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

Antoni Ribas (), Alain Algazi, Paolo A. Ascierto, Marcus O. Butler, Sunandana Chandra, Michael Gordon, Leonel Hernandez-Aya, Donald Lawrence, Jose Lutzky, Wilson H. Miller, Katie M. Campbell, Bruno Delafont, Shannon Marshall, Nancy Mueller and Caroline Robert
Additional contact information
Antoni Ribas: University of California Los Angeles (UCLA) and Jonsson Comprehensive Cancer Center at UCLA
Alain Algazi: UCSF Medical Center
Paolo A. Ascierto: Istituto Nazionale Tumori IRCCS Fondazione Pascale
Marcus O. Butler: Princess Margaret Cancer Centre
Sunandana Chandra: Northwestern Memorial Hospital
Michael Gordon: HonorHealth Research Institute
Leonel Hernandez-Aya: Washington University School of Medicine
Donald Lawrence: Massachusetts General Hospital
Jose Lutzky: Mount Sinai Medical Center
Wilson H. Miller: Segal Cancer Center, Jewish General Hospital, Rossy Cancer Network, McGill University
Katie M. Campbell: University of California Los Angeles (UCLA) and Jonsson Comprehensive Cancer Center at UCLA
Bruno Delafont: AstraZeneca
Shannon Marshall: AstraZeneca
Nancy Mueller: AstraZeneca
Caroline Robert: Gustave Roussy Cancer Campus and Paris-Saclay University

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19810-w

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