Risk of serious adverse events (SAEs) and fatal adverse events (FAEs) with sorafenib use in patients with solid cancers: a meta-analysis of phase 3 RCTs

Abstract

Background: Sorafenib is a commonly used vascular endothelial growth factor-tyrosine kinase inhibitor in a variety of cancers. There are concerns about the increased risk of SAEs and FAEs with sorafenib. We performed an up-to-date meta-analysis of all phase 3 randomized controlled trials (RCTs) of sorafenib to quantify the increased risk of SAEs and FAEs. Methods: We carried out a systematic search on PubMed for studies published in English. Eligibility criteria included phase 3 RCTs of solid tumors comparing sorafenib, alone or in combination with non-targeted chemotherapy (Sorafenib arm) versus placebo or non-targeted chemotherapy (control arm). Data on SAEs and FAEs for both the arms were extracted from each study and pooled to determine the overall incidence, relative risks (RRs) and 95% Confidence Intervals (CIs). Results: Of 471 studies identified, a total of 12 phase 3 RCTs involving 6,797 solid cancer patients comparing sorafenib with control met the eligibility criteria and included in this meta-analysis. 8 RCTs compared sorafenib alone with a placebo and 4 RCTs compared sorafenib plus chemotherapy with chemotherapy plus placebo. The RCTs involved Hepatocellular carcinoma (HCC, n = 5), Melanoma (n= 2), non-small cell lung cancer ( n = 2), pancreatic cancer, renal cell carcinoma and thyroid cancer ( n = 1 each). The overall incidence of SAEs and FAEs with sorafenib were 24.5% (95% CI: 16.0%-35.5%) and 1.6% (95% CI: 0.7%- 3.3%) respectively. Compared with control, sorafenib use significantly increased the risk of both SAEs ( RR : 1.51, 95% CI: 1.20-1.92, P < 0.001) and FAEs ( RR : 1.84, 95% CI: 1.29-2.64, P = 0.001). This association varied significantly with cancer types ( P = 0.001) and approval status ( P = 0.018) for SAEs but no evidence for heterogeneity was found for FAEs. The risk for SAEs was significantly higher for HCC (RR: 2.20, 95%CI: 1.18-4.10, P = 0.013) and non-approved use of sorafenib (RR: 1.68, 95% CI: 1.24-2.29, P = 0.001). Conclusions: This meta-analysis of phase 3 RCTs demonstrates an increased risk of SAEs and FAEs with sorafenib use in patients with solid cancers. Special vigilance is recommended while using sorafenib in non-approved settings.