Table 1.
Proposed Biomarkers in Recent Clinical Trials Using Immune Checkpoint Inhibitors for HCC
| Trial | Treatment | Line of Treatment | Number of Patients | Assay | Biomarker | Outcome | Ref. |
|---|---|---|---|---|---|---|---|
| KEYNOTE-224 (NCT02702414) | Pembrolizumab | Second line | N=52 | IHC | Baseline PD-L1 expression* | PD-L1 expression on tumor cells, lymphocytes and macrophages was associated with response. PD-L1 expression on tumor cells alone was not associated with response. | [11] |
| CheckMate 040 (NCT01658878) | Nivolumab and Ipilimumab | Second line | N=145 | IHC | Baseline tumor PD-L1 expression* | No association between baseline tumor PD-L1 expression and treatment response. | [15] |
| CheckMate 459 (NCT02576509) | Nivolumab vs Sorafenib | First line | N=743 | IHC | Baseline tumor PD-L1 expression* | Patients with PD-L1 ≥1% was found to be associated with longer median OS in those treated with Nivolumab vs Sorafenib. | [16] |
| CheckMate 040 | Nivolumab | First or second line | N=44 (Escalation phase), N=174 (Expansion phase) | IHC | Baseline tumor PD-L1 expression* | No association between baseline tumor PD-L1 expression and treatment response. | [10] |
| CheckMate 040 | Nivolumab | First or second line | N=195 (PD-L1), N=178 (PD-1) | IHC | Baseline tumor PD-L1 and PD-1 expressions* | Both were associated with improved OS. PD-1, but not PD-L1, was associated with ORR. |
[13] |
| N=189 (CD3), N=192 (CD8) |
IHC | Baseline CD3+ or CD8+ TILs* | CD3+ or CD8+ TILs exhibited a trend towards improved OS. | ||||
| N=189 (CD4), N=190 (FOXP3) | IHC | Baseline CD4+ or FOXP3+ TILs* | Not associated with OS. | ||||
| N=135 | IHC | Baseline CD68+ or CD163+ macrophages* | Not associated with OS. | ||||
| N=37 | RNA seq | Baseline inflammatory signature of tumor tissue* | Inflammatory signature consisting of CD274 (PD-L1), CD8A, LAG3, STAT1 was associated with both improved objective response rate and overall survival. | ||||
| N=242 (NLR), N=243 (PLR) | Flow cytometry | Baseline Neutrophil to lymphocyte ratio (NLR) or platelet to lymphocyte ratio (PLR)* | Lower NLR and PLR were found to be associated with PR and CR on nivolumab. | ||||
| N=149 | Serum AFP detection | Baseline Serum AFP | Low AFP (<400 µg/L) showed a numerical (although not statistically significant) association with response. | ||||
| GO30140 (NCT02715531) Imbrave150 (NCT03434379) |
Atezolizumab and Bevacizumab | First line | N=58 (GO30140) N=150 (Imbrave150) |
Serum AFP detection | Serum AFP | ≥75% decrease or ≤10% increase in AFP levels at 6 weeks after the treatment was significantly associated with improved OS and PFS. | [20] |
| GO300140 (NCT02715531) | Atezolizumab and Bevacizumab | First line | N=73 | WES | TMB# | Not associated with response or PFS. | [18] |
| N=90 | RNA seq | PD-L1 gene expression* | Associated with response and longer PFS. | ||||
| N=90 | RNA seq | T-effector signature (GZM, PRF1, CXCL9)* | Associated with response and longer PFS. | ||||
| N=90 | RNA seq | Notch pathway (HES1) activation genes# | Associated with lack of response and shorter PFS. | ||||
| GO300140 (NCT02715531) | Atezolizumab and Bevacizumab vs Atezolizumab alone | First line | N=91 | RNS seq | VEGFR2 expression^ | Associated with longer PFS in patients treated with atezolizumab + bevacizumab than in those treated with atezolizumab alone. | [18] |
| N=91 | RNA seq | Treg signature (CCR8, BATF, CTSC, TNFRSF4, FOXP3, TNFRSF18, IKZF2, and IL2RA)* | Associated with longer PFS in patients treated with atezolizumab + bevacizumab than in those treated with atezolizumab alone. | ||||
| N=91 | RNA seq | Myeloid inflammation signature (CXCL1, CXCL2, CXCL3, CXCL8, IL6, PTGS1)* | Associated with longer PFS in patients treated with atezolizumab + bevacizumab than in those treated with atezolizumab alone. | ||||
| N=91 | RNA seq | TREM1/MDSC signatures* | Associated with longer PFS in patients treated with atezolizumab + bevacizumab than in those treated with atezolizumab alone. | ||||
| NCT01853618 | Tremelimumab in combination with radiofrequency ablation or chemoablation | Adjuvant | N=9 | IHC | Post-treatment CD3+ and CD8+ TILs* | Responders had higher post-tremelimumab CD3+ and CD8+ TILs than non-responders. | [24] |
| NCT02658019 | Pembrolizumab | Second line | N=24 | ELISA | Baseline plasma IL‐1β, IL‐6, IL‐8, IL‐12, IL‐18, IFN‐γ, TGF‐β, IL‐10, CXCL9, CCL4, CCL5, PD‐L1, and PD‐L2* | High baseline plasma TGF‐β levels (≥200 pg/mL) significantly correlated with poor treatment outcomes. | [33] |
| NCT02407990, NCT04068519 | Tislelizumab | Second line | N=41 | NGS | Angiogenesis^ (TEK, KDR, HGF, and EGR1), Immune exhaustion* (CD274, CTLA4, TIGIT, and CD96), cell-cycle (E2F7, FOXA1, and FANCD2) gene signatures | Non-responders had elevated angiogenesis, immune exhaustion, and cell-cycle gene signature than responders. | [14] |
| NCT01853618 | Tremelimumab in combination with radiofrequency ablation or chemoablation | Adjuvant | N=34 | Flow Cytometry | Baseline CD4+PD1+ cells* | The frequency of CD4+ PD1+ cells in PBMC were higher in responder than in non-responder. |
[25] |
| N=19 (pre-treatment tissue), N=22 (post-treatment tissue) | IHC | Tumor CD3 and PD-1 expression* | Responders had higher CD3 and PD-1 expression in post-treatment tumor tissues. No statistically significant difference in pre-treatment tumor tissues. | ||||
| N=19 (pre-treatment tissue), N=22 (post-treatment tissue) | IHC | Tumor CD8 and CD68 expression* | No statistically significant difference between responder and non-responders in pre- and post-treatment tumor tissues. | ||||
| N=26 | TCR seq | T-cell repertoire* | Responders had high TIL clonality compared to non-responders. |
Notes: *Immune-related biomarkers. ^Angiogenesis-related biomarkers. #Genomic biomarkers.
Abbreviations: AFP, alpha feto protein; IHC, immunohistochemistry; NGS, next generation sequencing; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival; PLR, platelet-to-lymphocyte ratio; RNA seq, RNA sequencing; TCR, T cell receptor; TGFβ, transforming growth factor β; TILs, tumor infiltrating lymphocytes; TMB, tumor mutational burden; WES, whole exome sequencing.