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Douglas B. Johnson and Jeffrey A. Sosman

Melanoma is an aggressive skin cancer with historically limited treatment options. Approximately 50% of melanomas harbor BRAF V600 mutations. This report describes a 32-year-old man with metastatic BRAF V600-mutant melanoma who presented with cardiac involvement. Recently developed treatment options for patients with BRAF-mutant melanoma include BRAF inhibitors (vemurafenib, dabrafenib), MEK inhibitors (trametinib), and immune-based therapeutics (interleukin-2 or ipilimumab), but the most effective strategy for first-line therapy is heavily debated. Opinions vary for treatment selection, but the general consensus recommends immune-based therapies initially for asymptomatic patients with low-volume disease, and BRAF inhibitors for those with highly symptomatic or rapidly progressing disease. In this case, melanoma with cardiac involvement, although clinically uncommon, presents challenging management decisions.

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Presenters: Douglas B. Johnson, Susan M. Swetter, April K.S. Salama, and Evan Wuthrick

Several advances in diagnosis and treatment of cutaneous melanoma were discussed at the NCCN 2021 Virtual Annual Conference. First, advances in immunotherapies and targeted agents have enhanced the role of systemic therapies in the up-front management of brain metastases in melanoma while improving survival. With dual-agent immune checkpoint inhibitors, more than half of patients with asymptomatic brain metastases that are not in high-risk anatomic areas of the brain respond to treatment, and these responses appear to be durable, sparing many patients from neurosurgery and/or stereotactic radiosurgery. In addition, molecular tests increasingly have implications for clinical decision-making in later-stage disease. The most important genetic mutation in melanoma is the BRAF V600 mutation, which can be found in approximately 40% to 50% of cutaneous melanomas.

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Douglas B. Johnson, Riyue Bao, Kristin K. Ancell, Anthony B. Daniels, Deborah Wallace, Jeffrey A. Sosman, and Jason J. Luke

Background: Uveal melanoma (UM) is an uncommon melanoma subtype with poor prognosis. Agents that have transformed the management of cutaneous melanoma have made minimal inroads in UM. Methods: We conducted a single-arm phase II study of pembrolizumab in patients with metastatic UM and performed bioinformatics analyses of publicly available datasets to characterize the activity of anti–PD-1 in this setting and to understand the mutational and immunologic profile of this disease. Results: A total of 5 patients received pembrolizumab in this study. Median overall survival was not reached, and median progression-free survival was 11.0 months. One patient experienced a complete response after one dose and 2 others experienced prolonged stable disease (20% response rate, 60% clinical benefit rate); 2 additional patients had rapidly progressing disease. Notably, the patients who benefited had either no liver metastases or small-volume disease, whereas patients with rapidly progressing disease had bulky liver involvement. We performed a bioinformatics analysis of The Cancer Genome Atlas for UM and confirmed a low mutation burden and low rates of T-cell inflammation. Note that the lack of T-cell inflammation strongly correlated with MYC pathway overexpression. Conclusions: Anti–PD-1–based therapy may cause clinical benefit in metastatic UM, seemingly more often in patients without bulky liver metastases. Lack of mutation burden and T-cell infiltration and MYC overexpression may be factors limiting therapeutic responses.

ClinicalTrials.gov identifier: NCT02359851