On April 30, 2018 the FDA approved the combination of TAFINLAR® (dabrafenib) and MEKINIST® (trametinib) for the adjuvant treatment of patients with completely resected stage III melanoma whose tumors harbor a BRAF V600E or V600K mutation . Both dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, are tyrosine kinase inhibitors (TKIs) that block the cellular proliferation- and survival-supporting, mitogen-activated protein kinase (MAPK) pathway. Activating BRAF mutations are found in about 50% of melanoma samples, resulting in constitutive activation of the MAPK pathway; thus, BRAF and MEK inhibitors have been developed to treat BRAF-mutant-positive cancers . BRAF V600E and V600K are the most common BRAF mutations found in melanoma, and the combination of dabrafenib and trametinib has exhibited anti-tumor efficacy in patients with BRAF V600E/K-positive unresectable or metastatic melanoma [3, 4]. The combination has already been approved by the FDA for the treatment of unresectable or metastatic BRAF V600E/K-positive melanoma and metastatic BRAF V600E-positive non-small cell lung cancer .
The FDA approved the combination as an adjuvant treatment based on the results of a randomized phase 3 study investigating dabrafenib and trametinib vs. placebo as an adjuvant treatment for patients with completely resected, stage III BRAF V600E/K-positive melanoma (NCT01682083) . The estimated 3-year rate of relapse-free survival was enhanced in the arm receiving the combination at 58% vs. 39% respectively . The 3-year overall survival rate was also improved by the combination therapy with 86% survival and 77% survival, respectively. No new safety concerns were identified with the combination therapy in this patient population. This approval provides a therapeutic option for patients undergoing stage III melanoma resection whose tumors harbor BRAF V600E/K mutations.
–Zachary Moore, on behalf of the Medical Content Team
- TAFINLAR® (dabrafenib) capsules, for oral use Drugs@FDA: FDA Approved Drug Products 04/30/2018 [cited 2018 May 7]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202806s008lbl.pdf.
- Long, G.V., et al., Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol, 2011. 29(10): p. 1239-46.
- Long, G.V., et al., Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med, 2014. 371(20): p. 1877-88.
- Robert, C., et al., Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med, 2015. 372(1): p. 30-9.
- A Study of the BRAF Inhibitor Dabrafenib in Combination With the MEK Inhibitor Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection. (COMBI-AD). ClinicalTrials.gov May 8, 2018 [cited 2018 May 8]; Available from: https://clinicaltrials.gov/ct2/show/NCT01682083.
- Long, G.V., et al., Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med, 2017. 377(19): p. 1813-1823.