Possible immune adverse events as predictors of durable response to BRAF inhibitors in patients with BRAF V600-mutant metastatic melanoma.

Abstract

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are among the cornerstones of metastatic melanoma therapy demonstrating excellent response rates with duration of 7-12 m. Long-term benefit from these agents was reported in patients with normal lactate dehydrogenase (LDH) and less than three disease sites. However, a treatment-dependent marker for long-term efficacy is lacking. Data suggest that immune-related adverse events (irAEs) are associated with clinical benefit in patients treated with immunotherapy and that response to BRAF/MEK therapy may have an underlying immune mechanism. We hypothesised that AEs with an underlying immune mechanism may be associated with a durable response to targeted therapy. We retrospectively identified a cohort of 78 BRAF V600-mutant metastatic melanoma patients treated with BRAFi or BRAFi + MEKi between November 2010 and November 2013. Four treatment-related AEs including vitiligo, uveitis, erythema nodosum and keratitis sicca were defined as irAEs of interest. Retrospective analysis of AEs in relationship to progression-free survival (PFS), disease burden and LDH levels was performed. Median PFS (mPFS) for all patients was 7.5 months with responses ongoing in eight patients as of April 2017. Ten patients were identified with the AEs defined previously. Cox regression analysis revealed a very strong association between those AEs and PFS; mPFS was 42.8 m in patients with at least one AE versus 6.1 m in those without an AE (hazard ratio [HR] 0.22, p = 0.002). This association was independent of LDH levels and disease burden (HR 0.24, p = 0.035). This analysis demonstrates a strong association between immune AEs and durable response to targeted therapy and may provide a treatment-related biomarker to estimate the outcome of therapy.

• Authors: Guy Ben-Betzalel, Erez N Baruch, Ben Boursi, Yael Steinberg-Silman, Nethanel Asher, Ronnie Shapira-Frommer, Jacob Schachter, Gal Markel
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 101 Pg. 229-235 (09 2018) ISSN: 1879-0852 [Electronic] England
• PMID: 30096703 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Azetidines
• Imidazoles
• Oximes
• Piperidines
• Protein Kinase Inhibitors
• Pyridones
• Pyrimidinones
• Vemurafenib
• trametinib
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• MAP Kinase Kinase 1
• cobimetinib
• dabrafenib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Arthralgia (chemically induced)
• Azetidines (administration & dosage, adverse effects)
• Female
• Humans
• Imidazoles (administration & dosage, adverse effects)
• Kaplan-Meier Estimate
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• Male
• Melanoma (drug therapy, genetics, pathology)
• Middle Aged
• Mutation
• Neoplasm Metastasis
• Oximes (administration & dosage, adverse effects)
• Piperidines (administration & dosage, adverse effects)
• Protein Kinase Inhibitors (adverse effects, therapeutic use)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics)
• Pyridones (administration & dosage, adverse effects)
• Pyrimidinones (administration & dosage, adverse effects)
• Retrospective Studies
• Skin Diseases (chemically induced)
• Skin Neoplasms (drug therapy, genetics, pathology)
• Vemurafenib (administration & dosage, adverse effects)
• Young Adult