Abstract 2139: Evaluation of tissue- and plasma-derived tumor mutational burden and genomic alterations of interest from the CheckMate 848 clinical trial
Authors: He Jie , Kalinava Natallia , Doshi Parul , Ma Jie , Pavlick Dean C. , Albacker Lee A. , Tukachinsky Hanna , Fusaro Gina , Oxnard Geoffrey R. , Green George , Fabrizio David , Baden Jonathan 
Published: June 2022

Abstract
Tumor mutational burden (TMB) derived from tissue biopsies (tTMB) has been associated with clinical efficacy in patients treated with immune checkpoint inhibitors; the clinical utility of TMB derived from blood samples (bTMB) has also been demonstrated but is less widely studied. Little is known about the concordance between tissue- and blood-derived genomic assessments and the factors that contribute to their discordance, underlying the need for further investigation of sequence alteration profiles for successful adoption of noninvasive tumor profiling. We explored the genomic landscape, including concordance between tTMB and bTMB, in samples from patients who were screened for enrollment into CheckMate 848, a prospective, phase 2 study of nivolumab plus ipilimumab and nivolumab monotherapy in patients with advanced or metastatic solid tumors with high TMB (NCT03668119).
Of 1954 screened patients, 212 were randomized, with a cap of 15% per tumor type. Tissue- (FoundationOne® CDx—based Clinical Trial Assay) and blood-based (Foundation Medicine bTMB Clinical Trial Assay) genomic data were utilized for analysis of genomic variants, tTMB, and bTMB. In total, 1438 unique tissue and 1720 unique plasma samples were analyzed during trial screening (June 2021 database lock). Of over 100 screened disease ontologies (taken from the tissue diagnosis), pancreatic (9.7%), breast (8.8%), and ovarian (6.1%) cancers, as well as cholangiocarcinoma (5.2%), were the most common. A total of 1141 tissue and 1573 plasma samples passed established quality control criteria, resulting in ascertainment levels of 79.3% for tTMB and 91.5% for bTMB. A correlation between tTMB and bTMB scores was identified across 1017 tissue and plasma sample pairs (Spearman’s r, 0.48; P &lt; 0.0001). Median (range) tTMB and bTMB were 3.8 (0—452.6) and 3.5 (0—1027.5) mutations per megabase (mut/Mb), respectively. High microsatellite instability (MSI) was detected in 25 (2.5%) MSI-evaluable tissue samples; in these patients, median tTMB was 25.2 mut/Mb. At the prespecified cutoff of 10 mut/Mb, 15.8% and 20.7% of samples had high tTMB and bTMB, respectively; the positive (PPA), negative, and overall percentage agreements between assays were 60%, 88%, and 84%, respectively. TMB correlation (Spearman’s r, 0.54; P &lt; 0.0001) and PPA (66%) were improved among 806 (79.3%) sample pairs with plasma maximum somatic allele frequency ≥ 1%.
In CheckMate 848, data from paired biopsies revealed the complementary nature of TMB assessments from tissue and blood, suggesting that both approaches may have the potential to identify high mutational burden in samples obtained from patients with advanced solid tumors. Further interrogation of the biological and analytical factors affecting tumor- and blood-derived genomic profiling is warranted to support their implementation in clinical settings.
Citation Format: Jie He, Natallia Kalinava, Parul Doshi, Jie Ma, Dean C. Pavlick, Lee A. Albacker, Hanna Tukachinsky, Gina Fusaro, Geoffrey R. Oxnard, George Green, David Fabrizio, Jonathan Baden. Evaluation of tissue- and plasma-derived tumor mutational burden and genomic alterations of interest from the CheckMate 848 clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2139.