Dose Escalation of Axitinib as Second-Line Treatment of mRCC May Be Needed to Optimize Outcome

Wayne Kuznar

March 2012, Vol 3, No 2 - Genitourinary Cancers Symposium


San Francisco, CA—The dosage of axitinib, the standard second-line treatment for metastatic renal-cell carcinoma (mRCC), should be uptitrated in those patients who fail to achieve therapeutic blood levels on the standard 5-mg daily dosage, according to a new analysis of an international randomized trial presented at the 2012 Genitourinary Cancers Symposium. The primary results of the phase 3 AXIS study were reported previously and revealed a significantly longer progression-free survival (PFS) with axitinib versus sorafenib (mean PFS, 6.7 months vs 4.7 months, respectively) in patients with previously treated mRCC. In a secondary analysis of AXIS presented here, the clinical effect of dose titration on axitinib efficacy was evaluated. The results were presented by Brian I. Rini, MD, Associate Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland. He also reported on the effect of the duration of prior first-line treatment and response on axitinib efficacy.

AXIS included 723 patients with clear-cell mRCC who had measurable disease and who had progressed despite previous therapy with either sunitinib, cytokines, bevacizumab, or temsirolimus-based regimens. Patients were randomized to axitinib at a starting dosage of 5 mg twice daily or to sorafenib 400 mg twice daily. The axitinib dosage could be increased to 7 mg twice daily and then to 10 mg twice daily in patients who met the criteria for dose titration (no toxicity grade >2 for at least 2 weeks and a blood pressure <150/90 mm Hg without antihypertensive medication). Patients receiving titrated doses were allowed to reduce the dosage of axitinib if toxicity occurred.

Among patients assigned to axitinib, 37% met the criteria for dose escalation and were able to titrate their dosage to >5 mg twice daily. Of the 37%, approximately half titrated their dosage to 7 mg twice daily and half to 10 mg twice daily; 20% of those who titrated their dosage had to reduce it subsequently. Subtherapeutic exposure of axitinib was defined as an area under the curve at 12 hours <150 ng × hr/mL. With an increase in the dosage, axitinib drug levels increased to above the therapeutic threshold "not in all patients, but for many patients who were originally subtherapeutic at 5 mg twice daily," said Dr Rini. "Dose titration with axitinib serves to normalize plasma exposure," he explained. "We're not increasing their drug levels above what patients at 5 mg get, but, rather, the drug levels are catching up to what some patients are able to achieve without titration." The PFS was approximately the same in those who did or did not have dose escalation of axitinib, and it was superior to that in patients who received sorafenib in the second-line setting, said Dr Rini.

"Due to interpatient variability in pharmacokinetics, a dose increase [of axitinib] to >5 mg twice daily may be required to optimize exposures and efficacy," he said. Another finding from the secondary analysis was that PFS with previous sunitinib therapy appears to influence PFS with second-line vascular endothelial growth factor receptor tyrosine kinase inhibitors (ie, axitinib, sorafenib). Patients who received axitinib and had previously received sunitinib for ≥9 months had a median PFS of 6.3 months, whereas patients who received axitinib and had previously taken sunitinib for <9 months had a median PFS of 4.5 months. The trend toward superior PFS in patients who received sunitinib for >9 months was evident for both axitinib and sorafenib.