Neoadjuvant pembrolizumab, dabrafenib and trametinib in BRAF(V600)-mutant resectable melanoma: the randomized phase 2 NeoTrio trial

Long, GV; Carlino, MS; Au-Yeung, G; Spillane, AJ; Shannon, KF; Gyorki, DE; Hsiao, E; Kapoor, R; Thompson, JR; Batula, I; Howle, J; Ch&#39;ng, S; Gonzalez, M; Saw, RPM; Pennington, TE; Lo, SN; Scolyer, RA; Menzies, AM

Author(s): Long, GV; Carlino, MS; Au-Yeung, G; Spillane, AJ; Shannon, KF; Gyorki, DE; Hsiao, E; Kapoor, R; Thompson, JR; Batula, I; Howle, J; Ch'ng, S; Gonzalez, M; Saw, RPM; Pennington, TE; Lo, SN; Scolyer, RA; Menzies, AM;
Details: Publication Year 2024-09,Volume 30,Issue #9,Page 2540-2548
Journal Title: Nature Medicine
Abstract: 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 .
Keywords: Humans; *Melanoma/drug therapy/genetics/pathology; *Antibodies, Monoclonal, Humanized/therapeutic use/administration &; dosage/adverse effects; *Pyrimidinones/therapeutic use/administration & dosage; *Pyridones/therapeutic use/administration & dosage; *Proto-Oncogene Proteins B-raf/genetics; Female; Male; *Neoadjuvant Therapy; Middle Aged; *Oximes/administration & dosage/therapeutic use; Aged; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use; Adult; *Imidazoles/therapeutic use/administration & dosage; *Mutation; Immunotherapy/methods
Department(s): Surgical Oncology
Publisher's Version: https://doi.org/10.1038/s41591-024-03077-5
Open Access at Publisher's Site: https://doi.org/10.1038/s41591-024-03077-5
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-01 05:05:39

Last Modified: 2024-10-01 05:05:56