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Melanoma Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Stage IV and Recurrent Melanoma


Attempts to improve on this therapy have included the addition of lymphokine-activated killer cells (i.e., autologous lymphocytes activated by IL-2 ex vivo) and tumor-infiltrating lymphocytes (TIL) (i.e., lymphocytes derived from tumor isolates cultured in the presence of IL-2). A single-institution trial reports that adoptive cell therapy (ACT) with lymphodepletion (using cyclophosphamide plus fludarabine with or without total-body irradiation) followed by autologous TIL transfer and high-dose IL-2 may improve durable response.[23][Level of evidence: 3iiiDiv] A multicenter, randomized trial of high-dose IL-2 with and without a peptide vaccine [gp100:209–217(210M)] in patients with locally advanced stage III or stage IV melanoma who were HLA*A0201-positive reported an increase in response rate with the combination.[24][Level of evidence:1iiDiv] Multicenter, phase III trials powered for an assessment on OS are needed for validation, because response rates are not known to be a surrogate for OS in melanoma.

Signal transduction inhibitors

Studies to date indicate that both BRAF and MEK (mitogen-activated ERK-[extracellular signal-regulated kinase] activating kinase) inhibitors can significantly impact the natural history of melanoma, although as single agents, they do not appear to provide a cure.

BRAF inhibitors


Vemurafenib is an orally available, small molecule, selective BRAF inhibitor that is approved by the FDA for patients with unresectable or metastatic melanoma that tests positive for the BRAF V600E mutation. Treatment with vemurafenib is discouraged in wild-type BRAF melanoma because data from preclinical models has demonstrated that BRAF inhibitors can enhance rather than downregulate the MAPK (mitogen-activated protein kinase) pathway in tumor cells with wild-type BRAF and upstream RAS mutations.[25,26,27,28]

Previously untreated patients. The approval of vemurafenib was supported by an international, multicenter trial (BRIM-3 [NCT01006980]) that screened 2,107 patients with previously untreated, stage IIIC or IV melanoma for the BRAF V600 mutation and identified 675 patients by the cobas® 4800 BRAF V600 Mutation Test.[5] Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 intravenously [ IV] every 3 weeks). Coprimary endpoints were rates of OS and PFS.[5][Levels of evidence: 1iiA and 1iiDiii]

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