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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)
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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: One 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.

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 rechallenge with BRAFi ± MEKi was 43%: complete response (CR) 3%, partial response (PR) 39%, stable disease (SD) 24% and progressive disease 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 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).

Conclusion: Rechallenge with BRAFi ± MEKi results in a clinically meaningful benefit and should be considered for selected patients.

A corrigendum exists for this article and may be found in the European Journal of Cancer (2018) Vol. 93 p 158 at DOI: 10.1016/j.ejca.2018.02.001

Original languageEnglish
Pages (from-to)116-124
Number of pages9
JournalEuropean Journal of Cancer
Publication statusPublished - 1 Mar 2018
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


  • BRAF inhibitors
  • BRAFi
  • MEKi
  • metastatic melanoma


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