FDA Approvals: Pazopanib for Advanced Soft Tissue Sarcoma

CLINICAL CONTEXT

Pazopanib was first approved by the US Food and Drug Administration (FDA) in 2009 when it became the sixth drug approved to treat advanced renal cell carcinoma. It is a small molecule with a mechanism of action as a tyrosine kinase inhibitor, specifically targeting receptors involved in angiogenesis and tumor cell proliferation. These include vascular endothelial growth-factor receptors 1, 2, and 3; platelet-derived growth-factor receptors α and β; fibroblast growth-factor receptors 1 and 3; stem cell factor receptors; interleukin-2-inducible T-cell kinase; leukocyte-specific protein tyrosine kinase; and transmembrane glycoprotein-receptor tyrosine kinase.

STUDY SYNOPSIS AND PERSPECTIVE

The FDA has approved pazopanib (Votrient) for the treatment of advanced soft tissue sarcoma in patients who have received previous chemotherapy.

Pazopanib is already marketed for the treatment of advanced renal cell carcinoma; when it was approved in 2009, it became the sixth drug for this indication.

The approval for advanced soft tissue sarcoma comes on the heels of an 11 to 2 vote in favor of approval by the FDA Oncologic Drugs Advisory Committee last month. Although there were more than 20 subtypes of sarcoma involved in the clinical phase 3 trial leading to the approval, gastrointestinal stromal tumors and adipocytic sarcomas were not among them. Because the effectiveness of pazopanib for these tumors has not been demonstrated, they are not part of this approval.

"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," Richard Pazdur, MD, director of the office of hematology and oncology products at the FDA Center for Drug Evaluation and Research, said in a statement. "Drug development for sarcomas has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas."

Pazopanib is a small-molecule tyrosine kinase inhibitor that specifically targets receptors associated with angiogenesis and tumor cell proliferation. It inhibits vascular endothelial growth-factor receptors 1, 2, and 3, platelet-derived growth-factor receptors α and β, fibroblast growth-factor receptors 1 and 3, stem cell factor receptors, interleukin-2-inducible T-cell kinase, leukocyte-specific protein tyrosine kinase, and transmembrane glycoprotein-receptor tyrosine kinase.

Pivotal Clinical Trial

The safety and effectiveness of pazopanib was evaluated in a single phase 3 trial, called PALETTE (Pazopanib Explored in Soft Tissue Sarcoma), of 369 previously treated patients with advanced soft tissue sarcoma. Pazopanib demonstrated a statistically significant and clinically meaningful increase in progression-free survival, the primary end point of the study, compared with placebo.

Median progression-free survival was 1.6 months in the placebo group, compared with 4.6 months in the pazopanib group, with a corresponding hazard ratio (HR) of 0.35 (95% confidence interval, 0.26 to 0.48; P < .001).

Although overall survival results trended toward pazopanib over placebo (12.6 vs 10.7 months), the result was not statistically significant (HR, 0.87; P = .256).

The most common adverse effects associated with pazopanib were fatigue, diarrhea, nausea and vomiting, weight loss, hypertension, decreased appetite, headache, a distorted sense of taste, shortness of breath, and skin discoloration.

Boxed Warning

Pazopanib carries a boxed warning about the potential risk for severe and fatal hepatotoxicity, which has been observed in clinical studies. The product labeling states that patients should be monitored for hepatic function, and treatment should be discontinued in the event of declining liver function.

A recent meta-analysis found that pazopanib and 2 other vascular endothelial growth-factor receptor tyrosine kinase inhibitors are associated with fatal adverse events at a rate 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 drugs; in the placebo or control groups, it was 0.7% (relative risk, 2.23; P = .023).

The most common cause of death in the meta-analysis was hemorrhage, followed by myocardial ischemia, abnormal hepatic function or failure, sepsis, congestive heart failure, ischemic stroke, pulmonary embolism, dehydration, and sudden death.

More information on the pazopanib approval is available on the FDA Web site.

CLINICAL IMPLICATIONS

• The FDA has approved pazopanib to treat patients with advanced soft tissue sarcoma who have previously received chemotherapy. The approved indications do not include gastrointestinal stromal tumors and adipocytic sarcomas because these tumors were not among the 20 subtypes of sarcoma represented in the pivotal phase 3 trial leading to FDA approval.
• In the PALETTE phase 3 trial of 369 previously treated patients with advanced soft tissue sarcoma, pazopanib was associated with a statistically significant and clinically meaningful improvement vs placebo in progression-free survival, which was the main study outcome.
• A boxed warning for pazopanib notes the potential risk for severe and fatal hepatotoxicity. Patients should be monitored for hepatic enzyme levels, and treatment should be discontinued if liver function decreases. Common adverse effects include fatigue, diarrhea, nausea and vomiting, weight loss, hypertension, decreased appetite, and headache.