Approval of Axitinib Adds Another Therapy Option for Metastatic RCC

Published Online: Thursday, May 31, 2012
Dr. Brian Rini

Photo by © ASCO/Todd Buchanan 2012

Brian Rini, MD
Axitinib (Inlyta, Pfizer) is the seventh drug approved for the treatment of advanced renal cell carcinoma (RCC) since 2005. The small-molecule tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptors (VEGFR-1, 2, 3), platelet-derived growth factor receptor (PDGFR), and c- KIT was approved by the FDA in January of this year as a second-line treatment. Axitinib joins three other multi-tyrosine kinase inhibitors, two mTOR inhibitors, and an antiangiogenic therapy as available treatments for metastatic RCC.

“We went from almost no therapies to many promising therapies. Now, patients with metastatic disease are living more than twice as long as they did before—two years on average. It’s harder to measure quality of life and how much better they feel, but they feel better being alive than not, and that’s the ultimate test,” said Brian Rini, MD, associate professor of Medicine at Case Western Reserve University and a practicing oncologist at the Cleveland Clinic Taussig Cancer Institute in Cleveland, Ohio. Rini was the principal investigator of the pivotal phase III AXIS trial that led to the approval of axitinib in RCC.

Rini presented AXIS trial secondary results at the American Society of Clinical Oncology (ASCO) 2012 Genitourinary Cancers Symposium. The original trial results were presented at the annual 2011 ASCO conference. The 723 patients on the trial who had failed an initial systemic therapy (either sunitinib, bevacizumab plus interferon- alpha, temsirolimus, or cytokines) for treatment of their metastatic clear-cell RCC were randomized to either 5 mg of axitinib or 400 mg of sorafenib (Nexavar, Bayer)—both administered twice a day (BID). The majority of patients (54%) had received sunitinib as their initial therapy. Treatment was discontinued in 14 of 359 patients receiving axitinib and in 29 of 355 patients receiving sorafenib.

PFS was roughly equivalent in the titrated and nontitrated groups of axitinib-treated patients, and both groups had superior PFS versus sorafenib in this second-line setting. ”
–Brian I. Rini, MD
Patients in the axitinib arm began with a 5-mg dose; those who tolerated this dose could be titrated up to a 10-mg dose, depending on tolerability. The outcome and frequency of adverse events were similar in both patients whose axitinib dose was titrated and those who received a constant dose: Both subgroups showed superior responses compared with sorafenib. Progression- free survival (PFS), the primary outcome, favored the axitinib arm, which had a median PFS of 6.7 months compared with 4.7 months for the sorafenib arm (hazard ratio [HR] = 0.665; P < .0001). Prior treatment did not affect outcomes; both patients previously treated with sunitinib and cytokine therapy had a robust response to axitinib. The objective response rates were 19.4% for patients taking axitinib compared with 9.4% for those on sunitinib (P = .0001).

The AXIS trial was the first trial for kidney cancer to compare two kidney cancer drugs. “I started working with this drug eight years ago, so it’s been a long road,” Rini said. “Thousands, if not tens of thousands, of people must come together to make trials like this happen, not to mention the patients,” he said. “This is the fun part, when we get to the end and get results like this. It’s gratifying for all the hard work people have put in along the way.” Rini was also involved in the phase III trial of bevacizumab combined with standardof- care interferon-alfa that resulted in approval of the combination by the FDA in 2009 for metastatic RCC.

Because earlier-stage trials showed intrapatient variability on the ability to achieve therapeutic levels with the standard 5-mg BID dose, a dose-titration strategy was applied to normalize plasma levels of axitinib exposure. In the phase III study, criteria for dose titration included no toxicity greater than grade 2 for two weeks or more, a blood pressure of <150/90 mmHg, and no antihypertensive medication. Investigators had the discretion to titrate axitinib to 7 mg, and then to 10 mg, depending on patient reaction to the drug. A total of 25% of patients experienced dosage reductions or progression, and one-third did not need any dosage changes. Thirty-seven percent received escalating doses of axitinib—17% to 7 mg and 20% to 10 mg.

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