According to the results of a meta-analysis published early online in the Journal of Clinical Oncology, the use of small molecule vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) increases the risk of fatal adverse events (FAEs) in patients being treated for cancer.

The authors note that VEGF has emerged as an important target in cancer drug development.  There are currently three small-molecule TKIs of this pathway approved – sorafenib, sunitinib and pazopanib – and several trials investigating these drugs in new indications, and new agents targeting this pathway, are underway.  These agents may however be associated with serious adverse events, as the pathway is involved in several physiological processes, and the true incidence of FAEs may not be apparent during initial clinical testing and even at the time of approval.  The purpose of the current meta-analysis was to determine the risk of FAEs in patients with cancer treated with VEGFR TKIs.

The authors conducted a systematic search of the literature (MEDLINE and PubMed; Jan 1966 to Feb 2011) and identified ten randomised controlled trials (total n=4,679) evaluating pazopanib (n=435), sunitinib (n=1,388), or sorafenib (n=2,856) for the treatment of any type of primary cancer, and including an adequate safety profile report.  The main findings reported were as follows:
  

• The incidence of FAEs related to VEGFR TKIs was 1.5% (95% CI, 0.8% to 2.4%) with an RR of 2.23 (95% CI, 1.12 to 4.44; P = .023) compared with control patients.

• When stratified by each VEGFR TKI, the incidence was 1.4% (95% CI 0.6% to 3.2%) for sorafenib, 1.5% (95% CI 0.7% to 3.0%) for sunitinib, and 1.4% (95% CI, 0.5% to 3.6%) for pazopanib (no statistically significant difference was seen when comparing the hazard ratios between groups, although there may have been a lack of statistical power to detect any such differences).

• Haemorrhage was the most frequently occurring FAE reported in four trials and representing a total of 19 deaths or 47.5% of all study deaths. Myocardial infarction was the second most common FAE reported in five trials and representing 15% of all deaths. 

The authors acknowledge the limitations of their study, including the fact that confounding variables at the patient level could not be incorporated into the analysis, the low statistical power to detect any variations in FAE rate based on a specific drug or malignancy, and the fact that true incidence of FAEs could be higher as the studies included patients with adequate organ function.

The authors comment that despite current findings, it is important to remember that all three drugs benefit the overall patient population for their licensed indications, and that they should continue to be offered to these patients.  Practitioners should however be aware of the risks associated with their use and monitor patients rigorously.