Pazopanib (Votrient) Gets FDA Approval for Advanced Soft-Tissue Sarcoma

Earlier today the US Food and Drug Administration (FDA) approved pazopanib (Votrient), an oral multitargeted angiogenesis inhibitor, to treat patients with metastatic soft-tissue sarcoma who have previously received chemotherapy.

More than 20 subtypes of sarcoma were included in the clinical trial that led to the approval, but as gastrointestinal stromal tumors and adipocytic sarcomas were not among them, they are excluded from this indication.

Soft-tissue sarcomas are an uncommon set of malignancies that begin in muscle, fat, fibrous, and other tissues, and pose a therapeutic challenge. The biologic understanding of these tumors is limited because of a paucity of preclinical models and cell lines to evaluate in the laboratory. Soft-tissue sarcoma occurs in about 10,000 cases annually in the United States.

“Soft-tissue sarcomas are a diverse group of tumors and the approval of pazopanib for this general class of tumors is the first in decades,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Drug development for sarcomas has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas.”

PALETTE Trial

The safety and effectiveness of pazopanib as a second- or later-line treatment was evaluated in the PALETTE trial, a multicenter, international, double-blind, placebo-controlled phase III clinical trial that involved 369 patients (246 pazopanib, 123 placebo) with metastatic soft-tissue sarcoma who had had failed at least one anthracycline containing regimen.

Patients were randomized to receive either pazopanib 800 mg once daily or placebo until tumor progression. The study was designed to measure progression-free survival and found that pazopanib significantly prolonged disease progression. Patients on the drug had a median progression-free survival of 4.6 months, compared with 1.6 months for those receiving the placebo (HR=0.31, 95% CI 0.24-0.40; P < .0001).

Patients eligible for the study were at least 18 years of age (median age was 56 years) with angiogenesis inhibitor-nave, histologically proven, metastatic soft-tissue sarcoma.

When results of the PALETTE trial were reported at the 2011 Annual Meeting of the American Society of Clinical Oncology, the interim analysis for overall survival showed a statistically nonsignificant improvement of pazopanib vs placebo (median: 11.9 vs 10.4 months, HR=0.83, 95% CI 0.62-1.09). Those numbers have since been updated but were still found to be nonsignificant (12.6 vs 10.7 months).

The most common side effects in pazopanib-treated patients were fatigue, diarrhea, nausea, weight loss, headache, a distorted sense of taste, shortness of breath, high blood pressure, decreased appetite, vomiting, tumor and muscle pain, and skin discoloration.

As pazopanib carries a boxed warning alerting patients and health care professionals to the potential risk of hepatotoxicity, which can be fatal, patients should be monitored for liver function and treatment should be discontinued if liver function declines.

Pazopanib was granted an orphan drug status designation for this indication. An orphan designation is given to a drug intended to treat a disease affecting fewer than 200,000 patients in the United States. The drug was first granted approval for the treatment of advanced kidney cancer in October 2009.