Figure 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. These consensus recommendations are generally for patients with no CNS disease or CNS disease that has been treated and controlled. In patients with CNS metastases, the subcommittee recognizes emerging data concerning combination nivolumab + ipilimumab, and a minority of panelists (33.3%) recommended stereotactic radiation prior to systemic therapy for CNS lesions. (3) There is 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) For any patient with a good performance status and actionable BRAF mutation status, clinical trial was the favored first line approach by the panel. In the absence of an appropriate clinical trial, 46% of the panel recommended combination ipilimumab and nivolumab based on the high response rates reported. 29% of the subcommittee recommended single agent anti-PD-1 therapy (pembrolizumab or nivolumab), while only one member recommended treatment with BRAF/MEK inhibitors. Some panel members also noted that T-VEC in patients with accessible tumor for injection and limited visceral tumor burden may be an option, especially for elderly patients and those not eligible for checkpoint inhibitors. (6) Clinical trial enrollment was favored as the primary treatment option for any patient with a good performance status and no actionable BRAF mutation status. 50% of the panel recommended combination ipilimumab and nivolumab for these patients if clinical trial enrollment is unavailable. 33% of the subcommittee recommended single agent anti-PD-1 therapy, and again noted T-VEC as an option for select patients as described above. (7) In patients with poor performance status and a BRAF mutation who are not eligible or whose tumors progress after a clinical trial, 79% of the panelists recommended treatment with a BRAF and/or MEK inhibitor. This option was also considered appropriate for patients with uncontrolled CNS disease. Single agent anti-PD-1 treatment was recommended by 21% of the subcommittee for this patient population. (8) The majority of the subcommittee recommended clinical trial enrollment for patients with poor performance status and no actionable BRAF mutation. Outside of clinical trial enrollment, 71% of members recommended single agent anti-PD-1 therapy, while 25% recommended combination nivolumab + ipilimumab. One subcommittee member suggested single agent ipilimumab as an option for these patients. (9) In patients with disease progression following the first-line 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. Patients should have a good PS and otherwise qualify for IL‑2 administration per local institutional guidelines. 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.