TABLE 2.
Main studies of tumor TMB to predict antitumor immunotherapy in the last 5 years.
| Cancer type | Study design | Number of patients | Assay | Therapy | Key findings | References |
|---|---|---|---|---|---|---|
| 10 solid tumorsa | KEYNOTE‐158, phase 2 | 1066 | FoundationOne CDx | Pembrolizumab | Higher ORR were observed in patients with a TMB ≥ 10 muts/Mb vs. <10 muts/Mb (29 vs. 6.0%) | Marabelle et al. 36 |
| Untreated NSCLC | CheckMate 227, phase 3 | 1004 | FoundationOne CDx | Nivolumab plus ipilimumab/nivolumab/chemotherapy | Patients with high TMB (≥10 muts/Mb) showed longer PFS with nivolumab plus ipilimumab than with chemotherapy, irrespective of PD‐L1. | Hellmann et al. 37 |
| Untreated NSCLC | CheckMate‐568, phase 2 | FoundationOne CDx | Nivolumab plus ipilimumab | Patients with high TMB (≥10 muts/Mb) showed higher ORR with nivolumab plus ipilimumab than with chemotherapy, irrespective of PD‐L1. | Ready et al. 38 | |
| Pan‐tumor | KEYNOTE‐158, phase 2 | 2234 | FoundationOne CDx | Pembrolizumab/ chemotherapy | TMB ≥ 175 mutations/exome was associated with longer ORR, PFS, and OS of pembrolizumab but not of chemotherapy, regardless of PD‐L1 | Cristescu et al. 39 |
| Untreated NSCLC | DFCI,MSKCC,SU2C, retrospective | 1552 | OncoPanel (DFCI) and MSK‐IMPACT (MSKCC) NGS platforms | PD‐1/PD‐L1 blockade | High TMB (>19.0 Mut/Mb) and PD‐L1 expression (≥50%) have better ORR and OS. Increasing TMB levels are associated with CD8‐positive, PD‐L1+ T‐cell‐mediated response. | Ricciuti et al. 41 |
| Treated/untreated NSCLC | Pooled analysis of KEYNOTE‐021, −189, and −407 | 1298 | FoundationOne CDx | Pembrolizumab Plus Platinum‐Based Chemotherapy | First‐line pembrolizumab plus platinum‐based chemotherapy or chemotherapy alone did not significantly affect tumor TMB in NSCLC. | Powell et al. 42 |
| CRC, EGC, HNSCC, Melanoma, NSCLC | DFCI, DFCI/PROFILE; TCGA, MSKCC | 8193 | WES | Anti‐PD‐1/PD‐L1 or anti‐CTLA‐4 | After recalibrating TMB by regression‐based analysis, TMB‐c (true TMB‐high) provides a better outcome for people treated with ICIs than noncalibrated TMB. | Nassar et al. 43 |
ICIs, immune checkpoint inhibitors; PD‐1, programmed cell death protein‐1; PD‐L1, programmed cell death‐ligand 1; CTLA‐4, cytotoxic T‐lymphocyte antigen‐4; TMB, tumor mutation burden; DFCI, Dana‐Farber Cancer Institute; MSKCC, Memorial Sloan Kettering Cancer Center; SU2C, Stand Up To Cancer; WES, whole‐exome sequencing; CRC, colorectal cancer; EGC, esophagogastric cancer; HNSCC, head and neck squamous cell carcinoma; NSCLC, non‐small cell lung cancer; TCGA, The Cancer Genome Atlas; OS, overall survival; PFS, progression‐free survival; DCB, durable clinical benefit; ORR, objective response rate.
a10 solid tumors: anal squamous cell carcinoma (cohort A); biliary adenocarcinoma (except ampulla of Vater cancers; cohort B); neuroendocrine tumors of the lung, appendix, small intestine, colon, rectum, or pancreas (cohort C); endometrial carcinoma (except sarcomas and mesenchymal tumors; cohort D); cervical squamous cell carcinoma (cohort E); vulvar squamous cell carcinoma (cohort F); small‐cell lung carcinoma (cohort G); malignant pleural mesothelioma (cohort H); papillary or follicular thyroid carcinoma (cohort I); or salivary gland carcinoma, excluding sarcomas and mesenchymal tumors (cohort J).