Esther Drill, Ignace Vergote, Isabelle Ray-Coquard, Andrew Clamp, Gunnar Kristensen, Adam P Boyd, Cristina Churruca, David M O'Malley, Jalid Sehouli, Christian Marth, Regina Berger, Josep M Del Campo, Janna Christy-Bittel, Kathleen N Moore, David Cibula, Bradley J Monk, Nicoletta Colombo, Carol Aghajanian, Sandro Pignata, Martin K Oehler, Anneke Westermann, Amit M Oza, Felix Hilpert, Robert L Coleman, Peter Vuylsteke, Ignacio Romero, Mansoor Raza Mirza, Elsa Kalbacher, Susana Banerjee, Rachel N Grisham
Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2021;38(32):3753-3762
PMID: 32822286
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 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 mutation might predict response to binimetinib.
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