Table 2 Evidence of TMB as an immunotherapy-related biomarker in clinical trials involving ES-SCLC
TMB type | Trial | Phase | Yeara | Population | Treatment | TMB assay |
|---|---|---|---|---|---|---|
tTMB | First-line setting | |||||
CASPIAN [39] | III | 2017 | Untreated ES-SCLC | Durvalumab plus etoposide and platinum (EP) (D + EP), Durvalumab plus Tremelimumab plus EP (D + T + EP), EP alone | FoundationOne CDx | |
KEYNOTE-604 [60] | III | 2017 | Untreated ES-SCLC | Pembrolizumab plus EP, Placebo plus EP | WES | |
First-line maintenance | ||||||
CheckMate 451 [40] | III | 2015 | ES-SCLC first line maintenance | Nivolumab plus Ipilimumab, Nivolumab monotherapy, Placebo | FoundationOne CDx | |
Second- and later-line settings | ||||||
CheckMate 331 [44] | III | 2015 | Relapsed ES-SCLC | Nivolumab, Chemotherapy (topotecan or amrubicin) | Foundation-One CDx | |
KEYNOTE-158 [57] | II | 2015 | Relapsed ES-SCLC | Pembrolizumab | FoundationOne CDx | |
I/II | 2013 | Relapsed SCLC | Nivolumab, Nivolumab plus Ipilimumab | WES | ||
bTMB | IMpower133 [34] | I/III | 2016 | Untreated ES-SCLC | Atezolizumab plus carboplatin and etoposide (EC), Placebo plus EC | NR |
TMB type | Trial | Cutoff | N (BEP) | ORR% | mPFS (months) | mOS (months) |
|---|---|---|---|---|---|---|
tTMB | First-line setting | |||||
CASPIAN [39] | 6–14 mut/Mb | D + EP arm: 107, D + T + EP arm: 105, EP arm: 71 | D + EP vs. EP: ORs (95% CI) of 1.98 (0.99–4.01), 1.85 (0.87–3.92), 1.99 (0.88–4.54), 1.59 (0.67–3.73), 1.23 (0.46–3.22), 0.97 (0.34–2.69), 1.14 (0.38–3.29), 0.75 (0.22–2.39) and 0.46 (0.10–1.78), respectively, for the tTMB-high subgroups at cutoffs ranging from 6 to 14 mut/Mb; ORs of 1.39 (0.32–6.36), 1.96 (0.60–6.71), 1.76 (0.66–4.79), 2.42 (0.95–6.36), 2.73 (1.17–6.59), 2.90 (1.29–6.72), 2.53 (1.16–5.67), 2.90 (1.36–6.31) and 2.86 (1.40–5.95) for the tTMB-low subgroups; D + T + EP vs. EP: ORs of 0.87 (0.43–1.75), 0.78 (0.36–1.64), 0.71 (0.31–1.61), 0.64 (0.27–1.49), 0.46 (0.17–1.22), 0.32 (0.11–0.90), 0.30 (0.09–0.91), 0.33 (0.09–1.07) and 0.30 (0.07–1.11) for the tTMB-high subgroups; ORs of 0.81 (0.24–2.76), 1.04 (0.37–2.94), 1.09 (0.44–2.70), 1.19 (0.50–2.85), 1.32 (0.60–2.90), 1.50 (0.70–3.26), 1.41 (0.67–2.96), 1.25 (0.61–2.57) and 1.18 (0.59–2.36) for the tTMB-low subgroups; | D + EP vs. EP: HRs (95% CI) of 0.75 (0.53–1.09), 0.83 (0.56–1.23), 0.76 (0.50–1.17), 0.76 (0.49–1.20), 0.79 (0.48–1.32), 0.82 (0.49–1.40), 0.79 (0.46–1.38), 0.79 (0.43–1.45) and 0.79 (0.39–1.62), respectively, for the tTMB-high subgroups at cutoffs ranging from 6 to 14 mut/Mb; HRs of 0.67 (0.30–1.43), 0.45 (0.23–0.85), 0.70 (0.42–1.15), 0.70 (0.44–1.12), 0.68 (0.44–1.05), 0.68 (0.45–1.02), 0.69 (0.46–1.04), 0.71 (0.48–1.04) and 0.70 (0.49–1.01) for the tTMB-low subgroups; D + T + EP vs. EP: HRs of 0.90 (0.62–1.32), 0.93 (0.62–1.40), 0.94 (0.61–1.47), 0.91 (0.57–1.45), 1.04 (0.63–1.75), 1.22 (0.73–2.11), 1.25 (0.72–2.21), 1.14 (0.63–2.12) and 1.24 (0.65–2.46) for the tTMB-high subgroups; HRs of 0.62 (0.33–1.20), 0.66 (0.38–1.16), 0.73 (0.45–1.18), 0.78 (0.49–1.23), 0.73 (0.48–1.11), 0.67 (0.44–1.02), 0.69 (0.47–1.04), 0.74 (0.51–1.10) and 0.74 (0.51–1.08) for the tTMB-low subgroups; | D + EP vs. EP: HRs (95% CI) of 0.72 (0.50–1.03), 0.80 (0.54–1.18), 0.71 (0.47–1.09), 0.72 (0.46–1.13), 0.68 (0.42–1.14), 0.69 (0.41–1.19), 0.65 (0.37–1.15), 0.66 (0.36–1.24) and 0.62 (0.30–1.32), respectively, for the tTMB-high subgroups at cutoffs ranging from 6 to 14 