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The FDA has granted a priority review to a supplemental new drug application for the use of dabrafenib combined with trametinib as an adjuvant treatment for patients with BRAF V600E– or V600K–positive stage III melanoma following complete resection.
The FDA has granted a priority review to a supplemental new drug application (sNDA) for the use of dabrafenib (Tafinlar) combined with trametinib (Mekinist) as an adjuvant treatment for patients with BRAF V600E— or V600K–positive stage III melanoma following complete resection.
UPDATE 4/30/2018: FDA Approves Adjuvant Dabrafenib/Trametinib for BRAF+ Melanoma
The sNDA 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 priority review follows an FDA breakthrough therapy designation granted to the combination in October 2017 for use in this setting. Under the priority review, the FDA will issue its decision on the sNDA within 6 months of the application submission, as opposed to the 10-month standard review.
"The FDA's decision to grant Tafinlar in combination with Mekinist breakthrough therapy designation and priority review designation validates the potential of the combination to have a significant impact on the lives of melanoma patients treated in the adjuvant setting," Samit Hirawat, MD, head, Novartis Oncology Global Drug Development, the manufacturer of the two drugs, said in a statement. "There remains a need to address the high risk of recurrence seen in these patients and improve the quality of care they receive."
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.
The FDA initially granted an accelerated approval to the combination of dabrafenib and trametinib for patients with BRAF-mutant metastatic melanoma in January 2014. The combination received a full approval in November 2015, and is now also indicated for the treatment of patients with BRAF-mutant non—small cell lung cancer.