Cardiovascular toxicity associated with the multitargeted tyrosine kinase inhibitor anlotinib

Abstract

Background: Anlotinib, a multitargeted tyrosine kinase inhibitor, has been shown to have encouraging activity against many tumors, but its cardiovascular toxicity has not been investigated specifically. We reviewed anlotinib-associated cardiovascular adverse events in patients and explored its cardiotoxicity in vitro. Methods: We retrospectively reviewed all cardiovascular events in 62 patients with unresectable tumors who had taken anlotinib and mainly examined anlotinib’s effects on left ventricular ejection fraction (LVEF) and blood pressure. Besides, we investigated its cardiotoxicity in Neonatal Rat Ventricular Myocytes (NRVMs). Results: All-grade hypertension was seen in 60 patients (97%), and 25 individuals (40%) developed grade 3 hypertension. Significant univariate associations for predictors of post-treatment hypertension were age ( P<0.001), BMI ( P=0.003), ECOG PS( P<0.001), diabetes mellitus ( P=0.035), dose of anlotinib ( P=0.025). Multivariate analysis suggested that age [odds ratio (OR) 1.079, 95% confidence interval (CI): 1.029–1.130, P= 0.001] and BMI [OR 3.448, 95% CI: 1.410–8.433, P= 0.007] were the only significant independent predictors. No grade 3/4 left ventricular systolic dysfunction was reported. One patient (2%) had acute myocardial infarction, leading to cardiac death. In vitro, western blotting results showed that the levels of ANP, BNP, c-Myc and Cleaved Caspase3 were notably increased and cardiomyocyte apoptosis was strikingly increased in anlotinib group, as detected by TUNEL staining and Annexin V-FITC/PI flow cytometry. Conclusions: Our study results showed that anlotinib could induce rat cardiomyocytes apoptosis. Nonetheless, anlotinib-associated cardiovascular toxicity was acceptable and manageable for patients with unresectable tumors.

Immunotherapies targeting tumor vasculature: challenges and opportunities

“…In terms of function and structure of the approved biotherapeutic agent, after intravitreal drug injection, the full size of mAb limited their kidney excreted through urine and the Fc domain of mAb bind to neonatal Fc receptor (FcRn), expressed by ECs, resulting in prolonged systemic exposure as well as possible adverse events ( 50 ). Unlike mAbs that bind specific targets, multi-targeted TKIs have broader bioactivity and exhibit greater antitumor activity but are more toxic ( 51 ). In addition, productive anti-VEGF agents need to be administered frequently, which asides from drug resistance and commercially present a high cost of treatment that has limited their widespread use.…”