CHICAGO—Sunitinib (SU) and sorafenib (SO) for adjuvant therapy will likely not cause significant cardiac toxicity in patients with resected renal cell carcinoma (RCC), according to a study presented at the American Society of Clinical Oncology 2012 annual meeting

The study, by Naomi B. Haas, MD, Associate Professor of Medicine at the University of Pennsylvania in Philadelphia, Robert G. Uzzo, MD, Professor of Surgery at Temple University, and colleagues, involved a cardiac analysis of 1,943 patients with resected high-risk RCC and normal left ventricular ejection fraction (LVEF).

“This study is the first to demonstrate that in the adjuvant setting these two drugs do not cause increased risk of cardiac events,” said Dr. Uzzo, Chief of Surgery at Fox Chase Cancer Center in Philadelphia. “This is the largest adjuvant kidney cancer trial ever done. It is also the first in the targeted therapy era.”

Study patients had participated in E2805, a randomized, double-blind study in which patients were randomized to one of three treatment arms. Arm A included patients who received oral SU once daily for four weeks followed by rest for two weeks and oral placebo in place of SO twice daily for six weeks. Arm B included patients who received oral SO twice daily for six weeks and oral placebo in place of SU once daily for four weeks followed by rest for two weeks. Arm C included patients who received oral placebo in place of both drugs.

Tumor tissue was collected prior to or during nephrectomy. Blood and urine samples were collected at baseline and periodically during study for biomarker correlative studies.

The objectives of the study were to determine if patients treated with sunitinib (SU) or sorafenib (SO) experienced clinically significant decreases in LVEF and to describe the frequency of clinically significant heart failure (HF).

Dr. Haas' group evaluated heart function using multiple gated acquisition (MUGA) scans at baseline and at three, six, and 12 months, and at the end of treatment. They also obtained MUGA scans if symptoms developed and at three months after the last abnormal assessment.

Post-baseline MUGA scans were available for 1,589 of 1,943 patients; 1,293 patients had MUGA assessment at six months or later, including 397 in the SU arm, 394 in the SO arm, and 502 in the placebo group.

The researchers defined the primary cardiac endpoint as an LVEF decline below the institutional lower limit of normal (ILN)—a 16% or greater decline from baseline occurring within six months of the start of therapy. The primary cardiac endpoint occurred in nine patients (2.3%) in the SU arm, seven (1.8%) in the SO arm, and five (1%) in the placebo arm.

Clinically significant HF, which was defined as grade 3 or higher LV systolic or diastolic dysfunction, occurred in 11 patients: five SU recipients (1.2%)], four SO recipients (1%), and two placebo recipients (0.4%).

Eight patients had cardiac ischemia possibly or probably from treatment. Only one grade 4 event followed a primary LVEF event.

The researchers concluded that cardiac function in patients starting with normal EF was not impaired significantly in patients receiving SU and SO compared with placebo. Ischemic events were uncommon and not clearly associated with treatment.

“It is important to note therefore that although we don't know the efficacy of these drugs in the adjuvant setting this is important information regarding their safety,” Dr. Uzzo told Renal & Urology News. “The most important information to take home is that the drugs are safe in the adjuvant setting and that cardiac events are rarely the cause of stopping drug. We await the results to see if they are efficacious.”

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