October 21, 2009 — The US Food and Drug Administration (FDA) has approved pazopanib tablets (Votrient, GlaxoSmithKline) for the treatment of patients with advanced renal cell carcinoma.
Pazopanib is the sixth drug to be approved for the treatment of kidney cancer since 2005. This year, about 49,000 people have been diagnosed with the disease, and 11,000 have died, FDA officials said in a news release.
"The last five years have seen dramatic improvements in treatment options for patients with kidney cancer. Before 2005, the options available offered only limited effectiveness," noted Richard Pazdur, MD, director, Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research. Newly approved drugs include sorafenib, sunitinib, temsirolimus, everolimus, and bevacizumab.
FDA approval of pazopanib was based on data from a randomized, double-blind multicenter phase 3 study (n = 435), showing that its use significantly increased progression-free survival relative to placebo (9.2 months vs 4.2 months; P < .001).
The recommended dose of pazopanib is 800 mg taken once daily at least 1 hour before or 2 hours after a meal. Dose reductions to 400 mg are indicated for patients requiring concomitant treatment with strong cytochrome P 450 isoenzyme 3A4 (CYP 3A4) inhibitors; coadministration of strong CYP 3A4 inducers should be avoided.
Adverse events reported in 20% or more of patients receiving pazopanib include diarrhea, hypertension, hair depigmentation, nausea, anorexia, and vomiting.
Increases in serum transaminase and bilirubin levels were also observed, in some cases leading to severe and fatal hepatotoxicity. Liver chemistries should be measured at baseline and regularly during treatment with pazopanib. Dosing reductions are indicated for patients with moderate hepatic impairment; pazopanib is not recommended for patients with severe liver dysfunction.
Caution is advised when treating patients at increased risk for QT interval prolongation; monitoring electrocardiograms and electrolytes should be considered. Because of the risk for potentially fatal hemorrhagic events, pazopanib should not be used in patients with a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. Blood pressure should be well-controlled before initiating treatment with pazopanib, and patients should be monitored for hypertension and treated as needed. Pazopanib can cause fetal harm and should not be used in pregnancy, the FDA sa
Issued: Monday 1st June 2009, London, UK and Philadelphia, PA— Today, GlaxoSmithKline announced the results of a Phase III study demonstrating that pazopanib reduced the risk of tumor progression or death by 54 percent compared to placebo.1
Study findings demonstrated that the median time without tumor growth or death (progression free survival or PFS) in the pazopanib treated group was 9.2 months compared to 4.2 months in the placebo group. When specific patient groups were evaluated, those with no prior drug treatment experienced 11.1 months of median PFS with pazopanib versus 2.8 months with placebo. Patients who had previously received cytokine-based treatment showed 7.4 months of median PFS with pazopanib versus 4.2 months with placebo. These results were featured in an oral presentation at the annual American Society for Clinical Oncology (ASCO) meeting in Orlando, Florida.
“The study shows that pazopanib significantly improved PFS for patients regardless of whether or not they had prior therapy. While there have been many treatment advances for patients with advanced kidney cancer, there is still a need for medicines that are effective and well-tolerated,”said Dr. Cora N. Sternberg, Department of Medical Oncology, San Camillo and ForlaniniHospitals, Rome, Italy. “Additionally, patients did not experience a significant decline in health-related quality of life with no significant differences between pazopanib and placebo.”
The results are based on a global, double-blind, Phase III trial of 435 patients with advanced kidney cancer (renal cell carcinoma) who had either received no prior drug treatment or had received prior cytokine-based treatment.1 Patients were randomly assigned on a 2-to-1 basis to receive either pazopanib or placebo. Pazopanib reduced the risk of disease progression or death by 54% (hazard ratio = 0.46 with 95% confidence interval 0.34 to 0.62; P<0.0000001).1 The overall response rate in the pazopanib arm for the overall study population was 30% with duration of response of 59 weeks.
The majority of adverse events were mild to moderate, the most common (incidence ≥20%) being diarrhea, hypertension, hair color change, nausea, anorexia, and vomiting. The most common grade 3/4 adverse events (incidence >3%) were diarrhea (4%), hypertension (4%), and asthenia (3%). The most common laboratory abnormalities (incidence ≥50%) were elevated levels of liver enzymes known as transaminase, with elevated ALT as the most common grade 3/4 event (12%). Investigator-reported serious adverse events included liver-related events (3%), arterial thrombotic events (3%) and hemorrhage (3%).In this study, approximately 4% of patients on treatment compared to 3% of patients on placebo had a fatal event. Investigators attributed death due to study drug in approximately 1.4% of patients in the treatment arm. Some of these adverse events/serious adverse events have been reported with this class of agents.
Pazopanib is an oral medicine that prevents the growth of new blood vessels to tumors. The growth of new blood vessels is a process called angiogenesis. All solid tumors need blood vessels to survive, and by stopping or slowing this process, medicines in this category may halt the progression of tumor growth.7
In December 2008, GSK submitted a GSK new drug application (NDA) to the U.S. Food and Drug Administration (FDA) and, in early 2009, a European marketing authorization application (MAA) to the European Medicines Agency (EMEA) for pazopanib for the treatment of advanced renal cell carcinoma (RCC) based on these data. The submission was recently accepted by the FDA. Pazopanib is not yet approved in any country for any indication at this time.
“We’re extremely pleased to see the progress in developing pazopanib for advanced kidney cancer, but this represents just one type of cancer in need of new treatments. Our global studies using pazopanib are designed to find new ways to use a proven mechanism to fight a diverse group of cancers,” said Paolo Paoletti, Senior Vice President, R&D Oncology Unit. “This further demonstrates our efforts to discover new medicines that provide tangible clinical benefits for patients.”
About pazopanib
Pazopanib is an investigational, oral,
once-daily angiogenesis inhibitor targeting vascular endothelial growth factor
receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit. VEGF
and PDGF are growth factors critical to the development and growth of blood
vessels – a process known as angiogenesis. Angiogenesis plays a pivotal role in
the growth and spread of several tumor types, with VEGF and PDGF overexpression
linked to multiple cancers including cancers of the liver, lung, breast, kidney,
bladder, ovaries, and colon. [14] By inhibiting VEGFR, PDGFR, and
c-kit, pazopanib may stop or slow the rate of tumor growth and development.
Pazopanib is currently being studied in a number of different tumor types;
clinical trials are currently underway in RCC, breast cancer, ovarian cancer,
soft tissue sarcoma, NSCLC, cervical cancer and other solid tumors. It is being
evaluated as a monotherapy, in combination with targeted therapies [
and in combination with cytotoxic chemotherapy