Multicenter phase 2 trial of neoadjuvant pembrolizumab, dabrafenib, and trametinib in BRAF V600-mutant resectable melanoma

The multicenter non-comparative, randomized, phase 2 NeoTrio trial in Australia investigated whether BRAF-targeted therapy could boost the proportion of patients achieving long-term recurrence-free survival with neoadjuvant immunotherapy in resectable stage III BRAF^V600-mutant melanoma. Patients were randomized to pembrolizumab alone (n=20), sequential therapy (dabrafenib plus trametinib followed by pembrolizumab; n=20), or concurrent triple therapy (n=20), followed by surgery and adjuvant therapy. Primary outcome was pathological respons. The pathological response rate was 55% including 30% pathological complete responses with pembrolizumab, 50% including 15% pCRs with sequential therapy, and 80% including 50% pCRs with concurrent therapy, which met the primary outcome in each arm. Treatment-related adverse events affected 75% -100% during neoadjuvant treatment, with seven early discontinuations, all in the concurrent arm. At 2 years, event-free survival rate was 60% in the pembrolizumab arm, 80% in the sequential therapy arm, and 71% in the concurrent therapy arm. Recurrences after major pathological response were more common in the targeted therapy arms, suggesting a reduction in response ‘quality’ when targeted therapy is added to neoadjuvant immunotherapy. The authors conclude that, pending longer follow-up, immunotherapy and targeted therapy should not be combined in the neoadjuvant setting for melanoma.