Binimetinib Delayed Progression of NRAS-Mutant Melanoma

The MEK inhibitor binimetinib improved progression-free survival compared with dacarbazine in patients with NRAS-mutant melanoma, according to the phase III results of the NEMO trial published in Lancet Oncology.

In addition, improved progression-free survival was seen in patients who had previously failed immunotherapy, the current guideline-recommended first-line treatment.

“Future treatment algorithms for metastatic melanoma might incorporate binimetinib therapy in patients with advanced NRAS-mutant melanoma, including after the failure of immunotherapy,” wrote Reinhard Dummer, MD, of the department of dermatology at the University Hospital Zurich Skin Cancer Center in Switzerland, and colleagues.

Patients with NRAS-mutant melanoma appear to have more aggressive disease than patients with BRAF mutations, and there are currently no established therapies for this disease subtype. Recent advances with immunotherapy in certain subtypes of melanoma have not been seen in patients with NRAS mutations.

In this study, Dummer and colleagues compared the efficacy of binimetinib with dacarbazine in patients with treatment-naive disease or those who had previously received immunotherapy. The trial included 402 patients with NRAS-mutant disease who were randomly assigned 2:1 to binimetinib 45 mg orally twice daily or dacarbazine 1,000 mg/m² intravenously every 3 weeks.

“Progression-free survival was longer for patients who received binimetinib than for those who received dacarbazine; this was consistent in almost all subgroups analyzed, including in patients who received previous immunotherapy and in patients with characteristics associated with an unfavorable prognosis, such as stage M1c disease or elevated lactate dehydrogenase serum concentrations,” the researchers wrote.

With a median follow-up of 1.7 months, the median progression-free survival was 2.8 months for patients assigned binimetinib compared with 1.5 months for patients assigned dacarbazine (hazard ratio [HR], 0.62; 95% CI, 0.47–0.80; one-sided P < .001). Median follow-up for overall survival was 9.2 months. At the survival analysis, the median overall survival was 11.0 months for binimetinib compared with 10.1 months for dacarbazine.

Treatment with binimetinib was associated with a higher overall response rate compared with dacarbazine (41% vs 9%; P = .015). The median duration of objective response was 6.9 months for binimetinib and could not be estimated for dacarbazine.

Finally, a similar number of patients in each arm had prior treatment with an immunotherapy drug. Among these patients, the median progression-free survival was 2.8 months for patients assigned binimetinib compared with 1.5 months for those assigned dacarbazine.

Grade 3/4 adverse events seen in either group included increased creatine phosphokinase (19% for binimetinib vs 0% for dacarbazine), hypertension (7% vs 2%), anemia (2% vs 5%), and neutropenia (1% vs 9%). Thirty-four percent of patients assigned binimetinib experienced a serious adverse event of any grade compared with 22% of patients assigned dacarbazine.

In an editorial that accompanied the research, Michael A. Postow, MD, and Paul B. Chapman, MD, both of Memorial Sloan Kettering Cancer Center in New York, wrote: “Overall, the NEMO study should be viewed as a success for the melanoma field, which was able to conduct the first randomized trial in patients molecularly selected for NRAS mutations, an underserved patient population in need of novel therapeutics. After initial immunotherapy, MEK inhibition might ultimately have a role in treating NRAS-mutated melanoma. However, combining MEK inhibitors with other molecular inhibitors and immunotherapy will likely be necessary to establish MEK inhibition in the treatment of NRAS-mutant melanoma.”