Clinical

SAN FRANCISCO – Some patients with metastatic renal cell carcinoma may need a higher-than-standard dose of the newly approved antiangiogenic agent axitinib to achieve optimal benefit, according to a secondary analysis of data from the phase III AXIS trial.

Progression-free survival and adverse event rates were essentially the same for patients who continued on the standard dose of 5 mg twice daily of axitinib or less when compared with patients who tolerated the standard dose well enough to advance to a higher one – up to twice as high – lead investigator Dr. Brian I. Rini reported at the Genitourinary Cancers Symposium here.

Dr. Brian I. Rini

These findings are consistent with pharmacokinetic data from the phase II trial leading up to AXIS, which suggested that some patients simply need a higher dose of axitinib – an inhibitor of signaling in the vascular endothelial growth factor receptor (VEGFR) pathway – to achieve the same blood level of the drug, according to Dr. Rini, a urologic oncologist at the Cleveland Clinic Taussig Cancer Institute.

"Clearly, there is interpatient variability in the pharmacokinetics of axitinib, and therefore, dose increases to greater than 5 mg twice daily are likely required to optimize both exposure and clinical efficacy in this setting," he said.

An ongoing front-line trial is looking more closely at the issue by testing safety-based dose escalation in a randomized way, he added; results are likely to be reported at the main American Society of Clinical Oncology meeting later this year.

The analysis also found that a response to prior sunitinib (Sutent) did not affect progression-free survival with axitinib, but it did with sorafenib (Nexavar), the trial’s comparator drug, which also inhibits VEGFR signaling, as well as signaling in other pathways. Yet, for both trial drugs, longer progression-free survival on prior sunitinib portended longer progression-free survival with the trial drug.

Discussant Dr. Daniel Cho of Beth Israel Deaconess Medical Center in Boston noted that some might wonder whether axitinib’s superiority in the AXIS trial was due in part to lack of dose escalation of sorafenib, but data on the feasibility of dose escalating that agent are mixed. "It could very well be that the kind of more focused toxicity of the more novel TKIs [tyrosine kinase inhibitors], which allows them to be dose escalated, is a major advantage for these drugs," he commented.

Dr. Daniel Cho

The finding of longer progression-free survival with both trial drugs in patients faring better on prior sunitinib raises an important question relevant to treatment decisions, according to Dr. Cho: "Can a longer progression-free survival on your first VEGF TKI be helpful in determining the next line of therapy?"

"On one hand, you could hypothesize that patients who are on the VEGF TKI longer in the first-line setting represent a group that is more VEGF sensitive and should receive a VEGF TKI as the second-line treatment instead of an mTOR [mammalian target of rapamycin] inhibitor; on the other hand, this group could just sort of represent a group of people whose tumors are growing slower," he explained.

02/07/12  

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FROM THE GENITOURINARY CANCERS SYMPOSIUM

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Vitals

Major Finding: Patients who received 5 mg axitinib twice daily or less had progression-free survival and rates of adverse events similar to those of patients who received a higher dose

Data Source: A secondary analysis of data from a randomized phase III trial of axitinib vs. sorafenib as second-line therapy in 723 patients with metastatic clear-cell RCC (the AXIS trial).

Disclosures: Pfizer sponsored the AXIS trial. Dr. Rini disclosed that he is a consultant to, and receives research funding from, Pfizer. Dr. Cho disclosed that he has no relevant conflicts of interest.