71P A phase I study of binimetinib, a MEK inhibitor, in combination with pembrolizumab in patients with advanced non-small cell lung cancer (NCT03991819)

MEK inhibition combined with blocking the PD-1 axis may achieve a greater clinical response than either inhibitor alone due to increased T cell infiltration of tumours. We combined binimetinib with pembrolizumab in patients with stage IV advanced non-small cell lung cancer (NSCLC) and PD-L1 tumor proportion score>=50%. A 3 + 3 dose escalation design was used. Binimetinib at dose level 1 (DL1; 45 mg) or dose level -1 (DL-1; 30 mg) twice daily orally continuously was given with pembrolizumab 200 mg IV q 21 days. The primary objective was to define the recommended phase II dose (RP2D). Secondary outcomes included safety of the combination and response (RECIST 1.1) with a planned phase Ib expansion in patients with RAS/RAF/MEK dysregulated tumours via next generation gene sequencing. Genomic markers are being explored in tissue and plasma. Eleven patients (3 DL1= 45 mg, 8 DL-1= 30 mg) were enrolled: 7 with KRAS, 2 BRAF and 1 STK11 alteration which acts as a tumor suppressor gene encoding for LKB1. Two of 3 patients at DL1 experienced dose limiting toxicity (DLT) including grade 3 elevated amylase and diarrhea, grade 4 elevated lipase and a grade 2 rash requiring dose reduction. Of 8 patients treated at DL-1, 2 were not evaluable for DLT as 1 progressed in cycle 1 and another was noncompliant with treatment. Of the remaining 6 patients, 1 experienced a DLT with grade 3 rash. Common toxicities across all cycles were rash (100%), diarrhea (45%), pruritis (45%) and lower extremity edema (36%). A partial response was noted in 4 (36%), stable disease in 4 (36%) and progressive disease in 3 (27%) with an overall response rate of 36% and a disease control rate of 73%. All 4 responding patients had either a RAS or RAF alterations while 2 of the 3 patients with early disease progression had no RAS or RAF mutation. The RP2D of the combination in patients with advanced NSCLC is binimetinib 30 mg BID plus pembrolizumab 200 mg IV q21 days. There appears to be an early trend of patients responding to combination treatment who harbor a KRAS or BRAF mutation. Updated data including circulating tumor DNA variant allele frequency associated with response and final analysis of primary endpoints will be presented.