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The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended approval of the combination of dabrafenib and trametinib for the adjuvant treatment of adult patients with BRAF V600E– or V600K–positive stage III melanoma following complete resection.
Axel Hauschild, MD, PhD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) for the adjuvant treatment of adult patients with BRAF V600E— or V600K–positive stage III melanoma following complete resection.
The CHMP recommendation is based on findings from the phase III COMBI-AD study, in which 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 3-year relapse-free survival (RFS) rate with dabrafenib and trametinib was 58% compared with 39% for placebo (HR, 0.47; 95% CI, 0.39-0.58; P <.001).
The dabrafenib/trametinib application will now be reviewed by the European Commission for a final decision on whether the regimen will be approved for this indication in the European Union.
“These relapse-free survival results are unprecedented," COMBI-AD lead investigator Axel Hauschild, MD, PhD, professor of Dermatology, University Hospital Schleswig-Holstein, in Kiel, Germany, said in a statement.
"The overall survival improvements also demonstrated by Tafinlar in combination with Mekinist, among other key secondary endpoints, are encouraging in the treatment of stage III BRAF V600E/K mutation—positive melanoma. Adjuvant treatment options are critical for this patient community at risk for recurrence," added Hauschild.
The COMBI-AD study randomized 870 patients with BRAF V600E/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.
The median RFS was not reached with the combination versus 16.6 months for placebo. 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% and the 2-year rates were 67% versus 44% for dabrafenib and 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.