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

Table 2.

Summary of Proposed Prognostic and Predictive Biomarkers for TKIs and Anti-Angiogenesis Agents by Biomarker Studies from Major Clinical Trials

Treatment Trial (NCT) Trial Design; Biomarker Study Design Line of Tx Biomarkers Assays No. in Original Trial; No. in Biomarker Study (%)* Rationale Multivariate Analysis Validation AuthorsRef
Sorafenib vs Placebo SHARP (NCT00105443)
Phase 3, RCT
Post-hoc Exploratory		 1st Plasma ANG2, VEGF, s-c KIT, HGF Plasma, ELISA 602
491 (81.6%)

  • Baseline ANG2 and VEGF levels independently predict OS (Prognostic)

  • Sorafenib showed a trend toward OS (p=0.081) and TTP (0.052) benefit compared to placebo in high s-c KIT (Predictive – sorafenib)

  • Sorafenib showed a trend toward OS (p=0.073) benefit compared to placebo in low HGF (Predictive – sorafenib)

 Yes No validation Llovet et al69
SHARP (NCT00105443) + Asia-Pacific (NCT00492752)
Phase 3 RCTs
Post-hoc Exploratory		 1st NLR, AFP Serum, AFP, neutrophil, lymphocyte 828
827 (99.9%)

  • High AFP (>200 ng/mL) and NLR (> median) independently predict poor OS (Prognostic)

  • Sorafenib OS benefit was only observed in low NLR (≤ median) but not in high NLR (> median) (Predictive – sorafenib)

 Yes No validation Bruix et al71
Lenvatinib vs Sorafenib REFLECT (NCT01761266)
Phase 3 RCT
Post-hoc Exploratory		 1st Serum VEGF, ANG2, FGF21 Serum, ELISA 954
407 (42.7%)

  • Baseline high ANG2, FGF21, and VEGF were correlated with poor OS (Prognostic)

  • Lenvatinib showed OS benefit compared to sorafenib in high FGF21 but no OS benefit in low FGF21 (Predictive – lenvatinib)

 Yes No validation Finn et al85
Gene expression profiling, VEGF, FGF Gene panel 954
58 (6.1%)

  • VEGF/FGF-enriched groups showed longer OS compared to intermediate VEGF/FGF in lenvatinib

  • VEGF/FGF-enriched groups showed shorter OS compared to intermediate VEGF/FGF in sorafenib

 No No validation
Ramucirumab vs Placebo REACH2 (NCT02435433)
Biomarker-driven Phase 3 RCT
Pre-specified		 Later AFP ≥400 ng/mL Serum, AFP 292
292 (100.0%)

  • Ramucirumab showed improved OS and PFS compared to placebo in this biomarker-selected (AFP ≥400 ng/mL) RCT (Prognostic, Predictive – ramucirumab)

 Not applicable No validation Zhu et al10
REACH (NCT01140347) + REACH2 (NCT02435433)
Phase 3 RCTs
Post-hoc Exploratory		 NLR
AFP >1000 ng/mL		 Serum, AFP, neutrophil, lymphocyte 857
542 (63.2%)

  • Baseline high AFP (≥1000 ng/mL) and NLR independently predict poor OS (Prognostic)

 Yes No validation Llovet et al86
Regorafenib vs Placebo RESORCE (NCT01774344)
Phase 3 RCT
Post-hoc Exploratory		 Later Plasma AFP, c-MET, ANG1, Cystatin-B, LAP TGF-β1, LOX-1, MIP-1α Multiplex immunoassay 573
499 (87.1%)

  • High baseline AFP and c-MET were related to shorter OS independently of treatment (Prognostic)

  • Decreased baseline plasma ANG1, cystatin-B, LAP TGF-β1, LOX-1, and MIP-1α were related to longer OS with regorafenib (Predictive – regorafenib)

 Yes No validation Teufel et al87
miRNA miRNA PCR 573
349 (60.9%)

  • 9 plasma miRNAs (miR-15B, 30A, 107, 122, 125B, 200A, 320b, 374B, 645) were associated with OS in regorafenib (Predictive – regorafenib)

 Yes No validation
Atezo-Bev vs Atezo GO30140 (NCT02715531)
Phase 1b, RCT
Post-hoc Exploratory		 1st RNA RNA sequencing 119
91 (76.5%)

  • High expression of VEGF receptor 2 (KDR), Treg (CCR8, BATF, CTSC, TNFRSF4, FOXP3, TNFRSF18, IKZF2, IL-2RA), myeloid inflammation (CXCL1, CXCL2, CXCL3, CXCL8, IL-6, PTGS1), and Teff (CXCL9, PRF1, GZMB) signatures were associated with improved PFS in atezo-bev compared to atezo (Predictive – bevacizumab)

 Yes KDR, Treg were validated by a small population of 14 pts Zhu et al88
Tumor vessel density by CD31 Multiplex IHC panel 119
67 (56.3%)

  • High tissue blood vessel density by CD31 was associated with longer PFS in atezo-bev compared to atezo (Predictive – bevacizumab)

 Yes No validation
Cabozantinib vs Placebo CELESTIAL (NCT01908426)
Phase 3 RCT
Post-hoc Exploratory		 Later Plasma ANG2, GAS6, HGF, IGF-1, IL-8, MET Luminex (immunoassay) 707
674 (95.3%)

  • Low baseline levels of ANG2, GAS6, HGF, IL-8, MET were related to favorable survival (Prognostic)

  • High baseline levels of IGF-1 were related to favorable survival (Prognostic)

 Yes No validation Rimassa et al89

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

Abbreviations: atezo, atezolizumab; bev, bevacizumab; NLR, neutrophil to lymphocyte ratio; No., number; OS, overall survival; PFS, progression-free survival; RCT, randomized controlled trial; Teff, effector T cell; TKI, tyrosine kinase inhibitor; TTP, time to progression; Tx, treatment.