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Nat Rev Clin Oncol. 2017 Aug;14(8):463-482. doi: 10.1038/nrclinonc.2017.43. Epub 2017 Apr 4.

Targeted agents and immunotherapies: optimizing outcomes in melanoma.

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Department of Medicine, Division of Hematology/Oncology, University of Chicago Comprehensive Cancer Center, 5841 South Maryland Avenue MC2115, Chicago, Illinois 60637, USA.
Department of Medicine, Harvard Medical School, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.
Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles Jonsson Comprehensive Cancer Center, 10833 Le Conte Avenue, Los Angeles, California 90024, USA.
Melanoma Institute Australia, The University of Sydney, and The Mater Hospital, Rocklands Road, North Sydney, New South Wales 2060, Australia.
Royal North Shore Hospital, Reserve Road, St Leonards, New South Wales 2065, Australia.


Treatment options for patients with metastatic melanoma, and especially BRAF-mutant melanoma, have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents. During this period, the treatment paradigm for BRAF-mutant disease has evolved rapidly: the standard-of-care BRAF-targeted approach has shifted from single-agent BRAF inhibition to combination therapy with a BRAF and a MEK inhibitor. Concurrently, immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and, now, the programmed cell-death protein 1 (PD-1) immune checkpoints. These changes in the treatment landscape have dramatically improved patient outcomes, with the median overall survival of patients with advanced-stage melanoma increasing from approximately 9 months before 2011 to at least 2 years - and probably longer for those with BRAF-V600-mutant disease. Herein, we review the clinical trial data that established the standard-of-care treatment approaches for advanced-stage melanoma. Mechanisms of resistance and biomarkers of response to BRAF-targeted treatments and immunotherapies are discussed, and the contrasting clinical benefits and limitations of these therapies are explored. We summarize the state of the field and outline a rational approach to frontline-treatment selection for each individual patient with BRAF-mutant melanoma.

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