Table 1. Outcome of NSCLC patients treated with immune checkpoint inhibitors in relation to tumor mutational burden.
| Author, year (retro- or prospective) | NR of TMB evaluable NSCLC patients | Treatment | TMB test | Definition TMB high | TMB associated with PD-L1 status | ORR high vs. low TMB | DCB high vs. low TMB | PFS high vs. low TMB | OS high vs. low TMB |
|---|---|---|---|---|---|---|---|---|---|
| Samples used from trial patients | |||||||||
| Rizvi, 2015 (retrospective; unclear which trials) | 16 discovery 18 validation |
Pembro | WES | >200 (median) mutations | NA | 63% vs. 0% | 73% vs. 13% | mPFS: 14.5 vs. 3.7 mo (HR 0.19) | NA |
| Kowanetz, 2016 (retrospective; FIR, BIRCH, POPLAR) | 509 | Atezo (± vs. doc) | F1 LDT | ≥9.9 mut/Mb | weak | NA | NA | FIR + BIRCH: 1st line, PFS HR 0.49; 2nd line, PFS HR 0.64; POPLAR*: mPFS 7.3 vs. 2.8 mo (HR 0.49) |
FIR + BIRCH: 1st line, OS HR 0.71; 2nd line, OS HR 0.86; POPLAR*: mOS 16.2 vs. 8.3 mo (HR 0.48) |
| Gandara, 2017 (retrospective; POPLAR, OAK) | 794 | Atezo vs. doc | bTMB 394-gene panel | ≥10 mut/Mb | No | NA | NA | PFS HR*; OAK 0.73; POPLAR 0.68 | OS HR*; OAK 0.69; POPLAR 0.59 |
| Carbone, 2017 (retrospective; CheckMate 026) | 312 | Nivo vs. platinum-doublet chemo | WES | ≥243 mutations | No | 47% vs. 28%* | NA | mPFS* 9.7 vs. 5.8 mo (HR 0.62) | NA |
| Hellmann, 2017 (retrospective; CheckMate 012) | 75 | Nivo + ipi | WES | >158 (median) mutations | No | 51% vs. 13%** | 65% vs. 34%** | mPFS** 17.1 vs. 3.7 mo (HR 0.41) | NA |
| Ramalingam, 2018 (prospective; CheckMate 568) | 98 | Nivo + ipi | F1 CDxTM | ≥10 mut/Mb | No | 44% vs. 40%** | NA | mPFS 7.1 vs. 2.6 mo (HR NA) | NA |
| Hellmann, 2018 (prospective; CheckMate 227) | 299 | Nivo + ipi vs. platinum-doublet chemo or nivo | F1 CDxTM | ≥10 mut/Mb | No | 45.3% vs. 26.9%* | NA | mPFS* 7.2 vs. 5.5 mo (HR 0.58) 1-year PFS* 42.6% vs. 13.2% | NA |
| Samples used from patients treated in daily practice or unknown | |||||||||
| Spigel, 2016 (retrospective; unknown) | 64 | Nivo, atezo or pembro | FoundationOne®# | ≥15 mut/Mb | NA | NA | DoT 64 vs. 17 weeks (HR 0.40) | NA | NA |
| Park, 2017 (retrospective; daily practice) | 36 | Nivo | NA | ≥20 mut/Mb | NA | NA | NA | NA | mOS** NR vs. 10.3/12.4 mo (HR NA) |
| Singal, 2017 (retrospective; daily practice | 444 | Nivo | FoundationOne®# | ≥20 mut/Mb | NA | NA | DoT 7.5 vs. 4.6 mo (HR NA) | NA | NA |
| Ross, 2017 (retrospective; daily practice) | 1,619 | Not specified | FoundationOne®# | ≥20 mut/Mb | Weak | NA | High TMB predictive for longer DoT** (HR NA) | NA | BA |
| Rizvi, 2018 (retrospective; 78% treated in daily practice) | 240 | Anti-PD(L)1 + anti-CTLA4 | MSK-IMPACT assay | >7.4 mut/Hb | No | NA | 38.6% vs. 25.1% | PFS HR 1.38 (low vs. high TMB) | NA |
*, high TMB checkpoint inhibitor vs. high TMB chemotherapy instead of high versus low TMB when treated with checkpoint inhibitor; **, high TMB vs. low/intermediate TMB when treated with checkpoint inhibitor instead of high versus low TMB when treated with checkpoint inhibitor; #, not mentioned in abstract whether it was F1 LDT or F1 CDxTM assay. NSCLC, non-small cell lung cancer; TMB, tumor mutational burden; PD-L1, programmed death-ligand 1; pembro, pembrolizumab; WES, whole exome sequencing; NA, not available; ORR, objective response rate; mPFS, median progression free survival; mo, months; HR, hazard ratio; DCB, durable clinical benefit; atezo, atezolizumab; doc, docetaxel; bTMB, blood tumor mutational burden; mut, mutations; Mb, megabase; OS, overall survival; nivo, nivolumab; chemo, chemotherapy; ipi, ipilimumab; DoT, duration of therapy; NR, not reached; CTLA4, cytotoxic T-lymphocyte-associated antigen; LDT, laboratory developed test.