Reinhard Dummer, MD
The MEK inhibitor binimetinib reduced the risk of progression or death by 38% compared with dacarbazine in patients with NRAS
-mutant metastatic melanoma, according to findings from the phase III NEMO study presented at the 2016 ASCO Annual Meeting.
In the open-label trial, median progression-free survival (PFS) with binimetinib was 2.8 versus 1.5 months with dacarbazine (HR, 0.62; 95% CI, 0.47-0.80; P
<.0001). The objective response rate (ORR) with binimetinib was 15%, including 1 complete response, compared with 7% for dacarbazine.
Intriguingly, 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. Array BioPharma, the company developing the MEK inhibitor, plans to submit these data to the FDA later this month, according to a statement from the company.
"Binimetinib is a new treatment option in patients with NRAS-mutated melanoma who failed immunotherapy," said lead investigator Reinhard Dummer, MD, professor, Department of Dermatology, University of Zurich Hospital. "Binimetinib significantly prolonged progression-free survival and improved response rates versus dacarbazine, it is important to see how this therapy works in patients treated with prior immunotherapy."
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), ORR, and safety.
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, explained Dummer. 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.
"This study was done between 2013 and 2015, and there were many open expanded access programs that allowed access to immunotherapy, and many of these patients have gone on to another therapy that affected this dataset [for OS]," said Dummer.
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). 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.
"The safety profile was absolutely in the range that you would expect for this type of therapy," said Dummer. “The safety was of binimetinib was consistent with other currently marketed MEK inhibitors.”
In addition to NRAS-mutated tumors, binimetinib is also under exploring 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).
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