Journal
NATURE MEDICINE
Volume 25, Issue 6, Pages 936-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-019-0476-5
Keywords
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Funding
- Merck Sharpe & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
- Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
- NIH [R35 CA197633, P01 CA168585]
- Parker Institute for Cancer Immunotherapy
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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.
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