VEGFR Tyrosine Kinase Inhibitors Linked to Increased Risk of Fatal Adverse Events

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A meta-analysis of 10 randomized controlled trials involving 4,679 patients showed that the use of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors was associated with an increased risk of fatal adverse events. “The crude incidence of [fatal adverse events] in patients treated with a VEGFR [tyrosine kinase inhibitor] was 1.5% compared with 0.7% in patients from placebo/control arms.” However, despite the relatively low adverse event rate, the risk of developing a fatal adverse event was more than twofold higher among patients treated with VEGFR tyrosine kinase inhibitors vs patients treated in placebo/control arms, researchers reported in the Journal of Clinical Oncology.

The studies were culled from a search of MEDLINE and PubMed databases for articles published from January 1996 through February 2011. The studies could involve patients with any type of primary tumor but were limited to trials of FDA-approved VEGFR tyrosine kinase inhibitors, as of February 2011, the researchers noted. These agents were sorafenib (Nexavar), approved for renal cell and hepatocellular carcinoma, sunitinib (Sutent), approved for renal cell carcinoma and gastrointestinal stromal tumor, and pazopanib (Votrient), approved for renal cell carcinoma. Subgroup analysis found no difference in the rate of fatal adverse events between different VEGFR tyrosine kinase inhibitors or tumor types.

For the incidence of fatal adverse events, all tyrosine kinase inhibitor treatment arms were included, representing a total of 2,461 patients, the researchers reported. Hemorrhage was the most frequently occurring fatal adverse event reported in four trials and resulted in 19 deaths, or 47.5% of all study deaths. Myocardial infarction was the second most common fatal adverse event reported in five trials, representing 15% of study deaths. Other less frequent fatal adverse events were abnormal hepatic function or failure (n = 4), sepsis (n = 3), congestive heart failure (n = 2), and, resulting in 1 death each, ischemic stroke, pulmonary embolism, dehydration, and sudden death.

Relative Risks

The highest incidence of fatal adverse events occurred in a phase III trial of sorafenib in renal cell carcinoma. Overall, 19 deaths occurred in the six sorafenib trials, compared to 7 deaths in the three sunitinib trials, and 1 death in the single pazopanib trial. “This may be a result of the larger proportion of patients enrolled in sorafenib trials (62% of all patients in the analysis) rather than a unique property compared with the related molecules sunitinib and pazopanib,” the authors stated, noting that there were no statistically significant differences in relative risks. “All of these drugs antagonize the intracellular domain of the VEGFR and block the downstream signaling. In addition, all three drugs have similar toxicity class-effect profiles,” the researchers added.

Despite the current findings, the authors’ concluded, all three drugs benefit the overall population of patients with renal cell carcinoma, hepatocellular carcinoma, or gastrointestinal stromal tumor “by improving patients’ outcome and should continue to be offered to these patients. However, as this class of drugs gains greater clinical use, practitioners must be aware of the risks associated with their use and must provide rigorous monitoring to continue to improve patient outcomes.” ■

Schutz FAB, et al: J Clin Oncol. February 6, 2012 (early release online).




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