Table 2b. VEGF RTKi and soluble biomarkers.
| References | Drug, disease and trial | Biomarkers | N | Drug-induced changes | Prognostic and predictive values |
|---|---|---|---|---|---|
| Rini et al (2008a) | Sunitinib Bevacizumab refractory RCC Phase 2 | VEGF-A, VEGF-C, sVEGFR-3 PlGF | 61 | ↑VEGF-A and PlGF ↓VEGF-C and sVEGFR-3 | Low baseline VEGF-C (P=0.0006) and VEGF–R-3 (P=0.006) associated with longer PFS and ORR |
| Burstein et al (2008) | Sunitinib Metastatic breast cancer | VEGF, sVEGFR-2, sVEGFR-3, sKIT | 64 | ↑VEGF, ↓VEGFR-2, VEGFR-3 | ↓VEGFR-3 and ↑OS (P=0.07) ↓sKIT and ↑TTP and ↑OS (P=0.0194) |
| Bello et al (2006) | Sunitinib Neuroendocrine tumour | VEGF, IL-8, sVEGFR-2, sVEGFR-3 | 109 | ↑VEGF ↓VEGFR-2, ↓sVEGFR-3 | ↓VEGFR-3 with PR (n=11) ↑Il-8 with decreased tumour size |
| Norden-Zfoni et al (2007) | Sunitinib (SU11248) Imatinib-resistant GIST Phase1/2 | VEGF, sVEGFR-2 | 73 | ↑VEGF ↓sVEGFR-2 | NS |
| Azad et al (2008) | Sorafenib+Bevacizumab Advanced cancer Phase 1 | VEGF IL-6 IL-8 | 28 | ↑VEGF No change: IL-6, IL-8 | NS |
| Batchelor et al (2007) | Cediranib (AZD2171) Glioblastoma Phase 2 | VEGF, PlGF, sVEGFR-1, sVEGFR-2, FGF-2, SDF-1α, | 16 | ↑VEGF, ↑PlGF ↓sVEGFR-2 | PD-associated variables: ↓PlGF, ↑sVEGFR2, ↑bFGF, ↑SDF-1α |
| Drevs et al (2007) | Cediranib (AZD2171) Advanced cancer Phase 1 | sVEGFR-1 sVEGFR-2 FGF-2, PlGF,Tie-2, E-selectin, IL- 8 | 83 | ↓sVEGFR-2 ↑VEGF, ↑PlGF | NS |
| Rosen et al (2007) | AMG 706 Advanced cancer Phase 1 | PlGF, VEGF, FGF-2, sVEGFR-1 | 71 | ↑PlGF ↓sVEGFR-2 | ↑PlGF (P=0.003) and ↓VEGFR-2 (P=0.001) associated with change in tumour size |
| Jonker et al (2007) | Brivanib (BMS-582664) Advanced cancer; Phase 1 | sVEGFR-2, Collagen IV | 50 | ↓sVEGFR-2 ↓collagen IV | NS |
| Heymach et al (2008) | Vandetanib (AZD6474) NSCLC: 3; Phase 2 trials | VEGF | 251 | NS | Low baseline VEGF: low risk of disease progression |
| Kiura et al (2008) | Vandetanib (AZD6474) NSCLC; Phase 2 | VEGF, sVEGFR-2, Tie-2 | 53 | ↑VEGF ↓sVEGFR-2 | Low baseline VEGF and TTP Low baseline VEGF in patients with PR |
| Yamada et al (2008) | E7080 Advanced cancer; Phase 1 | VEGF, FGF-2 PDGF | 24 | ↑VEGF | NS |
| Drevs et al (2005) | Vatalanib (PTK/ZK) Advanced cancer, liver mets; Phase1/2 | VEGF, FGF-2, sTie-2, and E-selectin | 30 | ↑VEGF, FGF-2 | Change in VEGF correlates with outcome (P=0.027) |
| Heymach et al (2004) | Semaxinib (SU5416) Soft tissue sarcoma Phase 2 | Urine VEGF Urine FGF-2 | 13 | ↑VEGF, FGF-2 | High baseline VEGF associated with ↓OS (P=0.04) |
| Lara et al (2003) | IFNα+Semaxinib (SU5416) RCC; Phase 2 | VEGF PAI-1 | 25 | ↓VEGF, ↓PAI-1 | ↓PAI-1 levels in patients with SD ↓baseline VEGF in pts with PD |
| Stopeck et al (2002) | Semaxinib (SU5416) Advanced cancer; Phase 1 | Urine VEGF Urine FGF-2 | 22 | ↑Urine VEGF ↑Urine FGF-2 | ↑Urine VEGF in responders (P<0.05) |
| Fury et al (2007) | Semaxinib (SU5416) Head and neck cancer; Phase 2 | VEGF | 35 | ↑VEGF | NS |
| Peterson et al (2004) | Semaxinib (SU5416) Melanoma; Phase 2 | VEGF | 13 | ↑VEGF | NS |
| Stadler et al (2004) | Semaxinib (SU5416) Homone refractory prostate cancer; Phase 2 | VEGF bFGF | 22 | NA | NS |
| Norden-Zfoni et al (2007) | Sunitinib (SU11248) Imatin-resistant GIST Phase1/2 | CEC PBMC | 90 | ↑CECs ↓PBMC | Significant clinical correlation (P=0.03) |
| Batchelor et al (2007) | Cediranib (AZD2171) Glioblastoma Phase 2 | CEC CEPCs | 16 | ↓CEC ↓CEPC | ↑CECs with tumour progression. ↑CEPCs with relapse after drug holidays |
Abbreviations: VEGF=vascular endothelial growth factor; RTKi=receptor tyrosine kinase inhibitor; CEC=circulating endothelial cell; CEPC=circulating endothelial progenitor cell; FGF-2=fibroblast growth factor-2; GIST=gastrointestinal stromal tumour; HGF=hepatocyte growth factor; RCC=renal cell carcinoma; NA=not applicable; NS=not significant; NSCLC=non-small-cell lung cancer; OR=overall response; ORR=objective response rate; OS=overall survival; PAI-1=plasminogen activator inhibitor-1; PBMC=peripheral blood mononuclear cells; PD=progressive disease; PDGF=platelet-derived growth factor; PFS=progression-free survival PlGF=placental growth factor; PR=partial response; RR=response rate; SD=stable disease; SDF-1=stromal-cell derived factor-1; sVEGFR=soluble VEGF receptor; TTP=time to progression.