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. 2022 Apr 29;12:779786. doi: 10.3389/fonc.2022.779786

Table 1.

Summary of clinical trials evaluating the predictive value of the biomarkers for ICIs in TNBC.

Biomarkers Application Trials Treatment N Group Key Data
PD-L1 Early TNBC KEYNOTE-522 (29) Pembro /placebo +chemotherapy 602 • PD-L1+ • pCR: 68.9% vs 54.9%
PD-L1- • pCR: 45.3% vs 30.3%
Impassion031 (23) Atezo /placebo +chemotherapy 333 • PD-L1+ • pCR: 69% (95% CI, 57-79) vs 49% (95% CI, 38-61)
• PD-L1- • pCR: 48% vs 34%
Advanced TNBC Impassion130 (16, 18) Atezo /placebo + nab-paclitaxel 902 • PD-L1 + • m PFS: 7.5 (95%CI, 6.7-9.2) mo vs 5.0 (95%CI, 3.8-5.6) mo; HR=0.64 (0.51-0.80)
• m OS: 25.4 (95% CI, 19.6-30.7) mo vs 17.9 (95%CI, 13.6-20.3)mo; HR=0.67 (0.53-0.86)
• PD-L1- • m PFS: 5.6 mo vs 5.6 mo; HR=0.95 (0.79-1.15)
• m OS: 19.7 mo vs 19.7 mo; HR=1.05 (0.87-1.28)
KEYNOTE-012 (30) single-agent pembro 111 • PD-L1+ • m PFS: 1.9 (95% CI, 1.7-5.5) mo
• m OS: 11.2 (95% CI, 5.3- (not reached)) mo
KEYNOTE-086 (31, 32) single-agent pembro Cohort
A:170
B:84		 • Cohort A
(PD-L1+vs PD-L1-)		 • m PFS: 2.0 (95%CI, 1.9-2.1) mo vs 1.9 (95%CI, 1.7-2.0) mo
• m OS: 8.8 (95%CI, 7.1-11.2) mo vs 9.7 (95%CI, 6.2-12.6) mo
• Cohort B
(PD-L1+)		 • m PFS: 2.1 (95%CI, 2.0-2.2) mo
• m OS: 18.0 (95%CI, 12.9, 23.0) mo
PD-L1 Advanced TNBC KEYNOTE-119 (20) Pembro/ chemotherapyi 1098 • CPS ≥1 • m OS: 10.7 (95% CI, 9.3-12.5) mo vs 10.2 (95% CI, 7.9-12.6) mo; HR=0.86(0.69-1.06)
• CPS ≥10 • m OS: 12.7(95% CI, 9.9-16.3) mo vs 11.6 (95% CI, 8.3-13.7) mo; HR=0.78(0.57-1.06)
• CPS ≥20 • m OS: 14.9 mo vs 12.5 mo; HR=0.58(0.38-0.88)
KEYNOTE-355 (19, 33) Pembro /placebo+ chemotherapy 847 • CPS ≥1 • m PFS: 7.6 (95% CI, 6.6-8.0) mo vs 5.6 (95% CI, 5.4-7.4) mo; HR=0.75 (0.62-0.91)
• m OS: 17.6(95% CI, 15.5-19.5) mo vs 16.0 (95% CI, 12.8-17.4) mo; HR=0.86 (0.72-1.04)
• CPS ≥10 • m PFS: 9.7 (95% CI, 7.6-11.3) mo vs 5.6 (95% CI, 5.3-7.5) mo; HR=0.66 (0.50-0.88)
• m OS: 23.0(95% CI, 19.0-26.3) mo vs 16.1 (95% CI, 12.6-18.8) mo; HR=0.73(0.55-0.95)
JAVELIN (22) single-agent avelumab 168
(58 was TNBC)		 • TNBC
(PD-L1+ vs PD-L1-)		 • ORR: 22.2% vs. 2.6%
• ≥1% TC
(PD-L1+ vsPD-L1-)		 • mPFS:5.9(95%CI, 5.7-6.0)weeks vs 6.0(95% CI, 5.9-6.0) weeks; HR=1.183 (0.815-1.716)
• m OS: 6.5 (95% CI, 3.7-9.2) mo vs 8.3 (95% CI 6.3, ne) mo; HR=1.331 (0.815-2.174)
• ≥5% TC
(PD-L1+ vsPD-L1-)		 • mPFS:6.0(95% CI, 5.7-7.1)weeks vs 5.9(95%CI, 5.9-6.0) weeks; HR=0.782 (0.473-1.290)
• m OS: 6.5 (95% CI, 2.2-ne) mo vs 7.1 (95% CI, 5.1-11.3) mo; HR=1.057 (0.556-2.010)
• ≥25% TC
(PD-L1+ vsPD-L1-)		 • mPFS:6.0(95% CI 5.4- ne)weeks vs 5.9(95% CI 5.9- 6.0) weeks; HR=0.695 (0.172-2.813)
• m OS: 9.2 (95% CI, ne-ne) mo vs 6.8 (95% CI, 4.9-10.8) mo; HR=0.441 (0.061-3.177)
• ≥10% IC c
(PD-L1+ vsPD-L1-)		 • mPFS:6.1(95%CI, 2.3-24,1)weeks vs 5.9(95%CI, 5.9-6.0)weeks; HR=0.656 (0.341-1.263)
• m OS: 11.3 (95% CI, 1.4-ne) mo vs 6.8 (95% CI, 4.7-9.2) mo; HR=0.620 (0.250-1.541)
KEYNOTE-150 (34) Eribulin +pembro 107 • PD-L1+ • m PFS: 4.1 (95%CI, 2.1-4.8) mo
• PD-L1- • m PFS: 4.1 (95%CI, 2.3-6.3)mo
