Five-Year Survival Rates with BRAF-MEK Inhibitors in Metastatic Melanoma with BRAF Mutation
The introduction of BRAF– and MEK-targeted therapies and immune checkpoint inhibitors has significantly improved outcomes in patients with metastatic melanoma. However, many patients have drug resistance—acquired or primary—which results in death from underlying disease.
The COMBI-d and COMBI-v studies evaluated the efficacy and safety of the BRAF inhibitor dabrafenib (Tafinlar) plus the MEK inhibitor trametinib (Mekinist) versus BRAF inhibitor monotherapy in patients with unresectable or metastatic melanoma and BRAF V600E or V600K mutation. In a new study, researchers analyzed the 5-year outcomes of patients who received dabrafenib plus trametinib in these 2 clinical trials (Robert C, et al. N Engl J Med. 2019;381:626-636).
The researchers pooled 5-year survival data for 563 patients in COMBI-d (N = 211) or COMBI-v (N = 352). COMBI-d was a randomized, double-blind, phase 3 clinical trial comparing dabrafenib plus trametinib with dabrafenib plus placebo. COMBI-v was an open-label, randomized, phase 3 clinical trial comparing dabrafenib plus trametinib versus vemurafenib (Zelboraf). Both studies stratified patients by their BRAF genotype and baseline lactate dehydrogenase concentration.
The new study evaluated patients with metastatic melanoma and BRAF V600E or V600K mutation who had been randomized to dabrafenib and trametinib. The primary end points were progression-free survival (PFS) and overall survival (OS) in the COMBI-d and COMBI-v studies, respectively. The median follow-up was 22 months.
The PFS rates were 21% at 4 years and 19% at 5 years, and the OS rates were 37% at 4 years and 34% at 5 years. A multivariate analysis identified several baseline factors that were significantly associated with PFS and OS in both studies, including performance status, age, sex, number of metastatic organ sites, and lactate dehydrogenase level.
In all, 68% of patients demonstrated an objective response rate to treatment with dabrafenib plus trametinib. A complete response was observed in 109 (19%) patients and was associated with improved long-term outcomes, with a 5-year OS rate of 71% and a 5-year PFS rate of 49%.
No unexpected adverse events were reported with extended follow-up. Adverse events led to 18% of patients permanently discontinuing the study regimen.
“Having a complete response to the combined treatment appears to be a strong and early predictor of prolonged benefit,” concluded the researchers. “However, no biomarkers are currently available to determine which patients who discontinue therapy are likely to have disease progression.”