Rechallenge with BRAF-directed treatment in metastatic melanoma: A multi-institutional retrospective study.
Date
2018-03-01ICR Author
Author
Valpione, S
Carlino, MS
Mangana, J
Mooradian, MJ
McArthur, G
Schadendorf, D
Hauschild, A
Menzies, AM
Arance, A
Ascierto, PA
Di Giacomo, A
de Rosa, F
Larkin, J
Park, JJ
Goldinger, SM
Sullivan, RJ
Xu, W
Livingstone, E
Weichenthal, M
Rai, R
Gaba, L
Long, GV
Lorigan, P
Type
Journal Article
Metadata
Show full item recordAbstract
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 43.3%: 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). CONCLUSION: Rechallenge with BRAFi ± MEKi results in a clinically meaningful benefit and should be considered for selected patients.
Collections
Subject
BRAF inhibitors
BRAFi
MEKi
Metastatic melanoma
Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Australia
Clinical Decision-Making
Drug Administration Schedule
Drug Resistance, Neoplasm
Europe
Female
Humans
Kaplan-Meier Estimate
MAP Kinase Kinase Kinases
Male
Melanoma
Middle Aged
Proportional Hazards Models
Protein Kinase Inhibitors
Proto-Oncogene Proteins B-raf
Retrospective Studies
Risk Factors
Signal Transduction
Skin Neoplasms
Time Factors
Treatment Outcome
United States
Language
eng
Date accepted
2017-12-02
License start date
2018-03-01
Citation
European Journal of Cancer, 2018, 91 pp. 116 - 124
Publisher
ELSEVIER SCI LTD