Aveo Kidney Cancer Drug Shows Safety Edge in Pivotal Study

Xconomy Boston — 

Aveo Oncology is entering a competitive world for the treatment of kidney cancer, and it made a bold bet that its drug would prevail in the first head-to-head comparison of its kind against an active drug. Now the company is preparing to enter that competition with data that says its drug has a slight advantage over a rival on effectiveness, and a more meaningful edge on safety and ease of use.

Cambridge, MA-based Aveo (NASDAQ: AVEO) and its partner, Japan-based Astellas Pharma, are announcing today that their experimental drug tivozanib reached the main goal in a pivotal study of 517 patients with renal cell carcinoma. The new drug showed it was able to keep tumors from spreading a median time of 11.9 months, compared with 9.1 months for those who were randomly assigned to get Bayer and Onyx Pharmaceuticals’ sorafenib (Nexavar). The most common side effects for the new drug were high blood pressure, diarrhea, a skin rash called hand-foot syndrome, and fatigue.

Those effects are common for this class of therapy that cuts off blood flow to tumors, but what’s noteworthy here is that fewer patients on the new drug had to go on unplanned drug “holidays,” or have their doses reduced, because of severe side effects. A detailed summary of the findings is being posted on the American Society of Clinical Oncology’s website today, as a preview of an oral presentation at the ASCO conference on June 2.

Aveo CEO Tuan Ha-Ngoc

Aveo, which is seeking to introduce its first marketed product, has said it plans to seek FDA approval later this year based on the results described online today. Its drug, a once-daily pill, is designed to cut off blood flow to tumors by interfering with three different forms of the VEGF receptor, a marker on cells. If the drug can win FDA clearance, it will be in position to compete not just with Bayer/Onyx’s sorafenib (Nexavar), but also with Pfizer’s sunitinib (Sutent) and axitinib (Inlyta), Roche/Genentech’s bevacizumab (Avastin), and GlaxoSmithKline’s pazopanib (Votrient). There’s certainly a large pool of people who are candidates for the new drugs. About 61,000 new cases of kidney cancer were diagnosed in the U.S. last year, and 13,000 people died from the disease, according to the American Cancer Society.

“There are a lot of options but there are also problems with all the existing options,” says Michael Atkins, the deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington D.C., and an investigator on the study. “This drug addresses one of those problems, and is therefore an advance.”

Aveo reported the basic headline that the study was a success back in January, but today’s abstract goes into more detail about what researchers found in the study called TIVO-1. The key new information is in the product’s safety profile.

According to research being published today, about 44 percent of patients on the Aveo drug experienced high blood pressure, and 25 percent of those cases were graded moderate to severe, researchers said. That was a slightly higher rate than for patients who got the Bayer/Onyx drug. But that’s not much of a concern because that effect can be managed with anti-hypertensives, Atkins says.

More importantly, fewer patients on the Aveo drug reported hand-foot syndrome (skin rash) or diarrhea. About 13 percent on the Aveo drug reported hand-foot syndrome, compared with 54 percent who got the Bayer/Onyx drug, researchers said. About 22 percent on the Aveo drug reported diarrhea, compared with 32 percent in the control group.

While that might not sound like much of a difference, it translated into a significantly easier drug to administer to patients, Atkins says. Because the Aveo drug caused fewer significant side effects, only 18 percent of patients on the new drug had their dosages interrupted, compared with 35 percent on the rival drug. And 14 percent of patients on the Aveo drug had their doses reduced because of side effects, compared with 44 percent of the patients in the control group.

Extended dose interruptions, and dose reductions tend to worry physicians, who wonder if they are providing the cancer with an opportunity to worsen. The Aveo drug is designed to minimize that worry, by being administered once a day for three weeks, followed by a one-week “holiday.” Atkins points out that the Aveo drug has a long enough half-life so that it remains in the bloodstream during most of that one-week break, so it should maintain some effectiveness even while giving patients a respite from side effects. That’s different from the market leading treatment, Pfizer’s sunitinib (Sutent), which is given for four weeks, followed by a two-week break.

When patients have to go off the standard dosing regimen with a longer drug holiday, or a extended dose reduction, it creates a situation that the doctor and patient need to manage, Atkins says.

“That can be difficult for the physician and for the patient, as many patients gets sub-optimal therapy as a result,” Atkins says. With other drugs, “you have to manage, or hold therapy, or reduce the therapy. In this case, you give the treatment, and the patients for the most part don’t have major side effects.”

Still, like any study, this one has its limitations. Researchers don’t yet if the Aveo drug can help people live longer–follow-up data will have to wait until 2013. They also don’t have a strong sense of which patients are most likely to benefit from the new drug, Atkins says. The vast majority of patients in the TIVO-1 study enrolled in Eastern Europe and Asia—not in the U.S. or the wealthier countries of western Europe. That means fewer doctors here will have had experience with the drug once it hits the market, if it wins FDA approval.

Plus, there’s emerging competition from Pfizer’s axitinib (Inlyta). That drug won FDA approval earlier this year as a second-round treatment for kidney cancer, and it is likely to be shown effective among patients getting first-round therapy—the patient population Aveo is targeting. And Atkins says the entire class of VEGF inhibitors could face new competition in renal cell carcinoma drug from antibodies against new targets. One to watch, he says is an experimental drug from Bristol-Myers Squibb that’s designed to hit a marker on cells known as PD-1.