1. PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma.
- Author
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Ribas, Antoni, Algazi, Alain, Ascierto, Paolo A, Butler, Marcus O, Chandra, Sunandana, Gordon, Michael, Hernandez-Aya, Leonel, Lawrence, Donald, Lutzky, Jose, Miller, Wilson H, Campbell, Katie M, Delafont, Bruno, Marshall, Shannon, Mueller, Nancy, and Robert, Caroline
- Subjects
Humans ,Melanoma ,Skin Neoplasms ,Exanthema ,Diarrhea ,Oximes ,Imidazoles ,Pyridones ,Pyrimidinones ,Proto-Oncogene Proteins B-raf ,Mitogen-Activated Protein Kinases ,Antineoplastic Combined Chemotherapy Protocols ,Antibodies ,Monoclonal ,Cohort Studies ,Mutation ,Adult ,Aged ,Aged ,80 and over ,Middle Aged ,Female ,Male ,Young Adult ,B7-H1 Antigen ,Progression-Free Survival - 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