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Vandetanib Fails in Metastatic Bladder Cancer


 

FROM THE GENITOURINARY CANCERS SYMPOSIUM

ORLANDO – Adding the investigational agent vandetanib to docetaxel added toxicity but little clinical benefit in a double-blind, multicenter study of 142 patients with platinum-pretreated metastatic urothelial cancer.

The primary end point of median progression-free survival reached 1.58 months with placebo plus docetaxel (Taxotere) and 2.56 months with vandetanib plus docetaxel (hazard ratio 1.02). Median overall survival was actually longer with placebo at 7.03 months vs. 5.85 months with vandetanib (HR 1.21).

Treatment-related all-grade toxicity was reported in 66% of the vandetanib vs. 44% in the placebo arm (P = .012), and high-grade toxicity in 60% vs. 36% (P = .007), lead author Dr. Toni K. Choueiri reported in a late-breaking abstract at the Genitourinary Cancers Symposium.

"The addition of vandetanib, a dual EGFR/VEGFR antagonist, to docetaxel did not result in any benefit in terms of progression-free survival, response rate, or overall survival as compared to placebo plus docetaxel," he concluded. "Toxicities ran higher, but [were] manageable."

Vandetanib was an attractive agent to evaluate because it blocks the tyrosine kinase activity of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) receptor 2, two pathways that play an important role in urothelial cancer.

The researchers had hypothesized that simultaneous blockade of the pathways, in addition to the taxane docetaxel, might provide additional benefit, compared with chemotherapy alone. There is no standard of care for metastatic urothelial cancer that has progressed after treatment with a platinum-containing regimen. Taxanes often are used in the salvage setting, but with minimal activity, he said.

AstraZeneca is seeking approval of vandetanib for the treatment of unresectable locally advanced or metastatic medullary thyroid cancer. A Food and Drug Administration panel voted in late December that the risk-benefit profile of vandetanib is acceptable for patients with progressive, symptomatic medullary thyroid cancer, and added restrictive language to the proposed indication in light of toxicity concerns, particularly the possibility of QTc prolongation. On Jan. 7, the FDA extended the review time line for the new drug application to April 7, 2011.

In 2009, AstraZeneca filed for an advanced non–small cell lung cancer indication for vandetanib (under the proposed trade name Zactima) in the United States and Europe, but quickly withdrew the applications after preliminary feedback from regulators indicated progression-free survival data were not sufficient to support approval.

Dr. Choueiri and his associates assessed long-term outcomes among 142 patients with metastatic bladder cancer who had failed first-line platinum-based chemotherapy and received up to three prior systemic therapies including paclitaxel. They had a performance status of 0 or 1, and brain metastases were allowed.

Patients were randomized to docetaxel 75 mg/m2 every 21 days plus oral vandetanib 100 mg once daily or the same docetaxel regimen plus oral placebo until disease progression. Patients on the placebo arm were allowed to cross over to single-agent vandetanib.

Only 8 of the 72 (11%) placebo patients and 5 of the 70 (7%) vandetanib patients responded to treatment, Dr. Choueiri reported.

In all, 25% of the placebo arm experienced a grade 3/4 treatment-related nonhematologic adverse event vs. 50% of the vandetanib arm, including significantly more rash/photosensitivity (11% vs. 0%) and diarrhea (7% vs. 0%).

Single-agent activity with vandetanib was limited, said Dr. Choueiri, with the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston. A crossover analysis among 37 patients revealed one partial response and stable disease in 5 patients, with a median overall survival of 5.2 months. Two patients were unevaluable, and one patient recently crossed over without response data.

Exploratory analyses among all patients revealed no preferential activity with vandetanib for any subgroup with regard to progression-free or overall survival, Dr. Choueiri said.

"Clinical trials of rational drugs and combinations are urgently needed in this setting," he said.

The Dana-Farber Cancer Institute sponsored the study. Dr. Choueiri reported consultant/advisory roles with Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx Pharmaceuticals, and Pfizer.

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