 mg QD continuously and binimetinib 15 mg BID x 5 days/week. The most common AEs across all dose levels included diarrhea (69.8%), rash (44.2%), fatigue (32.6%), and nausea (32.6%). Adverse events were primarily grade 1 or 2. Among the 43 patients enrolled, 9 (21%) achieved partial response (PR), 10 (23%) achieved stable disease (SD), and 9 (21%) had progressive disease. The remaining 15 patients (36%) were not evaluable for response. Among KRAS-mutant patients, 1 (5%) had confirmed PR (with G12D) and 8 (36%) achieved SD. Among EGFR-mutant patients, 9 were TKI-naïve including 8 PR (89%); 8 were TKI-pretreated with no PR and 1 (13%) SD. Median OS overall was 17.0 months (95% CI: 12.0, N.E.) and median PFS was 5.5 months (95% CI: 3.6, 22.2). Pharmacokinetics of binimetinib were comparable to historical data with no evidence of sig