PURPOSE: We present the results of a post hoc tumor tissue analysis from the phase 3 MILO/ENGOT-ov11 study (NCT01849874). PATIENTS AND METHODS: Mutation/copy-number analysis was performed on tissue obtained pre-randomization. The 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. RESULTS: MILO/ENGOT-ov11 enrolled 341 patients, ranging in age from 22 to 79, from June, 2013 to April, 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 with those without, MAPK pathway alterations treated with binimetinib [HR, 0.5; 95% confidence interval (CI) 0.31-0.79]. There was a nonsignificant trend toward PFS improvement in PCC-treated patients with MAPK pathway alterations compared with those without (HR, 0.82; 95% CI, 0.43-1.59). CONCLUSIONS: Although this hypothesis-generating analysis is limited by multiple testing, higher RRs and longer PFS were seen in patients with low-grade serous ovarian cancer (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 used as a future stratification factor.

Arizona Oncology University of Arizona College of Medicine Creighton University School of Medicine Phoenix Arizona

Belgium and Luxemburg Gynaecological Oncology Group University Hospitals Leuven Leuven Belgium

Center for Oncological Surgery European Competence Center for Ovarian Cancer Campus Virchow Klinikum and Benjamin Franklin Charité Comprehensive Cancer Center Medical University of Berlin Berlin Germany

Centre Hospitalier Régional et Universitaire de Besançon CHRU de Besançon Besançon France

Centre Léon Bérard Netsarc Network Université Claude Bernard Lyon 1 Lyon France

Department for Gynecologic Oncology and Institute for Cancer Genetics and Informatics Oslo University Hospital Oslo Norway

Department of Gynaecological Oncology Royal Adelaide Hospital Adelaide South Australia Australia

Department of Medical Oncology The Christie National Health Service Foundation Trust and University of Manchester Manchester United Kingdom

Department of Medicine and Surgery University of Milano Bicocca Milan Italy

Department of Obstetrics and Gynecology 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czech Republic

Department of Obstetrics and Gynecology Dignity Health Cancer Institute at St Joseph's Hospital and Medical Center Creighton University School of Medicine at St Joseph's Hospital and Medical Center Phoenix Arizona

Department of Obstetrics and Gynecology Medical University of Innsbruck Austrian AGO Innsbruck Austria

Department of Urology and Gynecology Istituto Nazionale Tumori Fondazione G Pascale Napoli Italy

Dutch Gynaecological Oncology Group Amsterdam University Medical Centers University of Amsterdam Amsterdam the Netherlands

Gynecologic Oncology Program European Institute of Oncology IRCCS Milan Italy

Internal Medicine Department University of Botswana Gaborone Botswana

Medical Oncology CHU Université Catholique de Louvain Namur Sainte Elisabeth Namur Belgium

Medical Oncology Service Donostia University Hospital San Sebastian Spain

Memorial Sloan Kettering Cancer Center Weill Cornell Medical Center New York New York

Nordic Society of Gynaecological Oncology and Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Onkologisches Therapiezentrum am Krankenhaus Jerusalem Hamburg Germany

Princess Margaret Cancer Centre Toronto Ontario Canada

Royal Marsden National Health Service Foundation Trust and Institute of Cancer Research London United Kingdom

Sarah Cannon Research Institute Nashville Tennessee

Servicio de Oncologıa Medica Fundacion Instituto Valenciano de Oncologıa Valencia Spain

Stephenson Cancer Center at The University of Oklahoma Health Sciences Center Oklahoma City Oklahoma

The Ohio State University Comprehensive Cancer Center James Cancer Hospital and Solove Research Institute Columbus Ohio

University Clinic for Gynaecology and Obstetrics Medical University of Innsbruck Innsbruck Austria and Arbeitsgemeinschaft Gynäkologische Onkologie Austria

Vall d'Hebron University Hospital Barcelona Spain

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NCT01849874