A clinical and biological profile to predict risk of development of hypertension in patients with non-clear cell renal cell carcinoma treated with sunitinib.

Abstract

4601 Background: Hypertension (HTN) due to sunitinib is a common toxicity that has been linked to the development of severe adverse cardiovascular events. Intriguingly, recent observations also suggest a correlation between treatment related HTN and treatment response to anti-angiogenic therapies, including sunitinib. Risk predictors for the development of HTN have not been established. Methods: This is a single-arm phase II trial with a two-stage design to evaluate sunitinib (50 mg daily, 4/2 schedule) in non clear cell RCC (nccRCC). Eligibility criteria included PS 0-2, measurable disease, and a maximum of 2 prior regimens. Monitoring of cardiovascular events included coronary artery disease (CAD) risk-factor assessment and prospective monitoring of blood pressure and cardiac function. In addition, a panel of circulating angiogenic factors was measured prior to therapy and after the first cycle of therapy. Results: 46 pts (65% male, 26% >65 years of age) received an average of 2.6 cycles of sunitinib therapy for nccRCC from March 2007 to December 2009. There were 28 deaths (61%) which were due to progression of disease. 33% of pts developed Grade 2 or higher treatment-related HTN. 0/12 patients without established risk factors for CAD developed treatment related HTN, while 74% (13/17) of pts with two or more CAD risk factors developed treatment-related hypertension. Treatment with sunitinib was associated with a marked reduction in circulating VEGFR-2 levels after one cycle of treatment (p < 1 × 10-10). Intriguingly, baseline levels of soluble VGEFR-2 were two-fold lower in pts who developed treatment-related HTN (p < 0.05). An association between objective response rate and the development of HTN is being explored. Conclusions: HTN associated with sunitinib was observed at a much higher frequency in patients with underlying CAD risk factors. Soluble VEGFR-2 was significantly reduced after treatment in all patients, and was reduced at baseline in pts who developed treatment related HTN. Our observations suggest a complex and potentially important biological interaction between the host vasculature, tumor, and response to sunitinib therapy. No significant financial relationships to disclose.