Cardiac safety analysis for a phase III trial of sunitinib (SU) or sorafenib (SO) or placebo (PLC) in patients (pts) with resected renal cell carcinoma (RCC).

Abstract

4500 Background: We performed a cardiac analysis of E2805, a well population of pts with resected high risk RCC. The objectives were to determine if pts treated with SU or SO had clinically significant decreases in left ventricular (LV) ejection fraction (EF) and to describe the frequency of clinically significant heart failure (HF). We also report the frequency of other events including (un)stable angina or myocardial infarction. Methods: EF was measured by multiple gated acquisition scan (MUGA) at baseline, 3, 6, and 12 months (mo), and end of treatment, if symptoms developed, and 3 mo after the last abnormal assessment. The primary cardiac endpoint was defined as an EF decline < the institutional lower limit of normal (ILN) that was a ≥ 16% decline from baseline, and that occurred ≤ 6 mo into therapy. Clinically significant HF was ≥ Grade 3 LV systolic or diastolic dysfunction (severe symptoms with any activity or from drop in EF responsive (Grade 3) or refractory (Grade 4) to therapy. Late LVEF events were a drop in LVEF of ≥ 16% occurring after 6 mo of therapy. Event rates on each treatment arm were calculated, with 90% exact binomial confidence intervals (CI). Results: Post-baseline MUGAs are available for 1589 of 1943 total pts accrued. 1293 pts had MUGA assessment ≥ 6 mo. 21 pts had primary events (Table). 71 pts had worst LVEF declines of ≥16% from baseline, including 52 of which occurred ≤ 6 mo from baseline, with the majority not meeting full primary event criteria. There were 11 reported grade 3 LV systolic events (5 SU, 4 SO and 2 PLC). 8 pts had cardiac ischemia possibly or probably from agent. Only one grade 4 event followed a primary LVEF event. 4 of 7 pts who began treatment with LVEF <ILN had primary LVEF events. Conclusions: In detailed followup of SU and SO use, cardiac function in pts starting with normal EF, was not impaired significantly over placebo. Ischemic events were uncommon and not clearly associated with treatment. The data demonstrate that SU or SO for adjuvant therapy will likely not cause significant cardiac toxicity. [Table: see text]