Table 2:
Examples of blood TMB and response to immunotherapy (checkpoint inhibitors)
| Cancer type (N) |
TMB and response relationship | Assay type | Treatment Strategy |
Comments | References |
|---|---|---|---|---|---|
| Diverse cancers (69 pts) |
VUS > 3 vs. VUS ≤ 3 SD ≥6 months/PR/CR 45% versus 15%, respectively; P = 0.014 PFS: 3.84 vs 2.07 months (HR, 0.52; 95% CI, 0.31–0.87; P=0.019) OS: NR vs 10.72 (HR, 0.39; 95% CI, 0.18– 0.83; P=0.042) |
NGS 54-70 genes (Guardant) |
ICI | Design: retrospective analysis, single institutional data Drugs: multiple checkpoint inhibitors Of the 69 patients, 20 (29%) presented >3 VUS and 49 (71%) ≤ 3 VUS |
(Khagi et al., 2017) |
| NSCLC (583 pts, validation cohort) |
Atezolizumab vs docetaxel comparison bTMB ≥16 : PFS: HR 0.65 (0.47-0.92); OS: 0.64 (0.44-0.92) bTMB <16: PFS: HR 0.98 (0.80-1.20); OS: 0.65 (0.52-0.81) |
NGS 1.1 Mb (Foundation Medicine panel) |
ICI | Design: exploratory analysis of prospective randomized phase II (POPLAR NCT01903993) and phase III trial (OAK NCT02008227_ Drug: atezolizumab Correlation with tTMB by Foundation Medicine assay was demonstrated (Spearman correlation 0.93). |
(Gandara et al., 2018) |
| NSCLC (119 pts) |
bTMB ≥16 vs. <16 ORR: 28.6% vs 4.4% (P=0.0002) PFS: 5.0 vs 3.5 months (HR 0.80 90% CI 0.54-1.18) OS: 23.9 vs. 13.4 months (HR 0.66 90% CI 0.40-1.10) |
NGS 1.1 Mb (Foundation Medicine panel) |
ICI | Design: prospective analysis of B-F1RST single arm prospective trial (NCT02848651)_ Drug: atezolizumab bTMB was predictive of higher RR; no statistical significant benefits were detected for PFS or OS |
(Kim et al., 2018; Socinski et al., 2019) |
| NSCLC (809 pts) |
Durvalumab+Tremelimuab vs. CT bTMB ≥20mut/Mb: PFS 4.2 vs 4.4 months (HR 0.53 95% CI 0.34-0.81); OS 21.9 vs 10 months (HR 0.49 [95% CI 0.32-0.74) bTMB <20mut/Mb: PFS 2.0 vs 5.0 months (HR 1.55 95% CI 1.23-1.94); OS 8.5 vs 11.6 months (HR 1.16 95% CI 0.93-1.45) |
Guardant OMNI (Guardant Health) |
ICI+ICI | Design: exploratory analysis of prospective randomized phase III trial (MYSTIC NCT02453282) Drugs: durvalumab + tremelimumab bTMB was correlated with tTMB (Spearman’s correlation = 0.6) Cut-points for dichotomization of TMB may be made to optimize positive or negative predictive value. |
(Rizvi et al., 2020) |
| NSCLC (98 pts) |
bTMB ≥6 vs. <6 PFS: NR vs 2.9 months, (HR 0.39; 95% CI, 0.18-0.84; P = 0.01) RR: 39.3% vs. 9.1% (P=0.02) |
NGS 150 genes (NCC-GP150) |
ICI | Design: retrospective analysis of multi-institutional series_ Drugs: multiple PD-1/PD-L1 inhibitors The authors demonstrated a significant correlation between bTMB vs tissue TMB in a virtual comparison to TCGA (r2=0.91) and with matched tTMB calculated by WES (Spearman correlation = 0.62) |
(Wang et al., 2019) |
| NSCLC (66 pts) |
bTMB ≥16 vs. <16 ORR: 28.6% vs 4.4% (P=0.0002) PFS: 14.1 vs 4.7 months (HR 0.30 95% CI 0.16-0.60, p<0.001) OS: not reached vs. 8.8 months (HR 0.48 90% CI 0.22-1.03; p=0.061) |
Guardant OMNI (Guardant Health) |
ICI | Design: observational prospective cohort of single institutional data (NCT03047616) Drug: pembrolizumab bTMB>16 mut/Mb is associated with improved PFS; STK11/KEAP1/PTEN and ERBB2 mutations were common in unresponsive patients |
(Aggarwal et al., 2020) |
Abbreviations: bTMB = blood tumor mutational burden; CR = complete response; CT=chemotherapy; HR=hazard ratio; ICI=immune checkpoint inhibitor; mb = megabase; N = number; NGS = next generation sequencing; NR=not reached; NSCLC=non-small cell lung cancer; ORR = objective response rate; PFS = progression-free survival; PR = partial response; pts = patients; RR = response rate; SD = stable disease, tTMB=tissue tumor mutational burden; VUS = variant of unknown significance; WES = whole exome sequencing