title: Targeted agents and immunotherapies: optimizing outcomes in melanoma.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of Chicago Comprehensive Cancer Center, 5841 South Maryland Avenue MC2115, Chicago, Illinois 60637, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Luke
authors.affiliation: Department of Medicine, Harvard Medical School, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: 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.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: 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.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
mesh_terms: D006801:Humans; D007167:Immunotherapy; D008545:Melanoma / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D012878:Skin Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D016896:Treatment Outcome