Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma

• Published in: Nature medicine Vol. 25; no. 6; pp. 936 - 940
• Main Authors: Ribas, Antoni, Lawrence, Donald, Atkinson, Victoria, Agarwal, Sachin, Miller, Wilson H., Carlino, Matteo S., Fisher, Rosalie, Long, Georgina V., Hodi, F. Stephen, Tsoi, Jennifer, Grasso, Catherine S., Mookerjee, Bijoyesh, Zhao, Qing, Ghori, Razi, Moreno, Blanca Homet, Ibrahim, Nageatte, Hamid, Omid
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2019; Nature Publishing Group
• Subjects: 631/67/1059/2325; 631/67/1059/602; 631/67/1813/1634; 692/308/2779/109; Adult; Aged; Antibodies; Antibodies, Monoclonal, Humanized - administration & dosage; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents, Immunological - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor activity; Biomedical and Life Sciences; Biomedicine; Cancer Research; Confidence intervals; Drug therapy; Drug therapy, Combination; Female; Fever; Health aspects; Humans; Imidazoles - administration & dosage; Immunotherapy; Infectious Diseases; Inhibitors; Kinases; Letter; Male; MAP kinase; MAP Kinase Kinase Kinases - antagonists & inhibitors; MEK inhibitors; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - secondary; Metabolic Diseases; Metastases; Metastasis; Methods; Middle Aged; Mitogen-activated protein kinases; Molecular Medicine; Monoclonal antibodies; Mutation; Neurosciences; Oximes - administration & dosage; Patients; PD-1 protein; Pembrolizumab; Protein kinase; Protein Kinase Inhibitors - administration & dosage; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Proto-oncogenes; Pyridones - administration & dosage; Pyrimidinones - administration & dosage; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - therapy; Testing; Therapy; Young Adult
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-019-0476-5

Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAF V600 -mutated melanoma, with a median duration of response of approximately 1 year 1 – 3 . Immunotherapy with antibodies to programmed death 1 (PD-1) produces lower response rates but with long response duration. Preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity 4 – 6 , which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. We enrolled 15 patients with BRAF V600 -mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumab ( NCT02130466 ). Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 antibody or the targeted therapy combination. Eleven patients (73%; 95% confidence interval = 45–92%) had an objective response, and six (40%; 95% confidence interval = 16–68%) continued with a response at a median follow-up of 27 months (range = 10.3–38.4+ months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAF V600 -mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses. Triple therapy combining BRAF and MEK inhibitors with immune checkpoint blockade may benefit a subset of patients with BRAF V600 -mutated metastatic melanoma.