Cabozantinib is a multi-kinase inhibitor with a broad spectrum of anti-tumour activity and immunomodulation (Choueiri et al., 2021). It mainly targets MET and VEGFR, and also inhibits RET, KIT, AXL, and FLT3 (Yakes et al., 2011). The US Food and Drug Administration (USFDA) has approved cabozantinib for the treatment of several cancers since 2012, including advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) and progressive, metastatic medullary thyroid cancer (MTC) (Exelixis Inc., 2012). These approvals were based on the results of three pivotal clinical trials. A randomized phase 3 CELESTIAL trial indicated that treatment with cabozantinib resulted in longer overall survival (OS) and progression-free survival (PFS) than placebo in patients with HCC (Abou-Alfa et al., 2018), and a randomized phase 3 METEOR trial indicated that treatment with cabozantinib improved OS, PFS, and objective response (ORR) compared with everolimus in patients with advanced RCC (Choueiri et al., 2016), and a randomized phase 3 COSMIC-311 trial showed that cabozantinib significantly prolongs PFS than placebo in patients with MTC (Brose et al., 2021).

As second-line therapy, the efficacy of cabozantinib monotherapy has been indicated in the first-line of solid tumor (Choueiri et al., 2018, Kelley et al., 2022). Recently, cabozantinib was recommended as a first-line option for advanced kidney cancer by the RCC Guidelines Panel. (Bedke et al., 2021, Jonasch, 2018). Although cabozantinib can improve survival patients with multiple malignancies (Abou-Alfa et al., 2018, Brose et al., 2021, Choueiri et al., 2016), the treatment-related toxicity of cabozantinib cannot be ignored. Previous studies have reported that due to cabozantinib-related toxicity, 33% patients were required treatment discontinuation, and 67% were required dose reductions (Smith et al., 2016). And even worse, treatment-related deaths have been reported with cabozantinib (El-Khoueiry et al., 2021). Given its high incidence of adverse events, the USFDA has issued 15 boxed warnings of treatment-related toxicity of cabozantinib (Exelixis Inc, 2012).

Especially, hepatotoxicity, as a common side-effect, has been noted in many clinical trials, with the incidence of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations ranging from 12.1%−65% and 16%−55%, respectively, in patients who received treatment of cabozantinib (Basch et al., 2019, Choueiri et al., 2016, Choueiri et al., 2018, Kelley et al., 2022, Matulonis et al., 2019, Neal et al., 2016, Pal et al., 2021, Smith et al., 2016). In addition, several reports have indicated that the risk of cabozantinib-induced hepatotoxicity is higher compared with other conventional therapies (Basch et al., 2019, Neal et al., 2016, Smith et al., 2016). Recognition and management of cabozantinib-induced hepatotoxicity is of special importance, because poorly controlled hepatotoxicity could lead to many systemic symptoms (such as, pyrexia, fatigue, nausea, rash, abdominal pain, arthralgia and so on.) (Garcia-Cortes et al., 2020) and seriously reduce the quality of life of patients. In addition, drug-related hepatotoxicity can cause hepatitis, cirrhosis and liver failure, and even threaten the life safety of patients.

However, to our knowledge, there have been no systematic reviews and meta-analysis comparing the risk of hepatotoxicity between cabozantinib and other solid tumor drugs in cancer patients. To fill in the existing gaps in knowledge and evidence, we decided to conduct a meta-analysis to compare the risk of hepatotoxicity between cabozantinib and other approved drugs for the treatment of solid tumors, and to provide theoretical support for the clinical safe medication of cabozantinib.