Stage III melanoma

Patients with resected stage IIIB/C/D melanoma should be considered for adjuvant systemic therapy. The prognosis for patients with stage IIIA melanoma is good and adjuvant systemic therapy is not recommended for this sub-group. For patients with a BRAF V600 mutant melanoma, targeted therapy (combination BRAF and MEK inhibitors) or adjuvant immunotherapy (single agent anti PD-1) can be recommended. For patients without a BRAF mutation, adjuvant immunotherapy should be used. Therapy is given for up to a year.

Currently, there is strong evidence for clinically significant improvements in relapse-free survival with the adjuvant use of targeted therapy or anti-PD1 immunotherapy; however, improvements in overall survival from these treatments have not yet been demonstrated. These may emerge with further follow-up. The decision to recommend adjuvant treatment should be taken by a suitably experienced oncologist and consider the health status and preferences of the individual patient.

Unresectable stage III and stage IV melanoma

All patients with unresectable stage III or stage IV melanoma should be considered for systemic therapy. Enrolment into clinical trials is encouraged where possible.

Immunotherapy, with either anti-PD-1 agents (pembrolizumab or nivolumab) alone or with nivolumab in combination with the anti-CTLA-4 agent ipilimumab can be given as the first line of therapy for metastatic melanoma. Combination immunotherapy results in higher response rates and longer progression-free survival but has significantly greater toxicity, necessitating careful patient selection. Immunotherapy should be continued until disease progression, unacceptable toxicity or completion of two years of treatment. Immunotherapy can cause a unique set of side effects, referred to as immune-related adverse events (irAEs). These toxicities result in inflammation occurring in normal tissues and can affect any part of the body. The most common irAEs are rash, itch, thyroid dysfunction, hypophysitis, hepatitis, colitis, arthritis and pneumonitis. Patients with pre-existing autoimmune conditions are at risk of exacerbation of their autoimmune disease. Clinically significant irAEs require interruption of the immunotherapy and, usually, immunosuppressive doses of corticosteroids. As these are a unique set of toxicities very distinct from traditional chemotherapy side effects, practitioners involved in managing these patients should seek expert advice from the patient’s treating unit if toxicity is suspected.

Patients with BRAF V600 mutant melanoma are also candidates for targeted therapy. Combination therapy with both a BRAF and a MEK inhibitor should be used in preference to treatment with single-agent BRAF inhibition. Treatment with targeted therapy should continue until the development of disease progression or intolerable toxicity. There is no randomised data to suggest a superior sequence of treatment (targeted therapy followed by immunotherapy or vice versa) for metastatic BRAT-mutant melanoma.