Sunitinib, a small molecular weight tyrosine-kinase inhibitor, is found to have cardiac toxicity

December 16, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

Boston Sunitinib is approved for use in patients with advanced renal cell cancer and gastrointestinal stromal tumors. A new look at the safety of the tyrosine kinase inhibitor found an association with heart failure.

Small molecular weight tyrosine kinase inhibitors are the exemplar of biomedical research. Their history dates back to 1960, when Peter Nowell described the Philadelphia chromosome in patients with chronic myelogenous leukemia (CML), the earliest evidence for a genetic basis of cancer. The following decades saw the characterization of the ABL tyrosine kinase, the development of Gleevec, and the oncogene addiction hypothesis. These small molecular weight inhibitors have ushered in a new era of cancer therapeutics, tailored to individual cancer genetics.

Sunitinib (Sutent, Pfizer) is a relatively broad-specificity tyrosine kinase inhibitor, with activity against VEGF receptors, PDGF receptors, KIT, CSF-1, and the RET gene product. It was approved in 2006 by the FDA for use in GI stromal tumors that have progressed on Gleevec and for advanced renal cell cancer.

The investigators reviewed cardiac function and outcomes in 75 patients with Gleevec-resistant GI stromal tumors being treated with sunitinib at the Dana Farber Cancer Institute. Deaths were adjudicated by oncologists and cardiologists independently. The composite cardiovascular outcome was cardiovascular death, myocardial infarction, or congestive heart failure. There was no comparison arm to the study. Most patients were of good performance status (ECOG 0 or 1), 5% had known coronary artery disease, 30% had hypertension, 27% smoked, 11% were diabetic, and 11% had dyslipidemia. None had heart failure at baseline and all had left ventricular ejection fraction >50%.

During the 2 year trial, 8 patients (11%) had a cardiovascular event, 1 died post-operatively, 1 had a myocardial infarction, and 6 developed heart failure. More patients, however, had EF<50% during the trial (n=13, 20%), an increase in troponin-I (n=12, 18%), or developed significant hypertension (n=35, 47%). The major risk factor associated with a composite cardiac event or heart failure was a history of coronary artery disease (p=0.03). There was an almost linear association between treatment cycle number and decline in LVEF, and likewise a step-wise increase in the incidence of hypertension across treatment cycle. Endomyocardial biopsies from 2 patients who developed heart failure showed cardiomyocyte hypertrophy and diffuse vacuolization with abnormal mitochondria. No replacement fibrosis, focal necrosis or inflammation was observed. The researchers combined the clinical data to a mouse model of sunitinib safety. Mice treated with sunitinib developed mitochondrial dysfunction in their cardiomyocytes, and ex vivo studies of rat cardiomyocytes revealed increased apoptosis induced by sunitinib.

Lead author Maria Rupnick told Wikidoc "there is a pressing need to address the unexpected adverse cardiac events [of tyrosine kinase inhitors]. Determining the underlying mechanisms is vital for rational drug development, trial design, and patient selection, monitoring and management if these agents are to be used to their fullest."

Through carefully reviewing cardiovascular outcomes in the phase I/II trial of sunitinib, this study demonstrated cardiotoxicity not reported in larger studies of sunitinib. The authors point out that this study is especially relevant now that sunitinib has received approval, as many patients taking this medicine will have co-morbidities such as hypertension and coronary artery disease. "Sunitinib...is in more than 100 ongoing clinical trials registered, enrolling ~20,000 patients including children to examine >25 different tumor types, the majority of which do not include cardiac function or blood pressure in their exclusion criteria, and serial cardiac monitoring is rare. A desired outcome of our manuscript is to promote consideration of cardiac monitoring in trial designs for sunitinib and similar drugs, as well as in management guidelines for patients being treated off-trial."

Tammy F Chu, Maria A Rupnick, Risto Kerkela, Susan M Dallabrida, David Zurakowski, Lisa Nguyen, Kathleen Woulfe, Elke Pravda, Flavia Cassiola, Jayesh Desai, Suzanne George, Jeff rey A Morgan, David M Harris, Nesreen S Ismail, Jey-Hsin Chen, Frederick J Schoen, Annick D Van den Abbeele, George D Demetri, Thomas Force, Ming Hui Chen. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. The Lancet 2007; 370:2011-2019 DOI:10.1016/S0140-6736(07)61865-0