Table 4.
Method of TMB detection | TMB cutoff | Malignancy | Therapy | Result | References |
---|---|---|---|---|---|
Whole-exome sequencing of DNA (tumors and matched normal blood) | Cut-off: number of nonsynonymous mutations high > 100 and low < 100 per tumor | Melanoma | Anti-CTLA-4 |
Increased mutational burden correlated with benefit from therapy. OS for long-term benefit 4.4 year, for minimal or no benefit 0.9 year P = 0.01 |
Snyder et al. [11] |
Whole-exome sequencing of DNA (tumors and matched normal blood) | Cut-offs were high (> 200) and low (< 200) nonsynonymous mutation burden | NSCLC | Anti-PD-1 |
Nonsynonymous mutation burden significantly associated with clinical benefit from anti-PD-1 therapy ORR and PFS were higher in patients with high nonsynonymous burden [ORR 63% vs. 0%; median PFS 14.5 vs. 3.7 months) P = 0.03 |
Rizvi et al. [70] |
Whole-exome sequencing Tested nonsynonymous mutations in genes on the cancer gene panel (CGP): foundation medicine panel (FM-CGP) and institutional panel (HSL-CGP) |
Nonsynonymous mutations: high (≥ 7 for FM-CGP and ≥ 13 for HSL-CGP) and a low (< 7 for FM-CGP and < 13 for HSL-CGP) |
Melanoma NSCLC Melanoma |
Anti-PD-1 Anti-CTLA-4 |
CGP mutational load significantly associated with durable clinical benefit, PFS Median PFS 14.5 vs. 3.4 months P = 0.008 No clinical benefit with CGP-mutational load P = 0.24 |
Campesato et al. [163] |
FoundationOne assay—hybrid capture-based next-generation sequencing (base substitutions, indels, gene rearrangements, copy number changes). TMB detected from FoundationOne assay was extrapolated to whole-exome data | Cut-off: low: < 3.3 mutations/mb intermediate: 0.3–23.1 mutations/mb high: > 23.1 mutations/mb | Melanoma | PD-1 blockade |
High mutation load was also associated with superior OS and PFS using Cox proportional hazards model, adjusted for age, gender, stage, and prior ipilimumab (high vs. low HR 0.14, for PFS; HR 0.09, for OS) P < 0.001 |
Johnson et al. [164] |
FoundationOne assay | Low (1–5 mutations/mb), intermediate (6–19 mutations/mb), and high (≥ 20 mutations/mb) |
Melanoma NSCLC and other tumor types |
PD-1 or PD-L1 monotherapy Combination of anti-CTLA4 & anti-PD-1 therapy Anti-CTLA4 and IL2 |
The RR for patients with high (≥ 20 mutations/mb) vs. low to intermediate TMB was 22/38 (58%) vs. 23/113 (20%) (P = 0.001); median PFS, 12.8 vs. 3.3 months (P < 0.0001); median OS, not reached vs. 16.3 months (P = 0.0036). | Goodman et al. [76] |
FoundationOne assay | TMB high: ≥ 10 mutations/mb | NSCLC (CheckMate 227 trial) |
Anti-PD-1 Anti-CTLA-4 |
Significantly longer PFS in patients with ≥ 10 mutations/mb TMB treated with anti-PD-1 and anti-CTLA-4 therapy. The 1-year PFS rate was 42.6% with anti-PD-1 and anti-CTLA-4 therapy vs. 13.2% with chemotherapy; median PFS was 7.2 months vs. 5.5 months. ORR was 45.3% with anti-PD-1 and anti-CTLA-4 therapy and 26.9% with chemotherapy P < 0.01 |
Hellmann et al. [78] |
FoundationOne assay | Median TMB ≥ 9 mutations/mb, High TMB ≥ 13.5 mutations/mb | NSCLC | Anti-PDL1 |
Five-year RFS and OS of DEL, PM, and WT were 67.3/85.9%, 76.4/88.6%, 59.2/71.5%, respectively, and both survivals of each mutant were significantly better than those of WT P = 0.027 |
Kowanetz et al. [172] |
TMB: total number of somatic missense mutations. Used whole-exome sequence data, and compared to FoundationOne assay profile. | Low: 0 to < 143 mutations; medium: 143–247 mutations; high: ≥ 248 mutations | SCLC |
Anti-PD-1 Anti-CTLA-4 |
Within both the nivolumab monotherapy and nivolumab plus ipilimumab treatment groups, ORR were higher in those patients with high tumor mutational burden (21.3% and 46.2%, respectively) than in patients with low (4.8% and 22.2%, respectively) or medium (6.8% and 16.0%, respectively) TMB P = not reported |
Hellmann et al. [165] |
bTMB: hybridization-capture panel as the tumor FoundationOne TMB test | bTMB cut-points (≥ 10, ≥ 16 and ≥ 20) | NSCLC | Anti-PDL1 | Improved OS and PFS for all bTMB cut-points (P = 0.035). Cut-point ≥ 16 had stronger PFS (0.036). bTMB correlated with TMB, bTMB correlated with PFS (P = 0.013), bTMB did not associate with high PD-L1 expression | Gandara et al. [41] |
bTMB blood-tumor mutational burden, NSCLC non-small cell lung carcinoma, TMB tumor mutational burden, ORR objective response rate, OS overall survival, PFS progression-free survival, RR response rate, SCLC small cell lung carcinoma, RFS recurrence-free survival, DEL exon 19 deletions (EGRF), PM and exon 21 L858R (EGRF), WT wild type