The European Commission has approved the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) for the adjuvant treatment of patients with BRAF V600–positive stage III melanoma.
The European Commission has approved the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) for the adjuvant treatment of patients with BRAF V600—positive stage III melanoma following complete resection, according to Novartis, the manufacturer of both agents.
The approval is based on findings from the phase III COMBI-AD study, in which the primary analysis showed that adjuvant treatment with dabrafenib and trametinib reduced the risk of relapse or death by 53% compared with placebo for patients with BRAF-mutant stage III melanoma.1,2 After a median follow-up of 2.8 years, the median relapse-free survival (RFS) was not reached with the combination versus 16.6 months for placebo (HR, 0.47; 95% CI, 0.39-0.58; P <.001).
"Novartis's deep therapeutic knowledge and our ability to apply novel approaches to the development of new medicines has resulted again in a new treatment advance for melanoma patients," Liz Barrett, CEO, Novartis Oncology, said in a statement." The European approval of the Tafinlar and Mekinist combination illustrates Novartis's continued efforts to reimagine cancer by providing a highly effective, targeted therapy for earlier-stage melanoma patients."
The COMBI-AD study randomized 870 patients with BRAFV600E/K stage III melanoma to receive dabrafenib plus trametinib (n = 438) or placebo (n = 432). All patients were within 12 weeks of complete surgical resection and had stage IIIa (18%), IIIb (41%), and IIIc (40%) disease. Dabrafenib was given at 150 mg twice daily with trametinib at 2 mg once daily for 12 months. The salvage therapies received following the study were similar in each arm, and, in some cases, included a rechallenge with BRAF/MEK inhibition.
The baseline characteristics were similar between groups. In the combination arm, the median age of patients was 50 years and 91% of tumors had the BRAF V600E mutation with the remainder having the V600K alteration. Most patients (92%) had an ECOG performance status of 0. Twelve percent of patients in the combination group had in-transit metastases versus 8% with the placebo. Seventeen percent of patients had ≥4 positive lymph nodes, with the remainder having <4.
RFS was improved with dabrafenib/trametinib across all subgroups. Hazard ratios across all subgroups ranged from 0.33 to 0.55 in favor of dabrafenib and trametinib versus placebo.
Early data for overall survival (OS) showed that 86% of patients in the combination arm were alive at 3 years versus 77% with placebo (HR, 0.57; 95% CI, 0.42-0.79; P = .0006). At the interim analysis, the OS advantage was not yet deemed statistically significant, according to predefined criteria that required a P value of .000019.
The 1-year OS rates were 97% versus 94% and the 2-year OS rates were 91% and 83% for the combination and placebo groups, respectively. The 1-year RFS rates were 88% versus 56%, the 2-year rates were 67% versus 44%, and the 3-year rates were 59% versus 40% for dabrafenib/trametinib versus placebo, respectively. The most common locations of recurrence, for the combination and placebo, respectively, were locoregional (12% vs 25%), distant (22% vs 29%), and both local and distant (2% vs 2%).
The risk of distant metastases or death was reduced by 49% with the combination versus placebo (HR, 0.51; 95% CI, 0.40-0.65). Additionally, there was a 53% improvement in freedom from recurrence with the combination (HR, 0.47; 95% CI, 0.39-0.57).
Adverse events (AEs) were experienced by 97% of those treated with dabrafenib and trametinib versus 88% with placebo. The rates of grade 3/4 AEs were 41% and 14% for the combination and placebo, respectively. Overall, AEs led to discontinuation for 26% of those in the combination arm versus 3% with placebo. The most common all-grade AEs, which were mostly grade 1/2, with the combination were pyrexia (63%), fatigue (47%), and nausea (40%). There were no fatal adverse events with the combination of dabrafenib and trametinib.