Manifestations of cardiovascular toxicity associated with the approved tyrosine kinase inhibitors

14152 Background: Since 2001, 5 tyrosine kinase inhibitors (TKi’s; imatinib, erlotinib, sorafenib, sunitinib and dasatinib) have been approved for hematologic and solid tumor indications including, CML, ALL, GIST, RCC, pancreatic and NSCLC. While individual agents are designed to inhibit the TK activity of specific targets, “cross-talk” with non-target TKs (e.g., ABL, EGFR, VEGFRs, KIT, KDR, CSF1R, PDGFRs, RET, the SRC family, EPHA2, RAF, and FLT3) is extensive. The relationship between inhibition of individual kinases and the toxicity profile of each drug is unclear. Methods: Following from the observation of cardiovascular (CV) toxicity in clinical settings (pre- and post- marketing) and from the original non-clinical toxicologic evaluations, a new “class-related” review of non-clinical toxicological findings was conducted. To compare the non-clinical and clinical CV findings, the Adverse Event Reporting System (AERS) was searched for all events, excluding those of non-CV nature and those unlikely to be drug-related (e.g. hemorrhagic events were excluded from the initial analyses). Individual patient reports were not reviewed in full, therefore definitive attribution of disease related events can not be made. Results: While variable in expression, the non-clinical signs of toxicity included cardiac and vascular inflammation, cardiac degeneration and hypertrophy, decreased cardiac function (e.g. LVEF decreases), alterations in blood pressure, and QT prolongation. Clinical reports for the TKi’s have included hypo- and hypertension, conduction abnormalities and arrhythmias, cardiac hypertrophy and changes in cardiac function (LVEF and CHF). Conclusions: It is not possible at this time to relate the CV toxicities associated with the TKi’s to a specific pattern of TK inhibition. CV toxicity has been observed both clinically and non-clinically and warrants further investigation. No significant financial relationships to disclose.