ASCO 2009-ANOTHER "ME-TOO" DRUG FOR KIDNEY CANCER

June 11, 2009 (Orlando, Florida) —The investigational drug pazopanib showed significant activity against advanced renal cell cancer in a placebo-controlled phase 3 trial presented here at the American Society of Clinical Oncology 45th Annual Meeting. But in a discussion session, one expert suggested that it needs to show more because there are already similar drugs approved for this indication.

Pazopanib is not marketed yet. The study was funded by the manufacturer, GlaxoSmithKline, and the company has submitted these data for approval for this indication to both the US Food and Drug Administration and the European Medicines Evaluation Agency.

The results from the study showed "not surprisingly" that pazopanib was better than placebo, said Primo Lara, MD, professor of medicine at the University of California at Davis, speaking at a Highlights of the Day session. The hazard ratio (0.46) was similar to those seen in previous phase 3 trials in this setting, he noted, such as with sunitinib vs interferon and sorafenib vs placebo.

However, sunitinib (Sutent, Pfizer) and sorafenib (Nevaxar, Bayer) are already approved for use in kidney cancer, and pazopanib has a very similar mechanism of action to these drugs — acting as an inhibitor of vascular endothelial growth-factor receptor, platelet-derived growth-factor receptor, and c-Kit. In addition, all of these drugs are oral. This makes pazopanib a "me-too" drug in this indication and, as such, it needs to show something more, Dr. Lara commented.

"The threshold for me-too drug success, compared with available in-class agents, should be higher, much higher," he said. These need to demonstrate better efficacy or have less toxicity, or they should be less expensive, he suggested. The current phase 3 trial of pazopanib has not met any of these criteria, he added.

"Does pazopanib's win against placebo fulfill an unmet medical need? Not yet," he said. In fact, he questioned the use of a placebo control, saying that this is a "pure scientific design" but it would be impossible to carry out in countries where active targeted agents are available, such as in the United States and some parts of Western Europe. A trial comparing pazopanib with sunitinib is now ongoing, he noted.

The pazopanib results were presented at the meeting by Cora Sternberg, MD, from the San Camillo and Forlanini Hospitals in Rome, Italy. Her coauthors were from Poland, Slovakia, Chile, Korea, Australia, and the United Kingdom, and some were employees of GlaxoSmithKline.

The trial was conducted in 435 patients with advanced kidney cancer who had not received any previous therapy or had only received 1 cytokine-based therapy. Patients were randomized 2:1 to receive pazopanib (800 mg orally once daily) or placebo, and those in the placebo group were given pazopanib on disease progression.

The results showed an overall response rate of 30% for pazopanib, compared with 3% for placebo, and a median progression-free survival of 9.2 months with pazopanib and 4.2 months with placebo (hazard ratio, 0.46; P < .0000001).

Pazopanib was well tolerated, Dr. Sternberg noted, with the majority of adverse events being mild to moderate. The most common adverse events were diarrhea (in 52% patients, but grade 4 diarrhea was seen in only 4%), hypertension (40%, but grade 3/4 in only 4%), hair color change (38%; but grade 3/4 in less than 1%), nausea (26%, but grade 3/4 in less than 1%), anorexia (22%, but grade 3/4 in 2%), and vomiting (21%, but grade 3/4 in 2%). The most common laboratory abnormality was alanine aminotransferase elevation (53%, but grade 3 in 10% and grade 4 in 2%).