Table 1.

Studies on tumor mutational burden (TMB) analysis as a biomarker of response to immune checkpoint inhibitors (ICIs).

Drug Trial	Study Type/Phase	Line of Therapy	Pts, n	Patient Population	Tmb Method & Cutoff	Clinical Outcomes	Author/Year
Pembrolizumab	Retrospective	First line, second or higher	16 of POPLAR trial; 18 of OAK study	Advanced NSCLC	WES: high≥ 178 mutations	TMB was correlated with better ORR (63% vs. 0%, p = 0.03), PFS (14.5 vs. 3.7 m, p = 0.01) and DCB.	Rizvi NA 2015 [31]
CHECKMATE-026 Nivolumab (NCT02041533)	Exploratory retrospective analysis of phase III study	First line	312	Stage IV or recurrent NSCLC with PD-L1 ≥1%	WES: highTMB ≥243; low TMB <100 mutations	High TMB pts: PFS 9.7 vs. 5.8 m (HR 0.62; 95% CI, 0.38 to 1.00) and ORR (46.8% vs. 28.3%) in nivolumab group compared to chemotherapy.	Carbone D,2017 [33]
CHECKMATE-012 Nivolumab& ipilimumab (NCT01454102)	Phase I	First line	75	Advanced NSCLC	WES: high TMB > median, 158 mutations; low TMB ≤ median	ORR, DCB, PFS were superior in pts with high TMB vs. low TMB (ORR 51% vs. 13%, p = 0.0005; DCB 65% vs. 34%, p = 0.011; PFS HR 0.41).	Hellmann MD 2018 [34]
CHECKMATE-227 Nivolumab + ipilimumab (NCT02477826)	Phase III	First line	299	Stage IV or recurrent NSCLC	FoundationOne CDx assay; high TMB: ≥10 mut/MbV	PFS was longer among pts with high TMB (mPFS: 7.2 vs. 5.5 months, HR 0.58, p < 0.001) in nivolumab + ipilimumab group compared to chemotherapy	Hellman MD 2018 [35]
CHECKMATE-568 Nivolumab + ipilimumab (NCT02659059)	Phase II	First line	288	Stage IV NSCLC	FoundationOne CDx assay; high TMB: ≥10 mut/Mb	ORR was higher (>40%) in high TMB	Ramalingam SS 2018 [32]
CHECKMATE-032 Nivolumab ± ipilimumab (NCT01928394)	Exploratory	Second-line or higher	211	Advanced SCLC	WES: TMB was grouped by tertiles: low, 0 to <143; medium, 143 to 247; high, ≥248 mutations	ORR: 46.2% vs.16%; 1-year PFS: 30% vs. 6.2% 1-year OS: 62.4% vs. 23.4% was higher in pts with TMB high vs TMB low	Hellmann MD 2018 [36]
PD-1 or PD-L1 inhibitors	Retrospective	First line, second or higher	240	Advanced NSCLC	MSK-IMPACT TMB was grouped by percentiles: high TMB >50%	More disease control (complete/partial response vs stable/progression disease) and longer PFS for patients with high TMB >50%	Rizvi H, 2018 [25]
POPLAR & OAK Atezolizumab	Retrospective	Second-line or higher	211 (discovery cohort with 16 p) in POPLAR trial, 583 (validating cohort with 18 p) in OAK study	Advanced NSCLC	Foundation One; bTMB: High bTMB ≥16; low TMB ≤16.	High bTMB (≥16 mut/Mb) was associated with improved PFS, ORR and duration of response.	Gandara DR, 2018 [37]
LACE-BIO-2 Adjuvant Cisplatin (NCT01294280)	Retrospective	Adjuvant chemotherapy	>900	Early-stage NSCLC	Targeted NGS panel using Illumina HiSeq 2000. TMB was categorized into tertiles (low, ≤4 mutations/Mb; intermediate, >4 and ≤8 mutations/Mb; high, >8 mutations/Mb)	High TMB (>8 mut/Mb) was prognostic for favorable OS, PFS, LCSS in patients with resected NSCLC. LCSS benefit with adjuvant chemotherapy was more pronounced in low TMBs (≤4 mut/Mb).	Devarakonda S, 2018 [38]
Neoadjuvant nivolumab	Exploratory	Neoadjuvant PD-1 Blockade	22 (21 were eligible for inclusion)	Surgically resectable early (stage I, II, or IIIA) NSCLC.	WES: highTMB: 311 ± 55 media vs low TMB:74 ± 60 mean	In pts with high TMB (sequence alterations; mean, 311 ± 55 vs. 74 ± 60, p = 0.01) a major pathological response was observed.	Forde PM, 2018 [39]
B-F1RST Atezolizumab (NCT02848651)	Phase II	First line	152 (119 were included in the biomarker evaluable population)	Locally advanced or metastatic NSCLC	Foundation Medicine panel; bTMB: high bTMB ≥ 16, versus low bTMB ≤ 16	It was observed a relationship between increasing bTMB score and improved clinical outcomes. ORR and PFS were superior in pts with high bTMB vs low bTMB: ORR 28.6% vs. 4.4%; PFS 4.6 months vs. 3.7 months, HR 0.66 (90% CI 0.42–1.02).	Velcheti V, 2018 [40]