Binimetinib Improves PFS in NRAS-Mutated Metastatic Melanoma


The MEK inhibitor binimetinib resulted in improved progression-free survival and response rates vs dacarbazine in patients with NRAS-mutated metastatic melanoma.

The novel MEK inhibitor binimetinib resulted in improved progression-free survival (PFS) and response rates vs dacarbazine in patients with NRAS-mutated advanced unresectable/metastatic melanoma, according to results of an open-label phase III trial.

NRAS mutations are present in approximately 20% of all patients with metastatic melanoma,” said Reinhard Dummer, MD, of the University Hospital Zurich in Switzerland. “It activates the MAPK pathway and by this drives cell proliferation and anti-apoptotic mechanisms.” Preclinical studies have shown that NRAS-mutant melanoma is sensitive to MEK inhibition, and binimetinib inhibits both MEK1 and MEK2. A phase II study showed clinical activity in NRAS-mutant metastatic melanoma.

The NEMO trial included 402 patients randomized 2:1 to receive either binimetinib (269 patients) or dacarbazine (133 patients; 19 were not treated and were not evaluated for safety). Patients were either treatment-naive or had progressed on or after immunotherapy. The primary endpoint of the study was PFS. The results were presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting held earlier this month in Chicago (abstract 9500).

The median duration of exposure was 13 weeks with binimetinib and 9 weeks with dacarbazine. The median PFS with binimetinib was 2.8 months, compared with 1.5 months with dacarbazine, for a hazard ratio (HR) of 0.62 (95% CI, 0.47–0.80; P < .001).

Dummer said nearly every subgroup analyzed showed a PFS advantage with binimetinib. It was better than dacarbazine in both older (65 years and above) patients and younger patients in two lactate dehydrogenase categories, among others, though in some cases the benefit was not significant. A larger benefit was seen with binimetinib in those with metastases in at least three organs (HR, 0.4 [95% CI, 0.3–0.6]) vs those with two or fewer metastases (HR, 0.9 [95% CI, 0.6–1.3]). Though it did not reach significance, the HR favored dacarbazine in patients without visceral disease, while it significantly favored binimetinib in those with visceral disease.

Patients who had previously been treated with immunotherapy had a median PFS of 5.5 months with binimetinib, compared with 1.6 months with dacarbazine. The difference was not as stark in those with no prior immunotherapy treatment, at 2.8 months with binimetinib and 1.5 months with dacarbazine. “There is a suggestion that patients do better if they are pretreated with immunotherapy,” Dummer said.

The overall response rate was 15% with binimetinib and 7% with dacarbazine. The disease control rate was substantially better with the study drug, at 58% compared with 25% with dacarbazine.

Dummer cautioned that the overall survival data remain very immature at the time of presentation, but said that so far the median with binimetinib is 11.0 months, compared with 10.1 months with dacarbazine. That yields an HR of 1.00 (95% CI, 0.75–1.33; P = .499).

In the binimetinib patients, 68% had at least one grade 3/4 adverse event; in the dacarbazine group, this rate was 46%. Cutaneous toxicities are common with MEK inhibitors, and 19% of binimetinib patients had increased blood creatine phosphokinase. Twenty-five binimetinib patients discontinued treatment due to an adverse event, compared with 8 patients treated with dacarbazine.

“Based on these data, I think this is a new treatment option for patients with NRAS-mutated melanoma that failed immunotherapy,” Dummer concluded.

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