• Sara Valpione, Matteo S Carlino, Johanna Mangana, Meghan J Mooradian, Grant McArthur, Dirk Schadendorf, Axel Hauschild, Alexander M Menzies, Ana Arance, Paolo A Ascierto, AnnaMaria Di Giacomo, Francesco de Rosa, James Larkin, John J Park, Simone M Goldinger, Ryan J Sullivan, Wen Xu, Elisabeth Livingstone, Michael Weichenthal, Rajat Rai, Lydia Gaba, Georgina V Long, and Paul Lorigan.
• The Christie NHS Foundation Trust, and University of Manchester, Manchester, UK; CRUK Manchester Institute, Manchester, UK.
• Eur. J. Cancer. 2018 Mar 1; 91: 116-124.

BackgroundMost metastatic melanoma patients treated with BRAF inhibitors (BRAFi) ± MEK inhibitors (MEKi) eventually progress on treatment. Along with acquired resistance due to genetic changes, epigenetic mechanisms that could be reversed after BRAFi discontinuation have been described. The purpose of this study was to analyse retrospectively outcomes for patients retreated with BRAF-directed therapy.Patients And MethodsOne hundred sixteen metastatic melanoma patients who received BRAFi-based therapy and, after a break, were rechallenged with BRAFi ± MEKi at 14 centres in Europe, US and Australia were studied, respectively. Response rate (RR), overall survival (OS) and progression-free survival (PFS) from the start of retreatment were calculated.ResultsThe median duration of treatment was 9.4 months for first BRAFi ± MEKi treatment and 7.7 months for the subsequent treatment (immunotherapy 72%, other 17%, drug holiday 11%) after BRAFi discontinuation. Brain metastases were present in 51 (44%) patients at BRAFi retreatment. The RR to rechallenge with BRAFi ± MEKi was 43.3%: complete response (CR) 2.6%, partial response (PR) 40.7%, stable disease (SD) 24.8% and progressive disease 31.9%, 3 missing. Of 83 patients who previously discontinued BRAFi due to disease progression, 31 (37.3%) responded (30 PR and 1 CR) to retreatment. The median OS from retreatment was 9.8 months, and PFS was 5 months. Independent prognostic factors for survival at rechallenge included number of metastatic sites (hazard ratio [HR] = 1.32 for each additional organ with metastases, P < .001), lactic dehydrogenase (HR = 1.37 for each multiple of the upper normal limit, P < .001), while rechallenge with combination BRAFi + MEKi conferred a better OS versus BRAFi alone (HR = 0.5, P = .006).ConclusionRechallenge with BRAFi ± MEKi results in a clinically meaningful benefit and should be considered for selected patients.Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

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