Incidence and risk of proteinuria associated with newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: an up-to-date meta-analysis of randomized controlled trials

Expert Rev Clin Pharmacol. 2020 Mar;13(3):311-320. doi: 10.1080/17512433.2020.1734450. Epub 2020 Mar 5.


Objective: We performed a meta-analysis to quantify the overall incidence and risk of proteinuria associated with five newly approved VEGFR-TKIs (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) in cancer patients.Methods: Pubmed, Embase, ASCO abstracts, and ESMO abstracts were searched to identify relevant studies. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were estimated using random or fixed effects models according to the heterogeneity of included studies.Results: A total of 9,446 patients from 20 RCTs were included for the meta-analysis. The use of newly approved VEGFR-TKIs was associated with an increased risk of all-grade (RR 2.35, 95% CI 1.69-3.27, P < 0.001) and high-grade (RR 3.70, 95% CI 2.09-6.54, P < 0.001) proteinuria. On subgroup analysis, lenvatinib, axitinib, and vandetanib significantly increased the risk of all-grade proteinuria, and lenvatinib was associated with an increased risk of high-grade proteinuria. In addition, the risk of developing high-grade proteinuria events was significant for patients with hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), but not for patients with colorectal cancer (CRC) and thyroid cancer (TC).Conclusion: Treatment with newly approved VEGFR-TKIs significantly increases the risk of developing proteinuria events in cancer patients, especially for patients treated with lenvatinib.

Keywords: RCTs; VEGFR-TKIs; cancer patients; meta-analysis; proteinuria.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Humans
  • Incidence
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects*
  • Proteinuria / chemically induced*
  • Randomized Controlled Trials as Topic
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Risk


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Receptors, Vascular Endothelial Growth Factor