Improved Overall Survival in Metastatic Melanoma With First-Line Dabrafenib Plus Trametinib
In a phase III study reported in The New England Journal of Medicine, Robert et al found that the combination of the BRAF inhibitor dabrafenib (Tafinlar) plus the MEK inhibitor trametinib (Mekinist) significantly improved overall survival compared with the BRAF inhibitor vemurafenib (Zelboraf) in patients with BRAF-mutant metastatic melanoma. The trial was stopped after a preplanned interim analysis of overall survival established efficacy of the combination. This trial adds to other recent phase III studies showing benefit of combined BRAF and MEK inhibition in this setting.
Study Details
In this open-label trial, 704 patients with previously untreated metastatic melanoma with a BRAF V600 mutation were randomly assigned to receive dabrafenib at 150 mg twice daily plus trametinib 2 mg once daily (n= 352) or vemurafenib at 960 mg twice daily (n = 352). Patients were stratified for V600E vs V600K BRAF mutation and lactate dehydrogenase (LDH) level. The primary endpoint was overall survival.
The combination and vemurafenib groups were generally balanced for age (median, 55 and 54 years), sex (59% and 51% male), previous immunotherapy (17% and 26%), Eastern Cooperative Oncology Group (ECOG) performance status (0 for 71% and 70%, 1 for 29% and 30%), BRAF V600E mutation (90% in both), tumor stage (IVM1c in 63% and 59%; IIIc, IVM1a, or IVM1b in 37% and 41%), metastasis stage (M0 in 4% and 7%, M1a in 16% and 14%, M1b in 17% and 19%, M1c in 63% and 59%), LDH > upper limit of normal (34% and 32%), visceral disease (79% and 77%), and number of disease sites (fewer than three in 50% and 57%).
Overall Survival
At the interim overall survival analysis, performed after 77% of the expected events had occurred, 1-year overall survival was 72% (95% confidence interval [CI] = 67%–77%) in the dabrafenib/trametinib group vs 65% (95% CI = 59%–70%) in the vemurafenib group (hazard ratio [HR] = 0.69, 95% CI = 0.53–0.89, P = .005). The prespecified stopping boundary (P < .0214) was crossed and the trial was stopped early. Median overall survival was not reached vs 17.2 months. In subgroup analyses, HRs favored the combination in subgroups according to age, sex, V600E and V600K mutation, tumor stage, LDH level, number of disease sites, and in the subgroup with ECOG performance status of 0 but not in the subgroup with performance status of 1.
Progression-Free Survival and Response Rates
Median progression-free survival was 11.4 months vs 7.3 months (HR = 0.56, P < .001), with HRs favoring the combination in all subgroups. The objective response rate was 64% vs 51% (P < .001), including complete response in 13% vs 8%; median duration of response was 13.8 vs 7.5 months. Response rates were 64% vs 52% in patients with the V600E mutation and 65% vs 44% in those with the V600K mutation.
Anticancer therapy after study therapy was given to 20% of patients in the combination group and 43% of patients in the vemurafenib group, with the most common treatment being ipilimumab (12% and 22%).
Adverse Events
The most common adverse events of any grade were pyrexia (53%), nausea (35%), diarrhea (32%), chills (31%), fatigue (29%), headache (29%), and vomiting (29%) in the combination group and arthralgia (51%), rash (43%), alopecia (39%), diarrhea (38%), nausea (36%), and fatigue (33%) in the vemurafenib group. Cutaneous squamous cell carcinoma (including keratoacanthoma) occurred in 1% of the combination group vs 18% of the vemurafenib group. Grade 3 or 4 adverse events occurred in 52% vs 63%. The most common grade 3 events in the combination group were decreased left ventricular ejection fraction (4%, 8% any grade, vs 0% in vemurafenib group) and pyrexia (4%), and the most common in the vemurafenib group were cutaneous squamous cell carcinoma or keratoacanthoma (17% vs 1% in combination group), rash (9%), and arthralgia (4%). New primary melanoma was reported in two patients (1%) vs 7 patients (2%).
Grade 4 events occurred in three combination group patients (headache, asthenia, and elevated AST) and five vemurafenib patients (hypertension, constipation, elevated ALT, and squamous cell carcinoma). Grade 5 events occurred in three combination group patients (cerebral hemorrhage in two, brain-stem hemorrhage in one) and in three patients in the vemurafenib group (acute coronary syndrome, cerebral ischemia, pleural infection).
Adverse events led to dose reduction in 33% (pyrexia in 14%) vs 39% (rash in 11%) of patients, dose interruption in 55% (pyrexia in 30%) vs 56% (rash in 14%), and treatment discontinuation in 13% (pyrexia and reduced ejection fraction in 3% each) vs 12% (arthralgia in 2%).
The investigators concluded: “Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity.”
Caroline Robert, MD, PhD, of Gustave Roussy, Villejuif Cedex, France, is the corresponding author for The New England Journal of Medicine article.
The study was funded by GlaxoSmithKline. For full disclosures of the study authors, visit www.nejm.org.
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