Clinical Pearls & Morning Reports
For patients with high-risk resected melanoma, immune checkpoint inhibitors and BRAF plus MEK inhibitors (dabrafenib plus trametinib) are well-established adjuvant therapies. In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with BRAF V600E or V600K mutations. Dummer et al. recently published the results of a 5-year follow-up of patients in that trial. Read the NEJM Original Article here.
Q: Is ipilimumab among the adjuvant therapies recommended for patients with high-risk resected melanoma?
A: In extended follow-up from phase 3 trials of the immune checkpoint inhibitor ipilimumab (targeting cytotoxic T-lymphocyte–associated protein 4), results in one study showed relapse-free survival in 39% of the patients and overall survival of 60% at 7 years. However, ipilimumab is no longer considered to be a standard-of-care adjuvant therapy after recent advances with anti–PD-1 and BRAF-targeted therapies.
Q: Was relapse-free survival durable at 5 years after adjuvant therapy with dabrafenib plus trametinib in patients with resected stage III melanoma with BRAF V600 mutations?
A: At 5 years, in the trial by Dummer et al., the percentage of patients who were alive without relapse was 52% (95% CI, 48 to 58) in the combination-therapy group and 36% (95% CI, 32 to 41) in the placebo group, as compared with percentages of 55% (95% CI, 50 to 60) and 38% (95% CI, 34 to 43), respectively, at 4 years. The effect of adjuvant therapy with dabrafenib plus trametinib on long-term overall survival remains to be determined.
A: In the 5-year analysis, the duration of relapse-free survival was longer with dabrafenib plus trametinib than with placebo across all stage III substages on the basis of Kaplan–Meier analysis of survival data. Among the patients with stage IIIA disease, the percentage of patients who were alive without relapse was 65% (95% CI, 55 to 77) with dabrafenib plus trametinib and 58% (95% CI, 46 to 72) with placebo (hazard ratio for relapse or death, 0.61; 95% CI, 0.35 to 1.07). In those with stage IIIB disease, the percentage was 55% (95% CI, 47 to 63) and 34% (95% CI, 28 to 42), respectively, with a hazard ratio of 0.50 (95% CI, 0.37 to 0.67). In patients with stage IIIC disease, the percentage was 45% (95% CI, 38 to 53) and 29% (95% CI, 23 to 37), respectively, with a hazard ratio of 0.48 (95% CI, 0.36 to 0.64).
A: Survival without distant metastasis favored dabrafenib plus trametinib over placebo with extended follow-up. At 5 years, the percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) in the combination-therapy group and 54% (95% CI, 49 to 60) in the placebo group (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). There was no clinically meaningful difference between the combination-therapy group and the placebo group in the incidence or severity of serious adverse events reported during the follow-up period.