Caris Life Science Study Shows Ultra-Deep Whole Exome Sequencing Outperforms Targeted Gene Panels
Caris Life Science has published a study in Cancer Immunology, Immunotherapy demonstrating that measuring tumor mutational burden using ultra-deep Whole Exome Sequencing provides superior prediction of pembrolizumab immunotherapy benefit compared to estimates of TMB from targeted gene panels. TMB is a pan-tumor biomarker used to determine patients' eligibility for pembrolizumab. These findings highlight the importance of testing all cancer patients with ultra-deep WES, the only truly comprehensive genomic profile for therapy selection. The study used Caris' large-scale, real-world clinico-genomic database, containing 26,756 patients treated with pembrolizumab who were evaluable for this study. WES provides a true measurement of TMB by interrogating every protein-coding gene mutation that may create a neoantigen, in comparison to targeted panels that only estimate TMB with incomplete gene coverage. Key findings include: The analysis compared WES-measured TMB with commercially available targeted panel estimates of TMB and found discordance in 10-15% of cases, with error rates correlating to panel size. In discordant cases, WES TMB more accurately predicted overall survival in pembrolizumab-treated patients than panel-based estimates. In a subset of 'TMB reliant' patients, for example, patients with tumor types that lack disease-specific immune checkpoint inhibitor indications, the median overall survival in discordant cases was about five months longer for WES TMB-High and panel TMB-Low compared to WES TMB-Low and panel TMB-High cases treated with pembrolizumab. The study concludes that WES-based TMB measurements are a superior predictor of pembrolizumab benefit than panel-based TMB estimates and more reliably identify both patients who may benefit from therapy and those unlikely to respond, particularly in tumor types where TMB is the primary biomarker guiding access to immune checkpoint inhibitors.
