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Table 1 Overview of the main published studies on TMB quantification from gene panels

From: Tumor mutational burden quantification from targeted gene panels: major advancements and challenges

Reference Gene panel (version) Cancer type Study design Study ID ICI TMB cutoff (mut/Mb) Method of TMB cutoff determination TMB predictive value Clinical outcome N patients
Rosenberg, 2016 [5] FM1 (v3) urothelial carcinoma (metastatic or locally advanced) trial (single-arm, phase 2) NCT02108652 PD-(L)1 NA NA NA ORR 315
Balar, 2017 [16] FM1± urothelial carcinoma (metastatic) trial (single-arm, phase 2) NCT02108652 PD-(L)1 Q3 (> = 16) distribution NA OS 123
Powles, 2018 [15] FM1± urothelial carcinoma (metastatic) trial (randomized, phase 3) NCT02302807 PD-(L)1 Q2 (9.65) distribution NA OS 931
Kowanetz, 2016 [27] FM1 (v3) NSCLC trial (randomized, phase 2) NCT01903993 PD-(L)1 Q1, Q2 (9.9), Q3 distribution NA PFS, OS, ORR 454
trial (single-arm, phase 2) NCT02031458
trial (single-arm, phase 2) NCT01846416
Gandara, 2018 [61] a FM1 bTMB assay NSCLC trial (randomized, phase 2) NCT01903993 PD-(L)1 > = 14 positive and negative percentage agreement with the orthogonally validated FM1 NA PFS, OS 259
trial (randomized, phase 3) NCT02008227
Hellmann, 2018 [50] FM1 CDx NSCLC trial (randomized, phase 3) NCT02477826 combo > 10 based on NCT02659059 NA PFS 1004
Rizvi, 2018 [42] MSK-IMPACT (v1, v2, v3) NSCLC trial (randomized, phase 1) NCT01295827 PD-(L)1 Q2 (7.4) distribution AUC = 0.601 (DCB) DCB, PFS 240
Ready, 2019 [28] FM1 CDx NSCLC trial (non-randomized, phase 2) NCT02659059 combo 10 ROC AUC (95% CI) = 0.73 (0.62–0.84); TPR (95% CI) = 0.78 (0.63–0.93); FPR (95% CI) = (0.62 (0.49–0.73) ORR 98
Wang, 2019 [49] a NCC-GP150 NSCLC observational (cohort) NA PD-(L)1 6 (tot mut) best cutoff from in silico analysis on Rizvi 2015 WES NA PFS, ORR 50
Johnson, 2016 [12] FM1 (v2, v3) melanoma observational (retrospective) NA PD-(L)1 < 3.3, 3.3–23.1, > 23.1 ROC NA PFS, OS, ORR 65
Chalmers, 2017 [22] FM1 (v1, v2, v3, v4), FM1 Heme various locally advanced or metastatic solid tumors observational (retrospective) NA NA > 20 NA NA NA 102, 292
Goodman, 2017 [18] FM1 (v1, v2, v3) various locally advanced or metastatic solid tumors observational (cohort, retrospective) NCT02478931 PD-(L)1, CTLA-4, high-dose IL2 or combo < 6, 6–19, > 19 Foundation Medicine official reports NA PFS, OS, ORR 151
Khagi, 2017 [44] a Guardant360 various solid tumors observational (cohort, retrospective) NCT02478931 PD-(L)1, CTLA-4, combo or other mean (> 3 VUS) distribution NA PFS, OS, ORR 69
Zehir, 2017 [73] MSK-IMPACT (v1, v2) various primary and metastatic solid tumors observational (cohort, prospective) NCT01775072 NA > 13.8 distribution (median TMB +  2 × IQR_TMB) NA NA 10, 945
Samstein 2019 [43] MSK-IMPACT (v3) bladder observational (cohort, prospective) NCT01775072 PD-(L)1, CTLA-4 or combo 17.6 distribution (top 20%) NA OS, PFS, DCB 214
breast 5.9 45
breast ER+ 6.8 24
breast ER- 4.4 21
unknown primary 14.2 90
colorectal 52.2 110
esophagogastric 8.8 126
glioma 5.9 117
head and neck 10.3 138
melanoma 30.7 321
NSCLC 13.8 350
renal cell carcinoma 5.9 151
  1. ORR Objective Response Rates, DCB Durable Clinical Benefit, OS Overall Survival, PFS Progression-Free Survival, FM1 Foundation Medicine’s FoundationOne (v1: 185 genes, v2: 236 genes, v3: 315 genes, v4: 405 genes, Heme: 405 genes, CDx: 324 genes); ±: version not specified; MSK-IMPACT v1 341 genes, v2: 410 genes, v3 468 genes, NSCLC non-small cell lung cancer, ER Estrogen Receptor, VUS variants of unknown significance, PD-(L)1 anti-PD-1 or anti-PD-L1, CTLA-4 anti-CTLA-4, combo combined anti-PD-1/PD-L1 + anti-CTLA-4, Q1-Q4 quartiles, a: TMB quantification from blood
  2. Each study is described reporting gene panel, cancer type, study design, study ID (on ClinicalTrials.gov), immune checkpoint inhibitor treatment (ICI), proposed TMB cutoff, method for TMB cutoff determination, outcome analyzed to evaluate TMB clinical utility. AUC, TPR (True Positive Rate) and FPR (False Positive Rate) are provided, when available, as a measure of TMB predictive value for immunotherapy responder classification