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Identification of biomarkers of immune checkpoint blockade efficacy in recurrent or refractory solid tumor
Richard K Yang1, Yun Qing2, Fatima Zahra Jelloul1
1Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
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.
Insights
Immune checkpoint blockade (ICB) improves survival in advanced cancers. Higher tumor mutational burden (TMB) benefits patients receiving ICB, while high TMB without ICB is unfavorable.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Advanced solid malignancies resistant to standard therapies have limited options.
- Predictive biomarkers for immune checkpoint blockade (ICB) efficacy are not well-defined in this patient population.
Purpose of the Study:
- To analyze tumor mutational profiles in advanced solid tumors.
- To identify prognostic and predictive biomarkers for ICB efficacy.
Main Methods:
- Analysis of tumor mutational profiles from 490 patients with advanced solid tumors.
- Definition of ICB as treatment with CTLA-4, PD-1, and/or PD-L1 antibodies.
- Multivariate regression analysis incorporating tumor mutational burden (TMB), ICB, and their interaction.
Main Results:
- ICB treatment significantly improved overall survival compared to non-ICB therapy.
- High TMB without ICB was associated with unfavorable survival, but increasing TMB improved outcomes in ICB-treated patients.
- TP53 mutations correlated with worse survival, yet these patients still benefited from ICB. ICB was an independent predictor of improved survival.
Conclusions:
- ICB-based trials are beneficial for advanced solid malignancies.
- Optimal benefit from ICB may depend on a specific combination of TMB, tumor histology, and genotype.
