Identification of biomarkers of immune checkpoint blockade efficacy in recurrent or refractory solid tumor malignancies
Metrics: PDF 1308 views | Full Text 2639 views | ?
Richard K. Yang1, Yun Qing2, Fatima Zahra Jelloul1, Mark J. Routbort1, Peng Wang1, Kenna Shaw3, Jiexin Zhang4, Jack Lee2, L. Jeffrey Medeiros1, Scott Kopetz5, Michael T. Tetzlaff6 and Russell R. Broaddus7
1 Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
3 Institute for Personalized Cancer Treatment (IPCT), University of Texas MD Anderson Cancer Center, Houston, TX, USA
4 Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
5 Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
6 Departments of Anatomical Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
7 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
|Russell R. Broaddus,||email:||[email protected]|
Keywords: biomarkers; immunotherapy; mutations; TMB; histology
Received: October 21, 2019 Accepted: January 13, 2020 Published: February 11, 2020
Patients with advanced solid malignancies recurrent or resistant to standard therapy have limited treatment options. The role of molecular biomarkers for predicting immune checkpoint blockade (ICB) efficacy are not well characterized in these patients. Tumor mutational profiles of 490 patients with a variety of advanced solid tumors enrolled in a prospective protocol were analyzed to identify prognostic and predictive biomarkers. ICB therapy was defined as treatment with any CTLA-4, PD-1, and/or PD-L1 monoclonal antibody. ICB treatment was associated with significantly improved overall survival compared to non-ICB therapy. Multivariate regression analysis including the two variables of tumor mutation burden (TMB) and ICB, and their interaction term, showed favorable survival associated with ICB, unfavorable survival associated with TMB without ICB treatment, and improved outcome with increasing TMB in ICB treated patients. Tumor TP53 mutation was associated with worse survival, but these patients still benefitted from ICB. A more comprehensive multivariate analysis including cancer type, specific gene mutations, and TMB revealed that ICB treatment was an independent predictor of improved overall survival. Therefore, ICB-based therapeutic trials are beneficial in patients with advanced solid malignancies, but the most benefit may be restricted to patients with the right combination of TMB and specific tumor histology and genotype.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.