Format

Send to

Choose Destination
Nat Med. 2019 Jun;25(6):936-940. doi: 10.1038/s41591-019-0476-5. Epub 2019 Jun 6.

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

Author information

1
University of California, Los Angeles, Los Angeles, CA, USA. aribas@mednet.ucla.edu.
2
Massachusetts General Hospital, Boston, MA, USA.
3
Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, Queensland, Australia.
4
Indiana University Health Goshen Center for Cancer Care, Goshen, IN, USA.
5
Segal Cancer Centre, Montreal, Quebec, Canada.
6
Jewish General Hospital, Montreal, Quebec, Canada.
7
McGill University, Montreal, Quebec, Canada.
8
Westmead Hospital, Sydney, New South Wales, Australia.
9
Blacktown Hospital, Sydney, New South Wales, Australia.
10
The University of Sydney, Sydney, New South Wales, Australia.
11
Melanoma Institute Australia, Sydney, New South Wales, Australia.
12
Auckland District Health Board, Auckland, New Zealand.
13
Royal North Shore Hospital, Sydney, New South Wales, Australia.
14
Mater Hospital, Sydney, New South Wales, Australia.
15
Dana-Farber Cancer Institute, Boston, MA, USA.
16
University of California, Los Angeles, Los Angeles, CA, USA.
17
Novartis, East Hanover, NJ, USA.
18
Merck & Co., Inc., Kenilworth, NJ, USA.
19
The Angeles Clinic and Research Institute, Los Angeles, CA, USA.

Abstract

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 BRAFV600-mutated melanoma, with a median duration of response of approximately 1 year1-3. 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 activity4-6, 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 BRAFV600-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 BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.

PMID:
31171879
DOI:
10.1038/s41591-019-0476-5
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center