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.
Highlights
Patients with advanced cancers who are initially resistant to frontline therapy or who develop recurrent disease have a finite survival [1], and choosing the right therapy within this window is crucial
Multivariate regression analysis including the two variables of tumor mutation burden (TMB) and immune checkpoint blockade (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
The relationship between histology and TMB was comparable to previous reports (Figure 1A), demonstrating high TMB in melanoma, squamous cell carcinoma of the lung, and urothelial carcinoma as well as low TMB in non-medullary thyroid carcinoma, thymoma and low grade serous gynecologic carcinoma
Summary
Patients with advanced cancers who are initially resistant to frontline therapy or who develop recurrent disease have a finite survival [1], and choosing the right therapy within this window is crucial. In a prospective trial reported previously, a large next-generation sequencing (NGS) panel comprised of the entire coding regions of 409 cancer-related genes was employed to identify clinically actionable gene amplifications or mutations to help place patients onto matched targeted therapy trials [2]. Another potential use for such larger NGS panels is calculation of tumor mutation burden (TMB), a promising biomarker for prediction of response to immune checkpoint blockade [7]. It remains unclear what predictive and/or prognostic significance TMB has in patients with advanced stage, recurrent or treatment refractory solid malignancies
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