MEK Inhibition in BRAF-Mutated Melanoma

Until recently, there was no systemic therapy shown to improve overall survival among patients with metastatic melanoma, and only modest improvements were observed with interferon as an adjuvant drug. Ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and vemurafenib, a selective BRAF inhibitor, have both been shown to improve survival among patients with metastatic melanoma in randomized trials; however, the response has been limited. Activating mutations in serine-threonine protein kinase B-RAF (BRAF), a constituent of the MAP kinase signal-transduction pathway, have been identified in approximately 50% of patients with advanced melanoma. Activated BRAF phosphorylates activate MEK proteins (MEK1 and MEK2), which then activate downstream MAP kinases. The MAP kinase pathway is known to regulate proliferation and survival of tumor cells in many cancers.

 In this study [N Engl J Med. 2012;10.1056/NEJMoa1203421], a phase 3 open-label trial, a total of 322 eligible patients (281 with the V600E mutation, 40 with the V600K mutation, and 1 with both mutations) were assigned in a 2:1 ratio to receive oral trametinib (2 mg once daily) or intravenous chemotherapy consisting of either dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients who had histologically confirmed, unresectable stage IIIC or IV cutaneous melanoma with a V600E or V600K BRAF mutation were eligible for the study, in which investigators screened 1022 patients for V600E and V600K BRAF mutations in 103 centers worldwide between December 2010, and July 2011. Additional eligibility criteria were ≥18 years of age, measurable disease, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (fully active) or 1 (ambulatory, but restricted in physically strenuous activity), and adequate organ function.

Patients could have received 1 previous chemotherapy regimen for advanced or metastatic melanoma, with the exclusion of BRAF and MEK inhibitors and ipilimumab. Patients with stable brain metastases were allowed to enroll. Primary end point was progression-free survival; secondary end points included overall survival, overall response rate, duration of response, and safety.

There were 214 patients in the trametinib group and 108 in the chemotherapy group. There were no significant differences between groups at baseline, although more patients in the trametinib group had M1c disease (metastasis to sites beyond skin, lymph node, and lung). A total of 195 patients (61%) had disease progression or had died at the time of primary analysis.

In the intention-to-treat population, median duration of progression-free survival was 4.8 months in the trametinib group compared with 1.5 months in the chemotherapy group (hazard ratio for progression, 0.45; 95% confidence interval [CI], 0.33-0.63; P<.001). In the intention-to-treat population, there were 35 deaths (16%) in the trametinib group and 29 (27%) in the chemotherapy group at the time of data cutoff. The 6-month overall survival rate in the intention-to-treat population was 81% in the trametinib group and 67% in the chemotherapy group, findings that were identical to those in the primary efficacy population. The hazard ratio for death in the trametinib group was 0.54 (95% CI, 0.32-0.92; P=.01), even though 51 of 108 patients (47%) in the chemotherapy group crossed over to receive trametinib.

The most common adverse events in the trametinib group were rash, diarrhea, peripheral edema, fatigue, and dermatitis acneiform; among the patients with rash, <8% had grade 3 or 4 rash. A decreased ejection fraction or ventricular dysfunction was observed in 14 patients in the trametinib group (11 with a decreased ejection fraction and 3 with left ventricular dysfunction).