Journal Article

PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma

Mueller, Nancy, Robert, Caroline, Delafont, Bruno, Ribas, Antoni, Algazi, Alain, Gordon, Michael, Campbell, Katie M., Marshall, Shannon, Butler, Marcus O., Miller, Wilson H., Ascierto, Paolo A., Lutzky, Jose, Chandra, Sunandana, Lawrence, Donald, Hernandez-Aya, Leonel

2020

Overview

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. Immune checkpoints inhibitors or MAPK inhibitors are currently used as standard of care therapies for patients with advanced melanoma. Here the authors report a phase 1 clinical trial testing the anti-PD-L1 antibody durvalumab in combination with the BRAF inhibitor dafrafenib and the MEK inhibitor trametinib in patients with BRAFV600-mutant melanoma.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/250 / 631/67 / 82/51 / Adult / Aged / Aged, 80 and over / Antibodies / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - adverse effects / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - metabolism / Biopsy / Cohort Studies / Diarrhea - chemically induced / Exanthema - chemically induced / Female / Humanities and Social Sciences / Humans / Imidazoles - administration & dosage / Imidazoles - adverse effects / Immune checkpoint / Immunotherapy / Inhibitor drugs / Kinases / Life Sciences / Male / MAP kinase / MEK inhibitors / Melanoma / Melanoma - drug therapy / Melanoma - genetics / Melanoma - metabolism / Metastases / Middle Aged / Mitogen-Activated Protein Kinases - antagonists & inhibitors / Mitogen-Activated Protein Kinases - metabolism / Monoclonal antibodies / multidisciplinary / Mutation / Oximes - administration & dosage / Oximes - adverse effects / Patients / PD-L1 protein / Progression-Free Survival / Protein kinase / Proto-Oncogene Proteins B-raf - genetics / Pyridones - administration & dosage / Pyridones - adverse effects / Pyrimidinones - administration & dosage / Pyrimidinones - adverse effects / Science / Science (multidisciplinary) / Signaling / Skin Neoplasms - drug therapy / Skin Neoplasms - genetics / Skin Neoplasms - metabolism / Young Adult