Fig. 4

Stage IV melanoma immunotherapy treatment algorithm. All treatment options shown may be appropriate and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician’s discretion. These algorithms represent consensus sequencing suggestions by the panel. The panel recommended all patients be evaluated with full body imaging, histopathology review, serum LDH, and tumor mutation analysis with emphasis on BRAF mutations. Other factors to be considered in selecting appropriate treatment should include performance status, burden and tempo of disease and presence of CNS metastases. (1) All patients should be evaluated for resection by a multi-disciplinary team including surgical oncology before and after immunotherapy treatment, although the role of surgery is changing and may be appropriate for patients with solitary pulmonary lesions where complete extirpation is possible; each case must be individualized. (2) All patients should have an MRI of the brain prior to treatment to rule out or manage CNS metastasis. (3) There was level B data for a clinical benefit with surgical resection when complete excision of all disease is possible although first-line surgical resection was a minority opinion of the panel. (4) As determined by an experienced surgical oncologist, patient is eligible to receive surgical intervention as first-line treatment. (5) Immunotherapy was recommended for any patient with a good performance status regardless of BRAF mutation status and provided that any CNS disease was treated and controlled. Clinical trial was the favored first line approach by the panel. 6) In the absence of an appropriate clinical trial, the panel recommended combination ipilimumab and nivolumab based on the high response rates reported. This may also be preferred for patients with CNS disease with a minority of panelists (33.3%) recommending stereotactic radiation prior to systemic therapy for CNS lesions (7) Next, the panel recommended single agent anti-PD-1 therapy (pembrolizumab or nivolumab). The panel considered these agents to have the same therapeutic efficacy and treatment selection could be based on physician experience and patient preference. (8) The panel also recommended T-VEC in patients with accessible tumor for injection and limited visceral tumor burden. This option may be especially appropriate for elderly patients and those not eligible for checkpoint inhibitors. (9) Patients with poor performance status were not considered good candidates for combination immunotherapy and BRAF mutation was an important factor for determining therapeutic planning. Most panelists considered clinical trials to be the most important option in these patients, if available. In those patients without a BRAF mutation, the next option should be single agent anti-PD-1 therapy (pembrolizumab or nivolumab). (10) In patients with poor performance status and a BRAF mutation who are not eligible or whose tumors progress after a clinical trial, treatment with a BRAF and/or MEK inhibitor therapy is indicated. This option was also considered appropriate for patients with uncontrolled CNS disease. Single agent anti-PD-1 treatment could be considered if disease progression occurs after targeted therapy. (11) In patients with disease progression following the recommendations, management should be carefully considered. If patients can tolerate treatment, ipilimumab/nivolumab should be considered. If patients have a BRAF mutation and have not been treated with BRAF/MEK inhibitors previously these can be considered. Ipilimimab monotherapy and high-dose IL-2 can also be considered in these patients. (12) Patients should have a good PS and otherwise qualify for IL-2 administration per local institutional guidelines. (13) Dacarbazine is the only approved chemotherapy agent but temozolomide and carboplatin/paclitaxel are often used as well depending on patient preference and physician experience. Abbreviations: BRAF+, positive for actionable BRAF mutations; BRAF–, negative for actionable BRAF mutations; CNS, central nervous system; IL, interleukin; LDH, lactate dehydrogenase; PS, performance status