Phase II trial of vandetanib in Von Hippel-Lindau-associated renal cell carcinoma.

4584 Background: Germline mutations in the von Hippel Lindau (VHL) gene are associated with the development of bilateral multifocal clear-cell renal cell carcinoma (RCC). VHL patients with localized disease are surgically managed, with nephron sparing resection recommended once tumors reach 3 cm. Patients typically undergo multiple surgeries with significant cumulative morbidity. In this phase 2 trial of vandetanib, a dual VEGFR2/EGFR inhibitor, a systemic approach to these tumors was explored. Methods: Patients with VHL-associated RCC were treated with 300 mg vandetanib daily until disease progression or unacceptable toxicity. Cross sectional imaging was performed at baseline and every 12 weeks. The primary endpoint was overall renal tumor response assessed by RECIST. Results: A total of 34 subjects were enrolled, with a mean age of 47 years (range 28 – 72). The median number of targeted lesions per subject was 2 (range 1 – 6) and the mean tumor diameter was 2.3 cm (range 1.2 – 4.0). Twenty-seven (80%) subjects had baseline imaging and at least one follow-up study to allow response evaluation. Median time on study was 6.1 months (range 1.0 – 23.3). Thirteen (38%) subjects demonstrated overall reduction in tumor burden with a median reduction of 6% (range 4-54%). One (3%) subject had a PR by RECIST and 26 (77%) had stable disease as their best response. Eleven (32%) subjects were taken off study due to growth of at least one lesion that met criteria for surgical resection or disease progression. Nine (27%) subjects required dose reductions due to toxicity. Although the majority of adverse events encountered on trial were grade 2 or less, 9 (27%) subjects were taken off trial due to drug-related toxicities and 9 (27%) withdrew due to intolerable side effects. Rash (71%), and QTc prolongation (41%) were the most common adverse events noted. Conclusions: In the largest phase II study of a systemic agent for VHL-related RCC, vandetanib demonstrated anti-tumor activity. Despite a reasonable safety profile, poor tolerability necessitated drug withdrawal in a significant proportion of patients. Newer agents that selectively target the VEGF receptors may offer a more tolerable alternative and might optimize clinical benefits in this population. Clinical trial information: NCT0056695.