Binimetinib demonstrated activity as treatment of patients with low-grade serous ovarian carcinomas in the randomized phase 3 MILO/ENGOT-ov11 study.
Binimetinib (Mektovi), the MEK inhibitor, demonstrated activity as treatment of patients with low-grade serous ovarian carcinomas (LGSOCs) in the randomized phase 3 MILO/ENGOT-ov11 study (NCT01849874). However, the trial did not meet its primary end point of blinded independent central radiology review (BICR) progression-free survival (PFS).
The median PFS by BICR in the binimetinib arm was 9.1 months (95% CI, 7.3-11.3) compared with 10.6 (95% CI, 9.2-14.5) in the control arm (HR, 1.21; 95% CI, 0.79-1.86), in which patients received the physician’s choice of chemotherapy. Per local investigator assessment, the median PFS was 12.5 months with binimetinib (95% CI, 9.1-17.7) versus 11.6 months (95% CI, 10.0-16.1) in the chemotherapy arm (HR, 0.87; 95% CI, 0.56-1.34).
“Although the MILO/ENGOT-ov11 trial did not meet its primary end point, binimetinib did display a clinically meaningful PFS and ORR and, therefore, should be considered a viable treatment option in this setting,” the study authors, led by Bradley J. Monk, MD, wrote. “The median OS [overall survival] for patients with advanced LGSOC approaches 10 years, with patients often experiencing significant morbidity from their disease during that time. Currently, treatment options are limited for patients with this disease and few offer objective decreases in disease burden or delays in tumor progression.”
The study randomized patients 2:1 to receive either binimetinib at 45 mg twice daily (n = 201) or chemotherapy (n = 102), which was either pegylated liposomal doxorubicin (PLD), paclitaxel, or topotecan. Treatment was continued until either locally determined progressive disease, unacceptable toxicity, or inability to continue on protocol-directed treatment. Patients in the chemotherapy arm were allowed to crossover to binimetinib provided they met the eligibility requirements to do so.
At the time for data cutoff for the interim analysis, 82% of the binimetinib arm and 80% in the chemotherapy arm were alive. The median overall survival (OS) was 25.33 months (95% CI, 18.46-not reached [NR]) in the binimetinib arm versus 20.83 months (95% CI, 17.45-NR) in the chemotherapy arm (HR, 0.85; 95% CI, 0.49-1.48).
The objective response rate (ORR) by BICR was 16% with binimetinib versus 13% with chemotherapy, and the median duration of response (DOR) was 8.05 months (95% CI, 5.55-NR) versus 6.67 months (95% CI, 3.71-NR), respectively. Responses were ongoing in 23 patients from the binimetinib arm and 8 from the chemotherapy arm at the data cutoff. According to local investigator assessment, the ORR was 18% with binimetinib versus 13% with chemotherapy, and the median DOR was 15.84 months (95% CI, 10.41-NR) versus 9.89 months (95% CI, 6.41-9.89), respectively.
Upon completion of study enrollment in April 2016, patients were notified of the interim results and were allowed to continue receiving treatment should they desired to until treatment discontinuation criteria were met. At this time, crossover was stopped. Overall, 341 patients were evaluated for the updated analysis after remaining data were collected. The median PFS by BICR was 10.4 months with binimetinib (95% CI, 7.5-12.9) versus 11.5 months (95% CI, 9.9-14.8) in the chemotherapy arm (HR, 1.15; 95% CI, 0.76-1.74), and the median OS was 34.6 months with binimetinib (95% CI, 28.0-NR) versus 34.2 months (95% CI, 21.6-NR), respectively (HR, 0.93; 95% CI, 0.65-1.33). According to the updated response data by local investigator assessment, the ORR was 24% in both groups.
“It is important to note the median OS estimates in both arms increased at the follow-up analysis, possibly as a result of the instability of the median estimates at the time of the initial analysis, when the potential follow-up was substantially (3 years) shorter,” Monk et al wrote.
All consenting patients with adequate archival tissues had also undergone molecular testing (n = 215). Overall, 47 mutations were detected in at least 5% of patients. The most common mutation was KRAS, which occurred in 33% of patients and appeared to be evenly distributed in frequency among the 2 arms of the study, whereas 46 patients (32%) from the binimetinib arm and 24 patients (34%) in the chemotherapy arm had a KRASmutation.
Using an unbiased univariate analyses that evaluated the best ORR to therapy as a binary response, the KRAS mutation was significantly associated with response to binimetinib therapy (OR, 3.4; 95% CI, 1.53-7.66; P =.003) but not with chemotherapy treatment (OR, 2.13; 95% CI, 0.67-6.81; P =.2). This mutation also appeared to be associated with a prolonged PFS when binimetinib was used as treatment. The median PFS in KRAS-mutant patients who received binimetinib was 17.7 months (95% CI, 12-NR) and 10.8 months (95% CI, 5.5-16.7) in the KRAS wild-type arm (P =.006), whereas in the chemotherapy arm, the median PFS was 14.6 months (95% CI, 9.4-NA) in the KRAS-mutant group versus 11.5 months (95% CI, 5.7-26.6) in the KRAS wild-type group (P =.502).
The KRAS mutation was also significantly associated with local best response among patients treated with binimetinib who had available updated local RECIST 1.1 response and molecular data, in which 44% of KRAS-mutant patients had a complete response or partial response compared with 19% with KRAS wild-type (P=.004).
Overall, 76% of patients in the binimetinib arm versus 44% in the chemotherapy arm had experienced grade ≥ 3 adverse events (AEs). The most common grade 3 or higher AEs in the binimetinib arm included blood creatinine phosphokinase increase (26%), vomiting (10%), diarrhea (6%), and dermatitis acneiform (6%).
AEs that led to permanent treatment discontinuation occurred in 31% of the binimetinib arm versus 17% in the chemotherapy arm. Some of the most common reasons for treatment discontinuation in the binimetinib arm included decreased ejection fraction (4%), vomiting (3%), intestinal obstruction (2%), and retinal vein occlusion (2%), compared with palmar-plantar erythrodysesthesia syndrome (5%) in the chemotherapy arm. Six patients in the binimetinib arm had retinal vein occlusion, which resulted in treatment discontinuation for all 6 patients. The investigators noted that all events were resolved or resolving, and no permanent blindness or loss of vision were observed in the study.
The median duration of exposure to the study drug was 4.1 months (range, 0-24), while the median relative dose intensity was 67.6% (range, 6%-100%). The median duration of exposure in the chemotherapy arm was 4.1 months (range, 0-18), and in this group, 68% of patients received PLD, 27% paclitaxel, and 5% topotecan. The median relative dose intensity was 71.3% for topotecan, 95.9% for PLD, and 89.4% for paclitaxel.
Although the trial did not meet its primary end point, the Monk et al concluded, “binimetinib showed activity in LGSOC across the efficacy end points evaluated. Chemotherapy responses were greater than predicted. The safety results observed in this study are generally consistent with the known safety profile of binimetinib and with MEK inhibitor class effects.”
Monk BJ, Grisham RN, Banerjee S, et al. 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. Journ Clin Oncol. doi: 10.1200/JCO.20.01164