Advanced Melanoma: MEK Inhibitor Trametinib Tops Chemotherapy

The oral selective MEK inhibitor trametinib improved progression-free and overall survival over chemotherapy in patients with metastatic melanoma with a BRAF mutation, according to a new phase III trial.

Chemical structure of trametinib

Approximately 50% of patients with advanced melanoma have activating BRAF mutations, with the V600E and V600K mutations representing the bulk of those. BRAF inhibitors have been shown to improve survival, but the responses tend to be short-lived. Investigators led by Keith T. Flaherty, MD, of Massachusetts General Hospital Cancer Center in Boston, conducted an open-label, randomized trial of 322 patients with either of the two common BRAF mutations. A total of 214 patients received oral trametinib 2 mg once daily, and 108 patients received IV chemotherapy consisting of either dacarbazine or paclitaxel. The results were published in the New England Journal of Medicine.

The median duration of progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group, yielding a hazard ratio (HR) for progression of 0.45 with trametinib (95% CI, 0.33-0.63; P < .001). Among a primary efficacy population of 273 patients with the V600E mutation and no brain metastases at baseline the results were similar. Progression-free survival improvements were seen among all patients except those with the less common V600K mutation, and among those aged 65 years and older.

A total of 35 patients died in the trametinib group (16%), compared with 29 patients in the chemotherapy group (27%). At 6 months, the overall survival rates were 81% for trametinib-treated patients and 67% for chemotherapy-treated patients, for a HR of 0.54 (95% CI, 0.32-0.92; P = 0.01). That improved survival remained even though almost half (47%) of chemotherapy patients crossed over and received trametinib, as allowed by the study design.

Response rates were also better among trametinib patients. Of those who received trametinib, 22% achieved a complete or partial response, compared with 8% in the chemotherapy group (P = .01). The median response duration was 5.5 months for trametinib patients, and it had not yet been reached in 9 chemotherapy patients.

The investigators wrote that trametinib shows similar improvements to another targeted agent, the BRAF inhibitor vemurafenib. “Although the response rate associated with trametinib appears to be inferior to that with vemurafenib, the two agents appear to provide similar improvements in progression-free and overall survival, as compared with chemotherapy,” they wrote. The molecular mechanism that might explain a lower response rate remains unknown.

Further studies are needed to determine which of these drugs are superior, and trials are also ongoing that will examine the potential for improved response when the two are combined.

In an accompanying editorial in the New England Journal of Medicine, Edward A. Sausville, MD, PhD, of the University of Maryland School of Medicine, stressed the importance of drugs that target the RAS-RAF-MEK pathway. “We also need to maximize the promise of MEK inhibition by using trametinib perhaps in combination with other pathway inhibitors to define its potential value in tumors without a BRAF mutation but with MEK activation by other routes,” he wrote.