Impassion131 (21) Atezo/ placebo +paclitaxel 651 • PD-L1 + • m PFS: 6.0 (95% CI 5.6-7.4) mo vs 5.7 (95% CI 5.4-7.2) mo; HR=0.82 (0.60-1.12)
• Final OS: 22.1(95%CI 19.2-30.5) mo vs 28.3 (95% CI 19.1-NE) mo; HR=1.11(0.76-1.64)
TILs Early TNBC KEYNOTE-173 (35) Pembro + chemotherapy 60 • Available pre-treatment sTILs date of ypT0/Tis ypN0 • pCR : 60% vs 40% a
• Available on-treatment sTILs date of ypT0/Tis ypN0 • pCR : 57% vs 43% b
• Available pre-treatment sTILs date of ypT0 /ypN0 • pCR: 58% vs 42% c
• Available on-treatment sTILs date of ypT0 /ypN0 • pCR: 53% vs 47%d
GeparNuevo (28) Durva / placebo+ chemotherapy 174 • Durvalumab-arm
(sTILs)e 		• OR: 1.23 (95%CI, 1.04-1.6)
• Durvalumab-arm
(iTILs)e 		• OR: 1.58 (95%CI, 0.85-2.97)
• Durvalumab-arm
(iTILs post-pre)f 		• OR: 5.15 (95%CI, 1.1-24.05)
• Placebo-arm
(sTILs) e 		• OR: 1.39 (95%CI, 1.12-1.74)
• Placebo-arm
(iTILs) e 		• OR: 0.94 (95%CI, 0.73-1.22)
• Placebo-arm
(iTILs post-pre)f 		• OR: 1.19 (95%CI, 0.65-2.17)
Advanced TNBC KEYNOTE-086 (27, 31, 32) single-agent pembro •Cohort
A: 147
B:46		 • Cohort A • ORR: 6% vs 2%g
• Cohort B • ORR: 39% vs 9%h
TILs Advanced TNBC Impassion130 (24, 36, 37) Atezo/ placebo + nab-paclitaxel 902 • Any PD-L1, sTILs<10% •m PFS: 5.6 mo vs 5.4 mo; HR=0.86 (0.73-1.02)
•m OS: 19.2 mo vs 18.1 mo; HR=0.88 (0.72-1.08)
• Any PD-L1, sTILs≥10% •m PFS: 8.3 mo vs 6.1 mo; HR=0.64 (0.50-0.84)
•m OS: 25.0 mo vs 20.0 mo; HR=0.75 (0.54-1.03)
• PD-L1 ≥1%, sTILs<10% •m PFS: 6.4 mo vs 4.7 mo; HR=0.80 (0.59-1.10)
•m OS: 19.1 mo vs 17.6 mo; HR=0.74 (0.50-1.10)
• PD-L1 ≥1%, sTILs≥10% •m PFS: 9.0 mo vs 5.4 mo; HR=0.54 (0.39-0.75)
•m OS: 30.0 mo vs 18.2 mo; HR=0.54 (0.39-0.75)
• PD-L1 <1%, sTILs<10% •m PFS: 5.6 mo vs 5.5 mo; HR=0.90 (0.73-1.10)
•m OS: 19.3 mo vs 18.2 mo; HR=0.95 (0.75-1.20)
• PD-L1 <1%, sTILs≥10% •m PFS: 7.2 mo vs 9.0 mo; HR=0.92 (0.59-1.44)
•m OS: 23.7 mo vs 24.5 mo; HR=1.04 (0.59-1.82)
• Any PD-L1, CD8 <0.5% •m PFS: 5.6 mo vs 5.6 mo; HR=0.86 (0.65 to 1.14)
•m OS: 16.3 mo vs 22.3 mo; HR=1.16 (0.81 to 1.65)
• Any PD-L1, CD8 ≥0.5% •m PFS:7.4 mo vs 5.5 mo; HR=0.75 (0.62 to 0.91)
•m OS: 22.6 mo vs 18.1 mo; HR=0.69 (95%CI, 0.54-0.81)
• PD-L1 ≥1%,CD8<0.5% •m PFS: 9.2 mo vs3.8 mo; HR=0.33 (0.13 to 0.83)
•m OS:30.7 mo vs19.4 mo; HR=0.22 (0.06 to 0.90)
• PD-L1 ≥1%,CD8 ≥0.5% •m PFS: 7.7 mo vs 5.3 mo; HR=0.64 (0.49 to 0.83)
•m OS: 28.6 mo vs 17.7 mo; HR=0.63 (0.46 to 0.86)
• PD-L1<1%,CD8 <0.5% •m PFS: 5.6 mo vs 5.7 mo; HR=1.00 (0.73 to 1.37)
• m OS: 15.5 mo vs 22.3 mo; HR=1.39 (0.95 to 2.03)
• PD-L1<1%,CD8 ≥0.5% •m PFS: 6.5 mo vs 7.2 mo; HR=0.91 (0.68 to 1.21)
•m OS: 21.0 mo vs 19.6 mo; HR=0.78 (0.56 to 1.10)
TMB Early TNBC GeparNuevo (26) Durva / placebo+ chemotherapy 149j • Durvalumab-arm
(TMB≥2.05 muts/mb vs <2.05 muts/mb)		 • pCR: 63% vs 40%k
• Placebo-arm
(TMB≥2.05 muts/mb vs <2.05 muts/mb)		 •pCR: 52% vs 37%l
Advanced TNBC KEYNOTE-119 (25) Pembro/ chemotherapy 253i • TMB ≥10 •ORR: 14.3% (95%CI, 4.0-39.9) vs 8.3% (95%CI, 0.4-35.4)
• TMB<10 •ORR: 12.7% (95%CI, 7.9-19.9) vs 12.8% (95%CI, 7.8-20.4)
IL-8 Advanced TNBC A phase II trial (38, 129) Camrelizumab +apatinib 28m • Responder vs non-respondern •Levels of IL-8: 0 pg/ml vs 2.15 pg/mlO

