Clinical Pearls & Morning Reports
For early-stage melanoma, surgical resection is the standard treatment and is associated with an excellent long-term prognosis, with 5-year survival rates of 98% for stage I disease and 90% for stage II disease. However, patients with stage III disease, who have regional involvement at diagnosis, are at higher risk for recurrence after locoregional resection, and many will ultimately die from metastatic melanoma. Long et al. conducted the COMBI-AD trial, a double-blind, placebo-controlled, phase 3 trial which assessed whether the combination of dabrafenib and trametinib would improve relapse-free survival, overall survival, distant metastasis–free survival, and freedom from relapse in patients with stage III melanoma and BRAF V600E or V600K mutations who had undergone complete surgical resection. Read the latest NEJM Original Article.
Q: How common are BRAF mutations in melanoma?
A: Oncogenic mutations in BRAF are found in approximately 40% of melanomas and result in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway.
Q: What systemic adjuvant therapies have been approved by the Food and Drug Administration for the treatment of melanoma?
A: Systemic adjuvant therapies that have been approved by the Food and Drug Administration for the treatment of melanoma include interferon alfa-2b and pegylated interferon, which have shown inconsistent improvements in overall survival along with substantial toxic effects, and the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab. The use of adjuvant ipilimumab has resulted in a significantly higher rate of 5-year survival than placebo (65.4% vs. 54.4%; hazard ratio, 0.72), although ipilimumab has been associated with serious adverse events that have led to early treatment discontinuation in a substantial proportion of patients and with death in 1.1% of patients.
A: In the trial by Long et al., the adjuvant use of combination therapy with dabrafenib plus trametinib for 12 months resulted in a 53% lower risk of relapse (the primary end point) than the adjuvant use of placebo at a median follow-up of 2.8 years. At 3 years, the rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group. Fewer patients had distant metastases or died in the combination-therapy group than in the placebo group (110 patients [25%] vs. 152 [35%]; hazard ratio, 0.51; 95% CI, 0.40 to 0.65; P<0.001). The estimated rate of overall survival at 3 years was 86% in the combination-therapy group and 77% in the placebo group. The between-group difference (P=0.0006) did not reach the prespecified threshold of P=0.000019 to claim statistical significance in the first interim analysis of overall survival.
A: In the COMBI-AD trial, the most common adverse events associated with combination therapy were pyrexia and fatigue, events that were similar to those reported in key trials of dabrafenib plus trametinib in patients with stage IIIC unresectable melanoma or stage IV metastatic melanoma with BRAF V600E or V600K mutations.