Rechallenge with BRAF-directed treatment in metastatic melanoma: A multi-institutional retrospective study

S. Valpione, M S Carlino, Johanna Mangana, Meghan J Mooradian, G McArthur, Dirk Schadendorf, Axel Hauschild, Alexander M Menzies, Ana Arance, Paolo Ascierto, AnnaMaria Di Giacomo, Francesco de Rosa, James Larkin, John J Park, S M Goldinger, Ryan J Sullivan, Wen Xu, Elisabeth Livingstone , Michael Weichenthal, Rajat RaiLydia Gaba, Georgina V. Long, Paul Lorigan

Research output: Contribution to journalArticlepeer-review


Background Most 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 Methods 116 metastatic melanoma patients who received BRAFi based therapy and, after a break, were re-challenged 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. Results The 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 re-challenge with BRAFi +/- MEKi was 43%: complete response (CR) 3%, partial response (PR) 39%, stable disease (SD) 24% and progressive disease (PD) 30%, 4% 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 re-challenge included number of metastatic sites (HR=1.32 for each additional organ with metastases, p<.001), LDH (HR=1.37 for each multiple of the upper normal limit, p<.001), while re-challenge with combination BRAFi+MEKi conferred a better OS vs BRAFi alone (HR=0.5, P=.006). Conclusion Re-challenge with BRAFi +/- MEKi results in a clinically meaningful benefit and should be considered for selected patients.
Original languageEnglish
Pages (from-to)116-124
Number of pages9
JournalEuropean Journal of Cancer
Early online date19 Jan 2018
Publication statusPublished - Mar 2018

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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