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INTRODUCTION

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Metastatic melanoma continues to place a substantial economic burden on western caucasian populations because of the disproportionately high incidence in young patients.1 Historically, the prognosis for patients with metastatic disease has been dismal with a median overall survival (OS) of 6 to 9 months and a 5-year survival rate of less than 10%.2 Until 2011, only dacarbazine and high-dose interleukin 2 (IL-2) were approved for the treatment of metastatic disease. Dacarbazine gained approval in 1975 for its modest response rate of 10% and median OS of 5.6 to 9.7 months.2,3 Attempts to improve on this with other cytotoxics (temozolomide or fotemustine), cisplatin-based combination chemotherapy, biochemotherapy, and concurrent use of targeted agents with dacarbazine resulted in marginally higher response rates, additional toxicity but no added survival advantage over single agent dacarbazine.3-6 High-dose IL-2 has consistently demonstrated an objective response rate (ORR) of 16% to 23% with durable complete responses seen in approximately 5% to 10% of patients.7 High-dose IL-2, however, requires skilled inpatient management, which has largely restricted clinical application to a small number of highly specialized centers.

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Pleasingly, the outlook for patients with metastatic melanoma is rapidly improving with the advent of two distinct therapeutic approaches: (i) targeting key oncogenic driver mutations that underpin melanoma tumorigenesis and (ii) using immunomodulation to reverse immune suppression. Blocking the mitogen-activated protein kinase (MAPK) pathway with potent inhibitors of BRAF and MEK results in striking responses and a significant OS advantage;8-13 these combinations are now established as a new standard of treatment for patients with BRAFV600 mutant advanced melanoma. Ipilimumab, an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody results in durable responses in 20% of patients and an OS advantage for metastatic melanoma.14,15 Anti-programmed death 1 (PD1) and anti-programmed death ligand 1 (PDL-1) monoclonal antibodies are emerging as new treatments for melanoma with rapid, deep, and durable response in 40% of patients with an OS advantage.16-20 Many more novel agents and combinatory treatments intended to enhance efficacy and circumvent resistance are currently in preclinical and clinical development.

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ONCOGENIC SIGNALING IN MELANOMA AND THERAPEUTIC IMPLICATIONS

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The past decade has witnessed major advances in understanding the biology and genomic landscape of melanoma. Melanoma is driven by initiating and driving oncogenic aberrations that cooperate with loss of tumor suppressor function to promote cancer proliferation and survival.21,22 Commonly, these include aberrations in oncogenes (BRAF, NRAS, CDK4, KIT, CCND1, ERBB4, AKT, NEDD9, RAC1, GNAQ, and GNA11), transcription factors (MITF, MYC, and ETV1), and tumor suppressors (CDKN2A, NF1, TP53, BAP1, and PTEN).23 These insights into underlying "driver mutations" coupled with therapeutic development have paved the way for highly effective genome-specific targeted therapies in this disease.

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The RAS/RAF/MEK/ERK (MAPK) pathway (Fig. 18-1), implicated in regulating cell cycle, proliferation, and survival under normal conditions, is hijacked by oncogenic driver ...

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