Managing Metastatic Melanoma in 2022: A Clinical Review

Abstract

Cutaneous melanoma remains the most lethal of the primary cutaneous neoplasms, and although the incidence of primary melanoma continues to rise, the mortality from metastatic disease remains unchanged, in part through advances in treatment. Major developments in immunomodulatory and targeted therapies have provided robust improvements in response and survival trends that have transformed the clinical management of patients with metastatic melanoma. Additional advances in immunologic and cancer cell biology have contributed to further optimization in (1) risk stratification, (2) prognostication, (3) treatment, (4) toxicity management, and (5) surveillance approaches for patients with an advanced melanoma diagnosis. In this review, we provide a comprehensive overview of the historical and future advances regarding the translational and clinical implications of advanced melanoma and share multidisciplinary recommendations to aid clinicians in the navigation of current treatment approaches for a variety of patient cohorts.

FIG 1.

Recommended current clinical approach to patients with treatment-naive advanced metastatic melanoma. ^aInclude magnetic resonance imaging of brain if clinically indicated. ^bAdditional molecular analyses including mutational status of RAS, CKIT, and NF1 as well as expression of programmed death ligand 1 and quantification of tumor-infiltrating lymphocyte infiltration, tumor mutational burden, and circulating tumor DNA are not currently used as the standard of care but likely to provide clinical utility in the future and should be considered in appropriate experimental settings. ^cMedical therapies include talimogene laherparepvec for patients with locoregional (stage IIIB-IV-M1a) disease and systemic therapy (most commonly combined anti–PD-1 and anti-CTLA4 checkpoint inhibition) if visceral involvement. These treatments should not be delayed while undergoing consideration of additional interventions. ^dCombination of anti–PD-1 and anti-CTLA4 ICI is encouraged as standard first-line systemic therapy regardless of BRAF mutational status, with most enhanced benefits observed in patients with (1) CNS involvement, (2) elevated LDH, and/or (3) visceral metastatic disease, which warrants an enhanced response rate. Can consider anti–PD-1 monotherapy for clinical and/or toxicity concerns from combination ICI. ^eAppropriate to consider as frontline therapy with targeted (BRAF and MEK) inhibition in the subset of patients with BRAFV600 mutation who require brisk response because of rapid and/or symptomatic disease progression. CTLA, cytotoxic T-cell lymphocyte; ICI, immune checkpoint inhibitor; LDH, lactate dehydrogenase; PD-1, programmed cell death protein 1.