Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib.

Abstract

PURPOSE:

Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells.

PATIENTS AND METHODS:

We conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated BRAF V600-mutant metastatic melanoma from the randomized, phase III COMBI-v trial and treated with dabrafenib plus trametinib who had available tumor specimens from screening.

RESULTS:

Baseline cell-cycle gene expression signature was associated with progression-free survival (P = 0.007). Patients with high T-cell/low B-cell gene signatures had improved median overall survival (not reached [95% confidence interval (CI), 33.8 months-not reached]) compared with patients with high T-cell/high B-cell signatures (19.1 months; 95% CI, 13.4-38.6 months). Patients with high B-cell signatures had high B-cell infiltration into the tumor compartment, corresponding with decreased MAPK activity and increased expression of immunosuppressive markers.

CONCLUSIONS:

B cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed.

• Authors: Jan C Brase, Robert F H Walter, Alexander Savchenko, Daniel Gusenleitner, James Garrett, Tobias Schimming, Renata Varaljai, Deborah Castelletti, Ju Kim, Naveen Dakappagari, Ken Schultz, Caroline Robert, Georgina V Long, Paul D Nathan, Antoni Ribas, Keith T Flaherty, Boguslawa Karaszewska, Jacob Schachter, Antje Sucker, Kurt W Schmid, Lisa Zimmer, Elisabeth Livingstone, Eduard Gasal, Dirk Schadendorf, Alexander Roesch
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 16 Pg. 4500-4510 (08 15 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 34108180 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Imidazoles
• Oximes
• Pyridones
• Pyrimidinones
• trametinib
• dabrafenib

Topics

• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• B-Lymphocytes
• Humans
• Imidazoles (administration & dosage)
• Melanoma (drug therapy, pathology)
• Oximes (administration & dosage)
• Pyridones (administration & dosage)
• Pyrimidinones (administration & dosage)
• Skin Neoplasms (drug therapy, pathology)
• Treatment Outcome