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SU5416 Plus Interferon in Advanced Renal Cell Carcinoma

A Phase II California Cancer Consortium Study with Biological and Imaging Correlates of Angiogenesis Inhibition

University of California Davis Cancer Center, Sacramento, California 95817 [P. N. L., F. J. M., P. C. M., C. T., P. B., T. W., R. G., I. G., P. H. G., D. R. G.]; University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90033 [D. I. Q., H. J. L.]; City of Hope National Medical Center, Duarte, CA 90101 [K. M., J. L., P. F., J. H. D.]; and Northern California PET Imaging Center, Sacramento, CA 95817 [P. V., J. R.]

Purpose: Vascular endothelial growth factor (VEGF) is expressed in up to 70% of renal cell carcinomas (RCCs) and is a rational therapeutic target. SU5416 is a small molecule inhibitor of VEGF-mediated signaling through Flk-1, a transmembrane tyrosine kinase. IFN- also possesses dose- and schedule-dependent antiangiogenic effects at doses lower than those used for RCC therapy. We hypothesized that SU5416 plus low dose IFN- 2B (Intron-A) would result in a 1-year event-free survival (EFS), exceeding 20% in patients with metastatic RCC using the results of a randomized immunotherapy trial as historical control. Efficacy was correlated with serial plasma VEGF and plasminogen activator inhibitor-1 levels and with positron emission tomography scans.

Experimental Design: Thirty patients were treated with SU5416 145 mg/m² i.v. twice weekly plus Intron-A 1 million units s.c. twice daily, cycled every 6 weeks.

Results: Fifteen patients (50%) had stable disease (SD) at 12 weeks, including 1 minor response and 8 with progressive disease (27%). Median survival time was 10 months, and 1-year EFS was 6% (95% confidence interval, 1–35). The most common grade 3 or 4 toxicities included fatigue and lymphopenia, among others. There were 3 on-study deaths, 2 of which were infection-related. Significant declines in median plasma levels of VEGF pre- and posttherapy were observed. In 5 patients with paired FDG and O-15 positron emission tomography scans, tumor metabolism and perfusion were unchanged in 3 patients with SD, increased in 1 patient with progression, and decreased in 1 patient with SD.

Conclusions: Although SU5146 plus low-dose IFN exhibits biological activity in RCC as evidenced by significant declines in serial VEGF and plasminogen activator inhibitor-1 plasma levels, the 1-year EFS of 6% and adverse toxicity profile diminishes enthusiasm for additional studies with this combination in advanced RCC.

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