VOTRIENT NEAR APPROVAL FOR SARCOMA

March 21, 2012 — The US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee voted yesterday to approve a New Drug Application for pazopanib tablets (Votrient, GlaxoSmithKline) in the treatment of patients with advanced soft tissue sarcoma who have received previous chemotherapy.

It was noted by the committee that patients with gastrointestinal stromal tumors (GIST) and adipocytic sarcomas were not included in the phase 3 trial on which the approval was based.

The committee confirmed, in an 11 to 2 vote, that data from clinical studies support a favorable benefit/risk assessment for pazopanib.

According to an FDA briefing document, in the pivotal phase 3 trial, pazopanib demonstrated a statistically significant and clinically meaningful increase in progression-free survival, which was the primary end point, compared with placebo. Median progression-free survival was 1.6 months (95% confidence interval [CI], 1.0 to 1.9) in the placebo group and 4.6 months (95% CI, 4.1 to 4.9) in the pazopanib group, with a corresponding hazard ratio (HR) of 0.35 (95% CI, 0.26 to 0.48; P < .001).

Overall survival results numerically favored pazopanib; however, the result was not statistically significant. Median overall survival in the placebo group was 10.7 months (95% CI, 9.0 to 13.1) and in the pazopanib group was 12.6 months (95% CI, 10.9 to 14.9), with a corresponding HR of 0.87 (95.7% CI, 0.67 to 1.13; P = .256).

In data aggregated from phase 2 and phase 3 trials, the most common adverse events reported in the pazopanib group were fatigue, diarrhea, nausea, weight loss, hypertension, decreased appetite, hair color change, and vomiting. Myocardial dysfunction as an adverse events was seen in 9% of patients in the pazopanib group and 5% of patients in the placebo group.

However, a recent meta-analysis found that pazopanib and 2 other vascular endothelial growth-factor (VEGF) receptor tyrosine kinase inhibitors were associated with fatal adverse events at a rate that was about twice that seen in the placebo groups of their clinical trials. The crude incidence of fatal adverse events was 1.5% in patients taking these VEGF inhibitors, compared with 0.7% in patients in the placebo or control groups (relative risk, 2.23; P = .023).

The most common cause of death in the meta-analysis was hemorrhage; the second most common cause was myocardial ischemia. Liver failure and congestive heart failure were also reported.

GlaxoSmithKline emphasized that clinicians working with these patients need more treatments from which to choose.

"Treatment options for patients with advanced soft tissue sarcoma are limited; we are therefore pleased that the committee took a favorable view of the clinical data for [pazopanib]," said Rafael Amado, senior vice president of GlaxoSmithKline Oncology. "We look forward to continuing the regulatory process," he added.

The committee provides the FDA with independent expert advice and recommendations, and the FDA usually follows the committee's advice with regard to its final approval decision.

The FDA approved pazopanib for the treatment of advanced renal cell carcinoma in 2009.