Array BioPharma has withdrawn its new drug application (NDA) for the MEK inhibitor binimetinib as a treatment for patients with NRAS
-mutant advanced melanoma, based on feedback from the FDA during a preplanned review meeting.
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); however, overall survival (OS) was not improved with the MEK inhibitor.
"This action was based on thorough discussions and communications with the FDA, including exploration of various paths to approval, and followed the late cycle review meeting held with the FDA on Friday, March 17, 2017," the company said in a statement. "Based on feedback from the agency, Array concluded that the clinical benefit demonstrated in the phase III NEMO clinical trial would not be found sufficient to support approval of the NRAS-mutant melanoma NDA."
In addition to NRAS
-mutated tumors, binimetinib was also explored in combination with the BRAF inhibitor encorafenib as a treatment for BRAF
-mutant melanoma in the phase III COLUMBUS trial. The median PFS with the combination by independent review was 14.9 months with encorafenib plus binimetinib versus 7.3 months for vemurafenib (HR, 0.54; 95% CI, 0.41-0.71; P
The withdrawal of the NRAS
-mutant application will not impact the filing of data for an NDA from the COLUMBUS trial, Array noted in the statement. This application is anticipated by the middle of 2017.
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 objective response rate (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.
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.
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).