CHICAGO – Take your pick: The tyrosine kinase inhibitors sunitinib and sorafenib do/do not appear to have significant cardiac toxicity when used in adjuvant therapy for renal cell carcinoma.
Conflicting studies presented at the annual meeting of the American Society of Clinical Oncology suggest that – for now at least – it’s a toss-up.
Dr. Naomi B. Haas
A cardiac substudy of the phase III ECOG (Eastern Cooperative Oncology Group) E2805 ASSURE (Adjuvant Sunitinib or Sorafenib for Unfavorable Renal Carcinoma) trial, comparing either sunitinib (Sutent) or sorafenib (Nexavar) with placebo in patients with resected renal cell carcinoma (RCC), showed that neither TKI was associated with significant declines in left ventricular ejection fraction (LVEF) or other cardiac adverse events when compared with placebo, said Dr. Naomi B. Haas of the University of Pennsylvania, Philadelphia.
Left ventricular dysfunction that did occur with the TKIs was reversible, and ischemic events were uncommon and not clearly linked to therapy, she added.
"The implications for patients: Further prospective study on the effects of these agents is needed in patients who have preexisting cardiac dysfunction. This was a well population we were looking at," said Dr. Haas.
However, a retrospective study by Dr. Phillip S. Hall and colleagues at Stanford (Calif.) University found evidence of significant cardiac toxicity in patients with metastatic renal cell carcinoma that was treated with both agents and with other targeted therapies at their institution.
"Cardiovascular toxicity is an important adverse event related to targeted-therapy administration. Close monitoring for the development of CV toxicity with the use of these agents should become standard of care, as early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality," they wrote in a poster presentation.
TKIs on Trial
Previous studies, most of them retrospective, have reported cardiac dysfunction with TKI use ranging from 1% to 28%. The proposed mechanism of action is through the metabolic dysfunction of cardiac myocytes, Dr. Haas said.
She and her coinvestigators in the ECOG E2805 ASSURE trial looked at data from a cardiac substudy, and asked whether either sorafenib or sunitinib was associated with a decline in LVEF, clinically significant heart failure (HF) or other effects, using multigated acquisition scans (MUGA) at baseline and at 3, 6, and 12 months (study end) or at the end of treatment.
There were nine cases of the primary end point (a decline in LVEF of 16% or greater from baseline) among 397 patients on sunitinib, seven among 394 patients on sorafenib, and five among 502 patients on placebo. The respective event rates were 2.3%, 1.8%, and 1.0%; these differences were not clinically significant.
The numbers for other cardiac events – including LVEF decline of 16% or more below the institutional level of normal occurring after 6 months, or a grade 2 or 3 left ventricular systolic or diastolic dysfunction – were also similar among the groups, occurring in 12, 11, and 11 patients, respectively.
"Looking at the data as they stand, it on the face of it is very reassuring, with the primary end point being met in a very small proportion of patients," commented the invited discussant Dr. Tim Eisen, professor of oncology at the University of Cambridge (England).
He pointed out, however, that new cardiac events were seen in the study past 6 months of therapy, which indicated that investigators should continue to monitor patients for cardiotoxicities throughout the course of therapy and in follow-up.
TKIs in Practice
The Stanford investigators looked at the incidence of hypertension, left ventricular dysfunction, changes in serum markers of cardiovascular toxicity, and heart failure in 159 patients with metastatic RCC who were treated from 2004 through 2011. They found that 116 of 159 patients (73%) developed cardiovascular toxicities.
"Sunitinib was the most frequently used and most common offending agent, with 66 of 101 sunitinib-treated patients (65%) developing a form of CV toxicity, or 32 of 101 (32%) excluding hypertension. However, it was notable that CV toxicity was observed in 68%, 66%, and 51% of patients treated with bevacizumab, sorafenib, and pazopanib as well," the investigators wrote.
They noted that there were fewer toxicities with mTOR (mammalian target of rapamycin) inhibitors than with TKIs, but the sample sizes were small.
The ECOG E2805 trial was supported by the National Cancer Institute. The Stanford study was internally funded. Dr. Haas reported having a consulting or advisory role to Boehringer Ingelheim, Dendreon, Novartis, and Pfizer, and receiving research funding from GlaxoSmithKline. Dr. Hall reported having no relevant disclosures. Dr. Eisen has received honoraria and serves in a consulting or advisory role to Astellas and AVEO.