As reported in the Journal of Clinical Oncology by Bradley J. Monk, MD, and colleagues, the phase III MEK Inhibitor in Low-Grade Serous Ovarian Cancer (MILO)/ARRAY-162-311/ENGOT-ov11 trial showed that the MEK1/2 inhibitor binimetinib did not improve progression-free survival vs physician’s choice of chemotherapy in women with recurrent or persistent low-grade serous ovarian carcinomas. The trial was stopped early due to futility.

Bradley J. Monk, MD

Study Details

In the open-label trial, a total of 303 patients from sites in 20 countries had been randomly assigned 2:1 to receive binimetinib at 45 mg twice daily (n = 201) or physician’s choice of chemotherapy (n = 102) at the time of interim analysis in January 2016.  Patients had to have recurrent measurable low-grade serous ovarian carcinomas after one or more prior platinum-based chemotherapy but three or fewer prior chemotherapy lines. The primary endpoint was progression-free survival on blinded independent central review.

Progression-Free Survival

At interim analysis, median progression-free survival was 9.1 months (95% confidence interval [CI] = 7.3–11.3 months) in the binimetinib group vs 10.6 months (95% CI = 9.2–14.5 months) in the physician’s choice group (hazard ratio [HR] = 1.21, 95% CI = 0.79–1.86). Based on a futility boundary of hazard ratio > 0.84 for the 103 events that occurred at the time of interim analysis, the futility boundary was considered crossed, indicating a low probability of reaching statistical significance in favor of binimetinib with continued follow-up. The study was thus closed early after a total of 341 patients had enrolled.

On investigator assessment, median progression-free survival was 12.5 months (95% CI = 9.1–17.7 months) vs 11.6 months (95% CI = 10.0–16.1 months), with a hazard ratio of 0.87 (95% CI = 0.56–1.34). Overall response rate was 16% vs 13% and median duration of response was 8.1 months (range = 0.03–≥ 12.0 months) vs 6.7 months (range = 0.03–≥ 9.7 months). Median overall survival was 25.33 months (95% CI = 18.46 months–not reached) vs 20.83 months (95% CI = 17.45 months–not reached), with a hazard ratio of 0.85 (95% CI = 0.49–1.48).

Results for efficacy endpoints from an updated analysis in January 2019 among the total of 334 enrolled patients were consistent with results on interim analysis. 

A post hoc analysis suggested an association of presence of a KRAS mutation and response to binimetinib. KRAS mutation was present in 32% of patients in the binimetinib group and 34% of patients in the physician’s choice group.

Presence of KRAS mutation was significantly associated with response to treatment with binimetinib (odds ratio [OR] = 3.4, P = .003) but not physician’s choice of chemotherapy (OR = 2.13, P = .2). In the binimetinib group, objective response was observed in 44% of patients with KRAS mutation vs 19% of those with wild-type KRAS (P = .004). Compared with wild-type KRAS, KRAS mutation was also associated with prolonged progression-free survival in the binimetinib group (median = 17.7 months vs 10.8 months, P = .006) but not in the physician’s choice of chemotherapy group (median = 14.6 months vs 11.5 months, P = .502).

Adverse Events

Grade ≥ 3 adverse events occurred in 76% of patients in the binimetinib group and 44% of those in the physician’s choice of chemotherapy group, with the most common in the binimetinib group being increased creatine kinase (26%). Adverse events led to treatment discontinuation in 31% vs 17% of patients, with those leading to discontinuation in five or more patients in the binimetinib group consisting of decreased ejection fraction in eight (4%), vomiting in six (3%), and intestinal obstruction and retinal vein occlusion in five patients each (2%).

The investigators concluded: “Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary endpoint, binimetinib showed activity in [patients with] low-grade serous ovarian carcinomas across the efficacy endpoints evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.”

Dr. Monk is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019, and was also supported by the National Cancer Institute, Cycle for Survival, and Ovarian Cancer Research Fund Alliance. For full disclosures of the study authors, visit ascopubs.org.