Journal Article

Neoadjuvant pembrolizumab, dabrafenib and trametinib in BRAFV600-mutant resectable melanoma: the randomized phase 2 NeoTrio trial

Saw, Robyn P. M., Batula, Iris, Au-Yeung, George, Spillane, Andrew J., Menzies, Alexander M., Gonzalez, Maria, Lo, Serigne N., Carlino, Matteo S., Howle, Julie, Pennington, Thomas E., Thompson, Jake R., Ch’ng, Sydney, Scolyer, Richard A., Gyorki, David E., Shannon, Kerwin F., Kapoor, Rony, Hsiao, Edward, Long, Georgina V.

2024

Overview

Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma. Immune changes early during targeted therapy suggest the mechanisms of each drug class could work synergistically. In the non-comparative, randomized, phase 2 NeoTrio trial, we investigated whether 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. Sixty patients (42% females) 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. The primary outcome was pathological response; secondary outcomes included radiographic response, recurrence-free survival, overall survival, surgical outcomes, peripheral blood and tumor analyses and safety. The pathological response rate was 55% (11/20; including six pathological complete responses (pCRs)) with pembrolizumab, 50% (10/20; three pCRs) with sequential therapy and 80% (16/20; ten pCRs) with concurrent therapy, which met the primary outcome in each arm. Treatment-related adverse events affected 75–100% of patients during neoadjuvant treatment, with seven early discontinuations (all in the concurrent arm). At 2 years, event-free survival was 60% with pembrolizumab, 80% with sequential therapy and 71% with concurrent therapy. 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. Risking the curative potential of immunotherapy in melanoma cannot be justified. Pending longer follow-up, we suggest that immunotherapy and targeted therapy should not be combined in the neoadjuvant setting for melanoma. ClinicalTrials.gov registration: NCT02858921 . In this non-comparative trial, patients with BRAF V600 -mutant resectable melanoma received either pembrolizumab alone, a sequential combination of pembrolizumab, dabrafenib and trametinib, or a concurrent combination thereof, showing encouraging clinical response rates in the concurrent therapy arm and awaiting longer follow-up.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/1813/1634 / Biomedical and Life Sciences / Biomedicine / Cancer Research / Immune checkpoint inhibitors / Immunotherapy / Infectious Diseases / Inhibitor drugs / Melanoma / Metabolic Diseases / Molecular Medicine / Monoclonal antibodies / Mutants / Neurosciences / Patients / Pembrolizumab / Peripheral blood / Survival / Targeted cancer therapy / Therapy