Table 2.
Studies utilizing TMB as a predictor of response to treatment with ICIs
| Clinical trials | |||||
|---|---|---|---|---|---|
| Prespecified analysis | |||||
| Study | Drug | Tumor type and stage | Calculation methodology for TMB | Cut-off | Results |
| Checkmate 22767 | Nivo + Ipi | Stage IV or recurrent NSCLC | CGP (Foundation Medicine) | 10 per Mb | In patients with high TMB (≥10 per Mb), median PFS: 7.2 m vs 5.5 m (Nivo + Ipi vs Chemo) |
| Exploratory analysis | |||||
| Study | Drug | Tumor type and stage | Calculation methodology for TMB | Cut-off | Results |
| IMvigor 21068 | Atezo | Locally advanced and metastatic UC | CGP (Foundation Medicine) | Median TMB: 12.4 vs 6.4 per Mb (responders vs non-responders) | |
| Checkmate 02627 | Nivo | Stage IV or recurrent NSCLC | WES | Low TMB: 0–100 mutations Medium TMB: 100–242 mutations High TMB: ≥243 mutations | Among the patients with a high TMB, RR: 47% vs 28%, median PFS 9.7 m vs 5.8 m (Nivo vs Chemo) |
|
| |||||
| Retrospective study | |||||
|
| |||||
| Author | Drug | Tumor type and stage | Calculation methodology for TMB | Results | |
| Campesato et al66 | Pembro | NSCLC | CGP (Foundation Medicine) | TMB was calculated using just mutated genes present in the cancer gene panel High TMB vs low TMB: 69% vs 20% (proportions of patients experiencing durable clinical benefit) | |
| Rizvi et al65 | Pembro | NSCLC | WES | Higher somatic nonsynonymous mutation burden was associated with the clinical efficacy of Pembro Median number of nonsynonymous mutations: 302 vs 148 (patients with durable clinical benefit vs no durable benefit) | |
| Johnson et al64 | Nivo or Pembro or Atezo | Melanoma | CGP (Foundation Medicine) | Mutational load effectively stratified patients by likelihood of response Median TMB: 45.6 vs 3.9 per Mb (responders vs non-responders) Median PFS: not reached vs 89 days vs 86 days Median OS: not reached vs 300 days vs 375 days (high-TMB group vs intermediate-TMB group vs low-TMB group) | |
| Yaghmour et al63 | Ipi or Pembro or Nivo | Any solid tumor | Not mentioned | Higher TMB was associated with improved OS OS: 722 vs 432 days OR: 50% vs 20% (high-TMB group vs low-TMB group) | |
| Kowanetz et al61 | Atezo | NSCLC | CGP (Foundation Medicine) | OS, PFS, and RR were improved in patients with increased TMB treated with Atezo in both unselected and selected patients | |
| Goodman et al62 | anti-PD-1/PD-L1, anti-CTLA-4, anti-CTLA-4 + anti-PD-1/PD-L1, high-dose IL-2, and other agents1 | Melanoma, NSCLC, and other types2 | CGP (Foundation Medicine) | Higher TMB was independently associated with better outcome parameters RR: 58% vs 20% Median PFS: 12.8 m vs 3.3 m Median OS: not reached vs 16.3 m (high vs low-to-intermediate TMB) | |
Notes:
Other agents: OX40, anti-CD73, talimogene laherparepvec, OX40 + anti-PD-L1, and IDO + anti-PD-1.
Tumors included the following: adrenal carcinoma, appendix adenocarcinoma, basal cell carcinoma, bladder transitional cell carcinoma, breast cancer, cervical cancer, colon adenocarcinoma, cutaneous squamous cell carcinoma, hepatocellular carcinoma, head and neck, Merkel cell carcinoma, ovarian carcinoma, pleural mesothelioma, prostate cancer, renal cell carcinoma, sarcoma, thyroid cancer, unknown primary squamous cell carcinoma, and urethral squamous cell carcinoma
Abbreviations: Atezo, atezolizumab; Chemo, chemotherapy; CTLA-4, cytotoxic T-lymphocyte-associated antigen-4; CGP, comprehensive genomic profiling; ICI, immune checkpoint inhibitor; Ipi, ipilimumab; m, months; Mb, megabase; Nivo, nivolumab; NSCLC, non-small-cell lung cancer; Pembro, pembrolizumab; OR, odds ratio; OS, overall survival; PD-1, programmed death receptor-1; PD-L1, programmed death receptor-ligand 1; PFS, progression-free survival; RR, response rate; SCLC, small-cell lung cancer; TMB, tumor mutational burden; UC, urothelial carcinoma; WES, whole-exome sequencing.