This randomised phase II, multicentre, double-blind, placebo-controlled American study evaluated the efficacy of vandetanib in combination with docetaxel in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy. Vandetanib is an oral once-daily selective tyrosine kinase inhibitor which has activity against vascular endothelial growth factor receptor 2 (VEGFR-2) and epidermal growth factor receptor (EGFR). The researchers note that little progress has been made in the treatment of UC with there being no standard second line therapy. Various agents have been tested (including docetaxel, paclitaxel, and pemetrexed) with response rates between 10% and 20%, however, they add that no drug has been proven to prolong overall survival (OS).
Amongst other eligibility criteria, patients entered into the study had histologically or cytologically confirmed locally advanced or metastatic UC and progression of disease documented by the investigator after platinum-containing chemotherapy. Patients were randomly assigned 1:1 to vandetanib plus docetaxel or placebo plus docetaxel. Patients in both arms underwent 21-day dosing cycles with docetaxel 75 mg/m2 on day 1 and dexamethasone 8 mg at about 12, 3, and 1 hour before docetaxel. Vandetanib and matching placebo were given as 100-mg tablets orally once daily. Patients receiving placebo tablets were assigned to take them on the same schedule as the patients receiving vandetanib. The primary endpoint measure considered was progression free survival (PFS - defined as the time between random assignment and documented progression per RECIST criteria or death). The study was designed to detect a 60% improvement in median PFS with 80% power. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Secondary outcome measures included overall survival (OS), overall response rate (ORR), and safety. Overall, 149 patients (docetaxel plus vandetanib, n = 74; docetaxel plus placebo, n = 75) were enrolled and randomly assigned between February 2007 and May 2010 at 16 centres in the United States. Of these, 142 patients received at least one dose of treatment (docetaxel plus vandetanib, n = 70; docetaxel plus placebo, n = 72). The following results are reported:
• Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = 0.939 – no statistical significance).
• ORR and OS were not different between both arms.
• Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhoea (7% v 0%).
• Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months.
The authors conclude, “The addition of vandetanib to docetaxel did not result in clinical benefit in a population of patients with advanced UC who were previously treated with platinum-based therapies. At this time, vandetanib cannot be recommended for future studies in the salvage setting.”
A related editorial discusses this study and the future of drug development in UC.