Concordance of blood and tissue TMB from NGS testing in real-world settings and their ability to predict response to immunotherapy.

2540 Background: Tumor mutational burden (TMB) detected by tissue-based Next Generation Sequencing (NGS) is a biomarker for immunotherapy (IO) response. Plasma-based NGS vendors have developed methods for quantifying TMB from circulating tumor DNA; however, the concordance of blood-TMB (bTMB) and tissue-TMB (tTMB) in real-world settings has not been examined. In this study, we analyzed paired bTMB-tTMB values from cancer patients in community oncology clinics who underwent both plasma- and tissue-based NGS testing to determine whether bTMB predicts response to IO equal to tTMB. Methods: We analyzed 112 patient-matched bTMB-tTMB pairs from 102 unique patients in community oncology settings who received both plasma- and tissue-based NGS profiling at any point in care. NGS results were reported by Foundation Medicine (n = 28 plasma, n = 66 tissue), Guardant Health (n = 78 plasma), and Caris Life Sciences (n = 42 tissue). NGS results were linked with electronic medical records in Genospace, Sarah Cannon’s precision medicine platform. Pearson’s correlation (r) and Lin’s concordance (ρ) coefficients were used for statistical analysis. Results: bTMB exceeded the patient-matched tTMB by an average 2.4-fold; therefore, while the two values showed a positive linear correlation (r2= 0.62, p = 0.01e-27) their concordance was only moderate (ρ = 0.58, n = 112). Gastrointestinal cancers exhibited the lowest correlation (r2= 0.01, p = 0.5) and concordance (ρ = 0.03, n = 35). The discordance between bTMB and tTMB was not an outcome of the specimens being collected on different dates, as the bTMB/tTMB ratio did not correlate with the time between plasma and tissue specimen collection (r2= 0.003, p = 0.84, n = 112). While a majority of bTMB-tTMB pairs had agreement in high vs. low status (High ≥ 10 mut/Mb; Low < 10 mut/Mb), a considerable portion were bTMB-High/tTMB-Low (see table). Strikingly, the bTMB-High/tTMB-Low patients who received IO had an average time to treatment failure (TTF) that surpassed that of the bTMB-High/tTMB-High cohort (see table). Considering bTMB alone, patients with a high status outperformed those with a low status on IO (bTMB-High: TTF = 200 days, n = 21; bTMB-Low: TTF = 125 days, n = 12). Conclusions: In real-world settings where tissue- and plasma-based NGS panels are ordered as standard of care, bTMB values are consistently higher than tTMB values. This discrepancy leads to plasma-based tests resulting a TMB-High designation more frequently than tissue-based NGS tests. Patients who are TMB-High by plasma perform relatively well on IO, indicating that bTMB may be a particularly effective biomarker of IO sensitivity.[Table: see text]