MILO/ENGOT-ov11: Binimetinib Versus Physician’s Choice Chemotherapy in Recurrent or Persistent Low-Grade Serous Carcinomas of the Ovary, Fallopian Tube, or Primary Peritoneum

Bradley J. Monk, Rachel N. Grisham, Susana Banerjee, Elsa Kalbacher, Mansoor Raza Mirza, Ignacio Romero, Peter Vuylsteke, Robert L. Coleman, Felix Hilpert, Amit M. Oza, Anneke Westermann, Martin K. Oehler, Sandro Pignata, Carol Aghajanian, Nicoletta Colombo, Esther Drill, David Cibula, Kathleen N. Moore, Janna Christy-Bittel, Josep M. del CampoRegina Berger, Christian Marth, Jalid Sehouli, David M. O’Malley, Cristina Churruca, Adam P. Boyd, Gunnar Kristensen, Andrew Clamp, Isabelle Ray-Coquard, Ignace Vergote

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 5 341; 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.
Original languageEnglish
Pages (from-to)3753-3762
Number of pages10
JournalJournal of clinical oncology
Volume38
Issue number32
DOIs
Publication statusPublished - 10 Nov 2020

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