PURPOSE: Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC. METHODS: This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician's choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety. RESULTS: A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent. CONCLUSION: Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.

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

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

Belgium and Luxemburg Gynaecological Oncology Group University Hospitals Leuven Leuven Belgium

Biodonostia HRI Osasun Ikerketa Insitutua Insituto de Investigacion Sanitaria San Sebastián Gipuzkoa Spain

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

CHU Université catholique de Louvain Namur Sainte Elisabeth Namur Belgium

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 5005 Australia

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

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

Dipartimento Medicina e Chirurgia Università Milano Bicocca Programma Ginecologia Oncologica Istituto Europeo Oncologia IRCCS Milan Italy

Dutch Gynaecological Oncology Group Amsterdam University Medical Centers Amsterdam the Netherlands

Istituto Nazionale Tumori Fondazione Pascale IRCCS Naples Italy

MD Anderson Cancer Center Houston TX

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

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

Onkologisches Therapiezentrum am Krankenhaus Jerusalem Hamburg Germany

Pfizer New York NY

Princess Margaret Cancer Centre Toronto Ontario Canada

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

Servicio de Oncologıa Medica Fundacion Instituto Valenciano de Oncologıa Valencia Spain

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

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

University Clinic for Gynaecology and Obstetrics Medical University of Innsbruck Innsbruck 6020 Austria

University of Botswana Gaborone Botswana

Vall d'Hebron University Hospital Barcelona Spain

J Clin Oncol. 2020 Nov 10;38(32):3731-3734. doi: 10.1200/JCO.20.02190. PubMed

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ClinicalTrials.gov
NCT01849874