An Oct. 19 approval makes GlaxoSmithKline's Votrient (pazopanib) the sixth targeted renal cell carcinoma treatment to hit the market since 2005. To differentiate Votrient, GSK must make sure the drug's promising efficacy stands out despite a black box warning about severe and fatal hepatoxocity.

The firm plans to launch Votrient in mid-November. The once-daily, oral medication will join Bayer's Nexavar (sorafenib), Pfizer's Sutent (sunitinib), Wyeth's Torisel (temsirolimus), Novartis' Afinitor (everolimus), and Roche/Genentech's Avastin (bevacizumab) in combination with interferon alfa.

In that crowded field, only Avastin also carries a black box, but GSK probably wouldn't mind if Votrient carried Avastin's sales performance as well.

Votrient 54% Better Than Placebo, But No Comparative Data Exists

GSK declined to talk about marketing strategy, instead noting that FDA's approval signifies that the efficacy data for Votrient are compelling on their own. This also was the view of the agency's Oncologic Drugs Advisory Committee, which recommended the drug unanimously at a meeting just two weeks ago (Also see "Despite FDA Reservations, ODAC Votes Yes On Schering's PegIntron And GSK's Votrient" - Pink Sheet, 5 October, 2009.).

At that meeting, GSK consultant and Memorial Sloan Kettering oncologist Robert Motzer, who chairs the National Comprehensive Care Network Kidney Cancer Guidelines Panel, told ODAC that based on the available Phase III data, Votrient would likely receive a "Category 1" recommendation from the NCCN, which is the highest level of recommendation in a given setting.

"The goal of the NCCN hasn't been to pick the winner, it's really ... to assess the different agents on their own merit, based on their own data and level of evidence," Motzer said at the Oct. 5 meeting.

He noted other Category 1 recommendations as sunitinib; bevacizumab in combination with interferon in first-line therapy; temsirolimus in poor-risk patients; and everolimus given after a tyrosine kinase inhibitor.

In the Phase III data supporting the approval, Votrient reduced the risk of tumor progression or death by 54 percent compared to placebo, regardless of prior treatment. Overall median progression-free survival was 9.2 months with pazopanib and 4.2 months with placebo.

Treatment-naive patients who received Votrient experienced 11.1 months of median PFS versus 2.8 months with placebo, and patients previously treated with cytokine-based therapy achieved 7.4 months of median PFS with Votrient versus 4.2 months with placebo.

A Black Box For Liver Tox

But while Votrient may fall among the best on efficacy, it is only one of two approved RCC drugs to receive a black box warning in labeling. Its label states that "Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended."

Avastin's black box warning discusses gastrointestinal perforation, surgery and wound healing complications, and hemorrhage.

FDA included the liver toxicity warnings in Votrient's label despite a low level of concern about the risk from hepatologists on the ODAC panel (Also see "GSK's Votrient Clears ODAC Despite Outdated Trial, FDA Safety Concerns" - Pink Sheet, 12 October, 2009., p. 18). The experts on the committee said that though the four deaths in the trial were possibly related to liver toxicity, the cases were somewhat atypical of Hy's Law, the standard used by FDA to determine drug-induced liver injury.

Votrient will carry a wholesale acquisition cost of $5,496 per month. According to GSK, approximately 57,700 people in the U.S. will be diagnosed with kidney cancer this year, and 13,000 people will die from the disease.

-Jamie Hammon (j.hammon@elsevier.com)

GSK's Votrient Will Need To Show Efficacy Outweighs Black Box

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