1. PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma.
- Author
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Ribas A, Algazi A, Ascierto PA, Butler MO, Chandra S, Gordon M, Hernandez-Aya L, Lawrence D, Lutzky J, Miller WH Jr, Campbell KM, Delafont B, Marshall S, Mueller N, and Robert C
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, B7-H1 Antigen antagonists & inhibitors, B7-H1 Antigen metabolism, Cohort Studies, Diarrhea chemically induced, Exanthema chemically induced, Female, Humans, Imidazoles administration & dosage, Imidazoles adverse effects, Male, Melanoma genetics, Melanoma metabolism, Middle Aged, Mitogen-Activated Protein Kinases antagonists & inhibitors, Mitogen-Activated Protein Kinases metabolism, Mutation, Oximes administration & dosage, Oximes adverse effects, Progression-Free Survival, Proto-Oncogene Proteins B-raf genetics, Pyridones administration & dosage, Pyridones adverse effects, Pyrimidinones administration & dosage, Pyrimidinones adverse effects, Skin Neoplasms genetics, Skin Neoplasms metabolism, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Melanoma drug therapy, Skin Neoplasms drug therapy
- Abstract
Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti-PD-L1 therapy may provide treatment options for patients with advanced melanoma.
- Published
- 2020
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