title: Combination Treatment of Patients with BRAF-Mutant Melanoma: A New Standard of Care.
abstract: Raf-mitogen-activated protein kinase (Raf-MAPK) pathway inhibition with the BRAF inhibitors vemurafenib and dabrafenib, alone or in combination with a MEK inhibitor, has become a standard therapeutic approach in patients with BRAF-mutated metastatic melanoma. Both vemurafenib and dabrafenib have shown good safety and efficacy as monotherapy compared with chemotherapy. However, the duration of response is limited in the majority of patients treated with BRAF inhibitor monotherapy because of the development of acquired resistance. The addition of a MEK inhibitor can improve blockade of the MAPK pathway and may help to overcome resistance and thereby prolong efficacy, as well as reduce cutaneous toxicity. Combinations of BRAF inhibitors and MEK inhibitors (dabrafenib plus trametinib and vemurafenib plus cobimetinib) have been approved for the treatment of BRAF-mutant metastatic melanoma and may become a new standard of care. However, acquired resistance is still a significant concern with BRAF and MEK inhibitor combination therapy, and other strategies are being investigated, including the use of sequential and intermittent schedules. The combination of BRAF or MEK inhibitors with immunotherapy has been shown to hold considerable promise, with several combinations being evaluated in clinical trials. Preliminary results from clinical trials involving triple combination therapy with BRAF-MEK inhibitors and anti-PD-L1 antibodies appear promising and may indicate a new strategy to treat patients with BRAF-mutated metastatic melanoma. Biomarkers are needed to help identify patients with BRAFV600 mutations most likely to benefit from first-line BRAF/MEK inhibitor therapy rather than immunotherapy and vice versa.
authors.affiliation: Melanoma, Cancer Immunotherapy and Innovative Therapies Unit, Istituto Nazionale Tumori di Napoli Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Simeone
authors.affiliation: Melanoma, Cancer Immunotherapy and Innovative Therapies Unit, Istituto Nazionale Tumori di Napoli Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Grimaldi
authors.affiliation: Melanoma, Cancer Immunotherapy and Innovative Therapies Unit, Istituto Nazionale Tumori di Napoli Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Festino
authors.affiliation: Melanoma, Cancer Immunotherapy and Innovative Therapies Unit, Istituto Nazionale Tumori di Napoli Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Vanella
authors.affiliation: Melanoma, Cancer Immunotherapy and Innovative Therapies Unit, Istituto Nazionale Tumori di Napoli Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Palla
authors.affiliation: Melanoma, Cancer Immunotherapy and Innovative Therapies Unit, Istituto Nazionale Tumori di Napoli Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. paolo.ascierto@gmail.com.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002986:Clinical Trials as Topic / Q000379:methods; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D059039:Standard of Care / Q000639:trends
chemical_list: D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf