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Abstract 5528: Evaluation of tumor mutation burden as a biomarker for immune checkpoint inhibitor efficacy: A calibration study of whole exome sequencing with FoundationOne®

Background: Tumor mutation burden (TMB) is emerging as a potential predictive biomarker for the efficacy of immune checkpoint inhibitors. TMB has traditionally been evaluated using whole exome sequencing (WES), an established method for analysis of genomic alterations that requires both tumor and germline DNA. In the phase 3 CheckMate 026 study (NCT02041533) of nivolumab vs chemotherapy in first-line non-small cell lung cancer (NSCLC), exploratory analyses were performed to determine the value of TMB as a predictive biomarker in 312 tumor samples using WES. Patients with baseline TMB in the upper tertile were associated with an increased objective response rate to nivolumab and longer median PFS, relative to patients with TMB in the lowest 2 tertiles and compared with chemotherapy-treated patients in the upper tertile (Carbone et al. N Engl J Med. 2017). Increasingly, targeted cancer gene panels, including the FoundationOne® (F1) assay, are being assessed as an alternative to WES for clinical use. To determine the feasibility of transitioning from WES to a potential in vitro diagnostic next-generation sequencing (NGS) platform for TMB analysis, we performed a study comparing values generated by WES with those generated by the F1 assay. Methods: Using the 2 hybridization-capture/NGS methods (WES and F1), TMB was assessed in formalin-fixed, paraffin-embedded NSCLC tumor samples. For WES, coding regions of 21,522 genes were analyzed, with TMB defined as the total number of missense mutations in the tumor exome. The F1 assay is a targeted gene panel of 315 cancer-related genes (Frampton et al. Nat Biotechnol. 2013), with TMB defined as the number of somatic mutations per megabase of sequenced tumor genome. Results: TMB data from 44 NSCLC samples were available on both F1 and WES platforms. We determined an empirical method to convert TMB values derived from WES into those derived from F1 to establish calibration between the 2 methodologies. TMB assessed by WES and by F1 was highly correlated (Spearman9s r=0.9). As an additional test of concordance between the platforms, we examined agreement between the assays around the median WES value of 148 mutations. This value projects to 7.64 mutations per megabase on F1. The overall agreement between F1 and WES around these values was 86% (95% Wilson CI, 73-94). Positive and negative agreements between the 2 hybridization-capture/NGS methods were both 86% (95% Wilson CI, 67-95). Conclusion: Bridging TMB analysis by WES to F1 facilitates the transition of WES-derived biomarker data to the clinical in vitro diagnostic F1. This study demonstrates the feasibility of harmonization of TMB results across testing platforms, which provides alternative TMB testing options. Citation Format: Joseph D. Szustakowski, George Green, William J. Geese, Kim Zerba, Han Chang. Evaluation of tumor mutation burden as a biomarker for immune checkpoint inhibitor efficacy: A calibration study of whole exome sequencing with FoundationOne® [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5528.