N, number of patients; TC, tumor cells; IC, immune Cells; m PFS, median PFS; mo, months; m OS, median OS; HR, hazard ratio, HR(95%CI); Pembro, Pembrolizumab; Atezo, Atezolizumab; OR, odds ratio; Durva, durvalumab.

a: Levels of TILs: Median (IQR): 42% (95% CI,10-74) vs 10% (95% CI,5-25); b: Levels of TILs: Median (IQR): 65% (95% CI,5-89) vs 25% (95% CI,2-48); c: Levels of TILs: Median (IQR): 40% (95% CI,10-75) vs 10% (95% CI,5-38); d: Levels of TILs: Median (IQR): 65% (95% CI,5-86) vs 25% (95% CI,3-60); e: pre-therapeutic; f: difference of iTIL between post-window and pretherapeutic biopsy; g: Levels of TILs: Median (IQR): 10% (95% CI,7.5-25) vs 5% (95% CI,1-10); h: Levels of TILs: Median (IQR): 50% (95% CI,5-70) vs 15% (95% CI,5-37.5); i: TMB data were available for 253/601 (42.1%) treated patients (pembro, n = 132; chemo, n = 121); j: both whole exome sequencing and RNA-Seq data can be got from pretreatment samples of 149 TNBC of GeparNuevo; k: P=0.028; l: P=0.232; m: 28 Patients had biopsies and blood collected; n: responders (partial response ); non-responders (stable disease or progressive disease); o: P = 0.001.