Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib vs Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer

We present the results of a post-hoc tumor tissue analysis from the phase 3 MILO/ENGOT-ov11 study (NCT01849874). Mutation/copy number analysis was performed on tissue obtained pre-randomization. Kaplan-Meier method was used to estimate progression-free survival (PFS). Unbiased univariate analysis, Cox regression, and binary logistic regression were used to test associations between mutation status and outcomes, including PFS and binary response by local RECIST 1·1. MILO/ENGOT-ov11 enrolled 341 patients, ranging in age from 22-79, from 6/2013-4/2016. Patients were randomized 2:1 to binimetinib or physician's choice of chemotherapy (PCC). The most commonly altered gene was KRAS (33%). In 135 patients treated with binimetinib with response rate (RR) data, other detected MAPK pathway alterations included: NRAS (n=11, 8·1%), BRAF V600E (n=8, 5·9%), RAF1 (n=2, 1·5%), and NF1 (n=7, 5·2%). In those with and without MAPK pathway alterations, the RRs with binimetinib were 41% and 13%, respectively. PFS was significantly longer in patients with, compared to those without, MAPK pathway alterations treated with binimetinib (HR 0·5; 95% CI: 0·31, 0·79). There was a nonsignificant trend towards PFS improvement in PPC-treated patients with MAPK pathway alterations compared to those without (HR 0·82; 95% CI: 0·43-1·59). Although this hypothesis-generating analysis is limited by multiple testing, higher RRs and longer PFS were seen in patients with LGSOC treated with binimetinib, and to a lesser extent in those treated with PCC, who harbored MAPK pathway alterations. Somatic tumor testing should be routinely considered in patients with LGSOC and utilized as a future stratification factor.