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. 2023 Jul 18;10:1105–1127. doi: 10.2147/JHC.S341195

Table 3.

Summary of Proposed Prognostic and Predictive Biomarkers for CPIs by Biomarker Studies from Major Clinical Trials

Biomarker Assay Trial (NCT) Trial Design; Biomarker Study Design Treatment Line of Treatment No. in Original Trial; No. in Biomarker Study (%)* Rationale Multivariate Analysis Validation AuthorsRef
Tumor PD-L1 IHC CheckMate 040 (NCT01658878)
Phase 1/2, Non-comparative
Prespecified (2nd endpoint)		 Nivolumab 1st or later 214
174 (81.3%)

  • PD-L1 status did not have an apparent effect on ORR (PD-L1 was a secondary endpoint)

 Not applicable Not applicable El-Khoueiry et al90
CheckMate 040 (NCT01658878)
Phase 1/2, Non-comparative
Post-hoc Exploratory		 Nivolumab 1st or later 214
195 (91.1%)

  • PD-L1 expression ≥1% was associated with improved OS

  • ORR was higher in PD-L1 ≥1% vs PD-L1 <1 (28% vs 16%)

 No No validation Sangro et al91
CheckMate 040 (NCT01658878)
Phase 1/2 RCT
Prespecified (2nd endpoint)		 Nivolumab + Ipilimumab Later 148
145 (98.0%)

  • PD-L1 status did not have an apparent effect on ORR (PD-L1 was a secondary endpoint)

 Not applicable Not applicable Yau et al92
CheckMate 459 (NCT02576509)
Phase 3 RCT
Prespecified (2nd endpoint)		 Nivolumab vs Sorafenib 1st 743
730 (98.3%)

  • PD-L1 status did not have an apparent effect on ORR, PFS, or OS (PD-L1 was a secondary endpoint)

 Not applicable Not applicable Yau et al93
KEYNOTE-224 (NCT02702414)
Phase 2, Non-randomized
Prespecified exploratory endpoint		 Pembrolizumab Later 104
52 (50.0%)

  • Tumor PD-L1 expression alone was not significantly associated with ORR and PFS

  • Combined PD-L1 (tumor cells, macrophages, and lymphocytes) was associated with favorable ORR and PFS

 Yes No validation Zhu et al94
CD3+, CD8+ TILs IHC CheckMate 040 (NCT01658878)
Phase 1/2, Non-comparative
Post-hoc Exploratory		 Nivolumab 1st or later 214
195 (91.1%)

  • CD3 expression was related to better ORR

  • CD3 and CD8 expression in TIL showed a trend toward improved OS (p=0.08)

 No No validation Sangro et al91
IMbrave150 (NCT03434379)
Phase 3, RCT
Post-hoc Exploratory		 Atezo-bev vs Sorafenib 1st 501
177 (35.3%)

  • High CD8 showed a trend toward longer PFS (p=0.053) and significantly longer OS (p=0.001) in atezo-bev compared to sorafenib (Predictive – atezo-bev)

 Yes High CD8 was discovered by GO30140-A cohort and validated by IMbrave150 cohort Zhu et al88
PD-1+ TIL
Treg (CD4, FOXP3)
TAM (CD68, CD163) 		IHC CheckMate 040 (NCT01658878)
Phase 1/2, Non-comparative
Post-hoc Exploratory		 Nivolumab 1st or later 214
195 (91.1%)

  • PD-1 expression showed a trend toward increased OS (p=0.05)

  • Treg (CD4, FOXP3) was not associated with response or OS

  • TAM (CD68, CD163) was not associated with response or OS

 No No validation Sangro et al91
NLR, PLR Serum, neutrophil, lymphocyte

  • Lower baseline serum NLR and PLR were related to better OS

 No No validation Sangro et al91
GEP RNA sequencing CheckMate 040 (NCT01658878)
Phase 1/2, Non-comparative
Post-hoc Exploratory		 Nivolumab 1st or later 214
37 (17.3%)

  • Inflammatory signature improved nivolumab ORR and OS

  • Interferon-gamma and T-cell exhaustion signatures were associated with ORR and OS

 No No validation Sangro et al91
IMbrave150 (NCT03434379)
Phase 3, RCT
Post-hoc Exploratory		 Atezo-bev vs Sorafenib 1st 501177 (35.3%)

  • High ABRS, CD274, and Teff signatures were associated with better OS and PFS with atezo-bev compared to sorafenib (Predictive – atezo-bev)

  • Low Treg/Teff, AFP, and GPC3 expression was associated with better PFS and OS with atezo-bev compared to sorafenib (Predictive – atezo-bev)

 Yes ABRS, CD274, and Teff were discovered by GO30140-A cohort and validated by IMbrave150 cohort Zhu et al88
CheckMate 459 (NCT02576509)
Phase 3, RCT
Post-hoc Exploratory		 Nivolumab vs Sorafenib 1st 743
469 (63.1%)

  • High Gajewski inflammation gene signature was related to improved ORR, PFS, and OS with nivolumab but not sorafenib (Predictive – nivolumab)

  • Expression of inflammatory response and IL6-JAK-STAT3 signaling gene sets showed improved OS with nivolumab but not sorafenib (Predictive – nivolumab)

 Unknown No validation Neely et al95
IGF-1 Serum, IGF-1 IMbrave150 (NCT03434379)
Phase 3, RCT
Post-hoc Exploratory		 Atezo-bev vs Sorafenib 1st 501
371 (74.1%)

  • High baseline IGF-1 level was associated with improved OS in both arms (Prognostic)

  • Decreased IGF-1 during treatments showed poor OS (Surrogate, Prognostic)

 Yes No validation Kaseb et al96
AFP Serum, AFP IMbrave150 (NCT03434379)
Phase 3, RCT + GO30140 (NCT02715531)
Phase 1b, RCT
Post-hoc Exploratory		 Atezo-bev vs Sorafenib
Atezo-bev		 1st 605
208 (34.4%)

  • AFP level changes during treatment correlated with PFS and OS (Surrogate, Prognostic)

 Yes Identified by GO30140-A cohort and validated by IMbrave150 cohort Zhu et al97

Note: *(No. in original trial/No. in biomarker study) ×100.

Abbreviations: atezo, atezolizumab; bev, bevacizumab; CKI, checkpoint inhibitor; GEP, gene expression profiling; IHC, immunohistochemistry; NLR, neutrophil to lymphocyte ratio; No., number; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PLR, platelet to lymphocyte ratio; RCT, randomized controlled trial; TAM, tumor-associated macrophage; Teff, effector T cell; TIL, tumor-infiltrating lymphocyte; Treg, regulatory T cell.