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