mut/Mb; HRs of 0.76 (0.34–1.66), 0.58 (0.31–1.09), 0.75 (0.45–1.26), 0.72 (0.45–1.18), 0.77 (0.50–1.20), 0.77 (0.50–1.17), 0.80 (0.53–1.20), 0.77 (0.52–1.13) and 0.76 (0.53–1.10), respectively, for the tTMB-low subgroups; D + T + EP vs. EP: HRs (95% CI) of 0.80 (0.55–1.17), 0.85 (0.56–1.28), 0.80 (0.52–1.25), 0.79 (0.50–1.26), 0.77 (0.46–1.30), 0.86 (0.51–1.49), 0.86 (0.49–1.54), 0.80 (0.43–1.52) and 0.86 (0.44–1.75), respectively, for the tTMB-high subgroups at cutoffs ranging from 6 to 14 mut/Mb; HRs of 0.84 (0.43–1.68), 0.76 (0.43–1.35), 0.81 (0.50–1.35), 0.82 (0.51–1.33), 0.83 (0.54–1.29), 0.78 (0.51–1.19), 0.79 (0.53–1.18), 0.82 (0.56–1.22) and 0.82 (0.56–1.20), respectively, for the tTMB-low subgroups; | |
KEYNOTE-604 [60] | 175 mut/exome | Pembrolizum arm: 167, Placebo arm: 151 | NR | NR | Pembrolizum arm vs. placebo arm: 12.3 (8.3–15.5) vs. 12.0 (9.8–13.9) in TMB ≥ 175mut/exome (HR, 1.02; 95% CI 0.72–1.45); 10.2 (8.5–14.4) vs. 7.7 (6.6–9.3) in TMB < 175mut/exome (HR, 0.60; 95% CI 0.43–0.85) | |
First-line maintenance | ||||||
CheckMate 451 [40] | 10, 13 mut/Mb | Nivolumab plus Ipilimumab: 192 Nivolumab: 196 Placebo: 192 | Nivolumab plus Ipilimumab vs. Nivolumab vs. placebo: 14.0% vs. 14.3% vs. 5.3% in TMB ≥ 13mut/Mb; 6.5% vs. 9.5% vs. 4.0% in TMB < 13mut/Mb | Nivolumab plus Ipilimumab vs. Nivolumab vs. placebo: 2.7 (1.5–3.6) vs. 2.8 (1.6–4.1) vs. 1.6 (1.4–2.6) in TMB ≥ 13mut/Mb; 1.5 (1.4–2.0) vs. 1.6 (1.4–2.6) vs. 1.4 (1.4–1.4) in TMB < 13mut/Mb | Nivolumab plus Ipilimumab vs. placebo: 13.5 (9.3–21.8) vs. 9.5 (6.2–13.5) in TMB ≥ 13mut/Mb (HR, 0.61; 95% CI 0.39–0.94), 7.8 (6.7–9.7) vs. 10.0 (7.7–11.5) in TMB < 13mut/Mb (HR, 1.04; 95% CI 0.79–1.37); Nivolumab vs. placebo: 13.2 (10.0–17.9) vs. 9.5 (6.2–13.5) in TMB ≥ 13mut/Mb (HR, 0.67; 95% CI 0.45–1.01), 10.1 (8.7–11.3) vs. 10.0 (7.7–11.5) in TMB < 13mut/Mb (HR, 0.92; 95% CI 0.70–1.22) | |
Second- and later-line settings | ||||||
CheckMate 331 [44] | 10, 11, 13, 14, 15 mut/Mb | Nivolumab arm: 155, Chemotherapy arm: 157 | No significant difference reported (data not shown) | No significant difference reported (data not shown) | No significant difference reported (data not shown) | |
KEYNOTE-158 [57] | 10mut/Mb | SCLC cohort: 76 | High TMB vs. non-high-TMB: 29.4% vs. 9.5% | No specific data of SCLC cohort; No significant difference reported in ten tumor-type-specific cohorts | High TMB vs. non-high-TMB: 9.4(5.6–19.1) vs. 6.3(3.9–7.7) | |
143, 247 mutations | Nivolumab arm:133, Nivolumab plus Ipilimumab arm: 78 | Nivolumab arm vs. Nivolumab plus Ipilimumab arm: 21.3% vs. 46.2% in high TMB, 6.8% vs. 16.0% in medium TMB, 4.8% vs. 22.2% in low TMB | low TMB vs. medium TMB vs. high TMB: 1.3 (95% CI 1.2–1.4) vs. 1.3 (95% CI 1.2–1.4) vs. 1.4 (95% CI 1.3–2.7) in Nivolumab arm; 1.5 (95% CI 1.3–2.7) vs. 1.3 (95% CI 1.2–2.1) vs. 7.8 (95% CI 1.8–10.7) in Nivolumab plus Ipilimumab arm | low TMB vs. medium TMB vs. high TMB: 3.1 (95% CI 2.4–6.8) vs. 3.9 (95% CI 2.4–9.9) vs. 5.4 (95% CI 2.8–8.0) in Nivolumab arm; 3.4 (95% CI 2.8–7.3) vs. 3.6 (95% CI 1.8–7.7) vs. 22.0 (95% CI 8.2-not reached) in Nivolumab plus Ipilimumab arm | ||
bTMB | IMpower133 [34] | 10, 16 mut/Mb | 346 | NR | NR | Atezolizumab arm vs. placebo arm: 11.8 vs. 9.4 in bTMB < 10mut/Mb (HR, 0.73; 95% CI 0.49–1.08), 14.9 vs. 11.2 in bTMB ≥ 10mut/Mb (HR, 0.73; 95% CI 0.53–1.00); 12.5 vs. 10.0 in bTMB < 16mut/Mb (HR, 0.79; 95% CI 0.60–1.04), 17.1 vs. 11.9 in bTMB ≥ 16mut/Mb (HR, 0.58; 95% CI 0.34–0.99) |