Approximately one-third of patients with unresectable or metastatic melanoma and a BRAF V600E or V600K mutation may experience improved long-term outcomes with first-line dabrafenib plus trametinib treatment, a study in the New England Journal of Medicine suggests.1
Extended-survival data from the COMBI-d2 and COMBI-v3 trials were assessed in this pooled analysis. Patients in the two trials had previously untreated unresectable or metastatic melanoma and a BRAF V600E or V600K mutation. Trial participants were randomly assigned to either twice-daily dabrafenib at 150 mg per dose plus once-daily trametinib at 2 mg per dose or placebo (COMBI-d) or twice-daily vemurafenib at 960 mg per dose (COMBI-v). Progression-free survival (PFS) and overall survival (OS) comprised the primary endpoints in the COMBI-d and COMBI-v trials, respectively. Overall, the median follow-up duration was 22 months (range, 0-76).
A total of 563 patients were included in both trials, with 211 patients in the COMBI-d trial and 352 in the COMBI-v trial who were randomly assigned to the dabrafenib and trametinib combination. The overall rates of PFS were 21% (95% CI, 17-24) and 19% (95% CI, 15-22) at 4 years and 5 years, respectively. At 4 years and 5 years, the OS rates were 37% (95% CI, 33-42) and 34% (95% CI, 30-38), respectively.
In the multivariate analysis of baseline factors, PFS was associated with Eastern Cooperative Oncology Group performance status score (0 vs ≥1; hazard ratio [HR], 0.68; 95% CI, 0.55-0.85; P <.001), age (10-year increment; HR, 0.92; 95% CI, 0.85-0.99; P =.02), sex (female vs male; HR, 0.74; 95% CI, 0.61-0.90; P =.003), number of organ sites with metastasis (<3 sites vs ≥3 sites; HR, 0.72; 95% CI, 0.58-0.91; P =.005), and lactate dehydrogenase level (normal vs elevated; HR, 0.50; 95% CI, 0.40-0.64; P <.001).
Similarly, OS was also associated with Eastern Cooperative Oncology Group performance status score (0 vs ≥1; HR, 0.49; 95% CI, 0.39-0.62; P <.001), age (10-year increment; HR, 0.92; 95% CI, 0.85-1.00; P =.04), sex (female vs male; HR, 0.68; 95% CI, 0.55-0.84; P <.001), number of organ sites with metastasis (<3 sites vs ≥3 sites; HR, 0.58; 95% CI, 0.46-0.74; P <.001), and lactate dehydrogenase level (normal vs elevated; HR, 0.47; 95% CI, 0.37-0.61; P <.001).
Approximately 19% (n=109) of patients had a complete response which was associated with an improved long-term outcome and an OS rate of 71% (95% CI, 62-79) at 5 years. The majority of patients (98%) reported adverse events; however, no reports of unexpected events were found.
A limitation of the trials was the lack of availability of biomarkers that may predict disease progression in patients who discontinue the studied therapy.
Based on their findings, the researchers concluded that achievement of “a complete response to the combined treatment appears to be a strong and early predictor of prolonged benefit.”
Disclosure: This clinical trial was supported by GlaxoSmithKline and Novartis. Please see the original reference for a full list of authors’ disclosures.
1. Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381(7):626-636.
2. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877-1888.
3. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39.