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  • Mutations in the RAS-RAF-MAPK signaling pathway are detected in most cutaneous melanomas, most commonly affecting BRAF, NRAS, and Nf1. The prevalence and pattern of mutations differs between cutaneous melanomas and noncutaneous (ie, mucosal, uveal) melanomas.

  • Surgery is the mainstay of initial treatment for patients with primary cutaneous melanoma without clinical evidence of regional nodal or distant metastatic disease. Sentinel lymph node biopsy should be considered in patients with a significant risk of regional metastasis. For patients with sentinel lymph node involvement, it is no longer standard practice to perform completion lymph node dissection based on recent prospective trials that showed no significant impact on melanoma-specific survival (MSS). Surgery is an important component in the multidisciplinary management of patients with clinically detected regional nodal disease and in select patients with distant metastases.

  • Adjuvant radiation therapy (RT) reduces the risk of locoregional recurrence in patients with regionally metastatic disease but without significant impact on overall survival (OS). Radiation may provide palliative benefit in patients with distant metastases. Treatment decisions regarding radiation should be tailored based on potential risks, benefits, and multidisciplinary input.

  • Several adjuvant systemic therapies reduce the risk of recurrence in patients with regionally metastatic disease. While adjuvant immune checkpoint inhibitor immunotherapy was first approved for the anti–CTLA-4 (cytotoxic Tlymphocyte-associated antigen 4) antibody ipilimumab, adjuvant therapy with anti–PD-1 (programmed cell death protein 1) antibodies (nivolumab, pembrolizumab) was shown to be safer and more effective. Adjuvant targeted therapy with the combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, is approved for stage III melanomas with a BRAF V600 mutation. No prospective trials to date have compared adjuvant immunotherapy versus adjuvant targeted therapy. Both immunotherapy and targeted therapy are being investigated in the neoadjuvant setting.

  • After decades without progress, in the past decade, multiple systemic therapies have been approved for the treatment for patients with stage IV or unresectable stage III disease. Ipilimumab was the first immunotherapy to be approved in this setting. Subsequent trials demonstrated improved safety and efficacy with single-agent nivolumab and with single-agent pembrolizumab versus ipilimumab, leading to their approval. Combination immunotherapy with ipilimumab and nivolumab is also more effective than ipilimumab and has been approved, but the combination has increased toxicity versus either agent alone. For patients with a BRAF V600 mutation, three different targeted therapy combinations of a BRAF and a MEK inhibitor (dabrafenib + trametinib; vemurafenib + cobimetinib; encorafenib + binimetinib) have been approved after demonstrating superiority compared to single-agent BRAF inhibitor therapy. The BRAF + MEK inhibitor combinations have not been compared in prospective clinical trials versus each other or versus immunotherapy. Intratumoral injection of talimogene laherparepvec is approved for patients with unresectable injectable metastatic disease.

  • Although much progress has been made for patients with cutaneous melanoma, the efficacy of immune checkpoint inhibitors is much lower in patients with mucosal and with uveal melanoma. These tumor types also have a much lower prevalence of targetable mutations.


Melanoma is ...

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