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

ABSTRACT

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:

• VEGFR-TKIs
• proteinuria
• meta-analysis
• cancer patients
• RCTs

Article Highlights

• Since 2011, the United States Food and Drug Administration (FDA) has approved five VEGFR-TKIs for malignant tumors including: regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib.

• Proteinuria, as a common adverse event associated with VEGFR-TKIs, has been frequently reported in many clinical trials.

• An updated meta-analysis of published RCTs was conducted to determine the incidence and risk of proteinuria associated with these newly approved VEGFR-TKIs.

• 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 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).

• As severe proteinuria is associated with increased risk of renal damage and cardiovascular events, a correct recognition and a prompt and proactive management should be emphasized when managing VEGFR-TKIs.

Author Contribution Statement

YGR and WZ conceived and designed the study. LJF, FT, and YHL assisted with search and collection of the data. XZ and LJF involved in the analysis and interpretation of the data. WZ and YGR drafted the manuscript. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of work.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

A reviewer on this manuscript has disclosed being a consultant for Bristol-Myers Squibb, Exelixis, Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, AstraZeneca, Merck, Genentech, EMD Serono, Astellas and Seattle Genetics; research support to institution from Astrazeneca, Bayer, Amgen, Boehringer Ingelheim, Janssen, Merck, Sanofi, and Pfizer; Steering committee for BMS, Astrazeneca, Bavarian Nordic, Debiopharm, Astellas; an author for UpToDate; and also a speaker for Clinical Care Options, Physicians’ Education Resource, Research to Practice, and OncLive. Other Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

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Funding

This paper was not funded.