FDA Accepts Binimetinib NDA for NRAS-Mutant Melanoma

The FDA has assigned a standard review designation to a new drug application for binimetinib as a treatment for patients with NRAS-mutant advanced melanoma.

Victor Sandor, MD

The FDA has assigned a standard review designation to a new drug application (NDA) for binimetinib as a treatment for patients with NRAS-mutant advanced melanoma, according to a statement from the developer of the MEK inhibitor, Array BioPharma.

The application for binimetinib was based on data from the phase III NEMO study, which was presented at the 2016 ASCO Annual Meeting. In the open-label study, median progression-free survival (PFS) with binimetinib was 2.8 versus 1.5 months with dacarbazine, representing a 38% reduction in the risk of progression or death (HR, 0.62; 95% CI, 0.47-0.80; P <.0001).

Under the Prescription Drug User Fee Act, the agency is scheduled to make a decision on the NDA by June 30, 2017. Additionally, while accepting the application, the agency advised Array BioPharma of plans to call an Oncologic Drugs Advisory Committee (ODAC) meeting as part of the review process, to discuss the drug's risks and benefits. A date for this meeting has not yet been scheduled.

"There are very few treatment advances beyond immunotherapy for this devastating disease, which impacts one out of five advanced melanoma patients," Victor Sandor, MD, chief medical officer, Array BioPharma, said in a statement. "Binimetinib is the first and only MEK inhibitor to demonstrate improvement on progression-free survival in a phase III trial for NRAS-mutant melanoma patients."

In the NEMO study, 402 patients were randomized in a 2:1 ratio to receive 45 mg of binimetinib twice daily (n = 269) or 1,000 mg/m2 of dacarbazine every 3 weeks (n = 133). Patients in the study had stage IIIC, IVM1a, and IVM1b NRAS Q61-mutant melanoma, and may have received prior treatment with immunotherapy. Patients with untreated CNS metastases and those who received a prior MEK inhibitor were excluded from the trial.

In the binimetinib and dacarbazine arms, respectively, patients were aged 65 and 62 years, and most were male (62% and 64%). The most common ECOG performance status in both arms was 0 (72%). LDH levels were greater than the upper limit of normal for a quarter of patients in each arm. Twenty-one percent of patients had received prior immunotherapy, primarily ipilimumab (13%).

The primary endpoint of the study was PFS by blinded independent review. Secondary outcome measures focused on overall survival (OS), objective response rate (ORR), and safety.

The ORR with binimetinib was 15%, including 1 complete response, compared with 7% for dacarbazine. When adding those with stable disease to ORR, the disease control rate was 58% with the targeted therapy versus 25% with dacarbazine. The median duration of response was 6.9 months with binimetinib and was not evaluated with dacarbazine.

The median OS with binimetinib was 11.0 months compared with 10.1 months with dacarbazine (HR, 1.00; 95% CI, 0.75-1.33; P = .4); however, these data were still being fully analyzed. Following the trial, 46% of those in the binimetinib arm and 44% of patients in the dacarbazine arm went on to receive immunotherapy, which was most commonly ipilimumab.

The PFS benefits associated with binimetinib versus dacarbazine were observed across patient populations, except for those with ECOG performance status 1 (HR, 1.0; 95% CI, 0.6-1.6) and those without visceral disease (HR, 1.3; 95% CI, 0.6-2.6). The greatest benefit was seen for those with metastases in ≥3 organs (HR, 0.4; 95% CI, 0.3-0.6).

Median PFS was greater in patients treated with prior immunotherapy. In those pretreated with immunotherapy, the median PFS was 5.5 months with binimetinib versus 1.6 months with dacarbazine. Patients treated with other frontline therapies other than immunotherapy experienced a median PFS that was similar to the full trial (2.8 vs 1.5 months).

All patients in the binimetinib arm experienced adverse events (AEs) compared with 91% of those in the dacarbazine group. Grade 3/4 AEs were experienced by 68% of those in the targeted therapy arm versus 46% in the dacarbazine group.

The most common all-grade AEs with binimetinib were CPK elevation (42%), diarrhea (40%), peripheral edema (36%), dermatitis acneiform (35%), nausea (29%), fatigue (22%), vomiting (21%), and asthenia (18%). AEs leading to discontinuation occurred in 25% of patients in the binimetinib arm, and included ejection fraction decrease (4%), blood CPK increase (2%), and retinal vein occlusion (2%). AEs led to discontinuation for 8% of those in the dacarbazine arm.

In addition to NRAS-mutated tumors, binimetinib is also under exploration as a treatment for BRAF-mutant melanoma. The phase III COLUMBUS trial is currently exploring the combination binimetinib and the BRAF inhibitor encorafenib compared with the BRAF inhibitor vemurafenib alone or encorafenib alone. The trial has fully enrolled approximately 900 participants, and results are anticipated in 2016.

Dummer R, Schadendorf D, Ascierto PA, et al. Results of NEMO: A phase III trial of binimetinib (BINI) vs dacarbazine (DTIC) in NRAS-mutant cutaneous melanoma. J Clin Oncol. 2016;34 (suppl; abstr 9500).