Titration of renal cell carcinoma treatment may be needed for optimum efficacy

May 15, 2012

Dose titration of the vascular endothelial growth factor receptor inhibitor axitinib (Inlyta) to achieve therapeutic blood levels may be required for patients with metastatic renal cell carcinoma to derive optimal benefit from the drug as second-line therapy.

San Francisco-Dose titration of the vascular endothelial growth factor receptor inhibitor axitinib (Inlyta) to achieve therapeutic blood levels may be required for patients with metastatic renal cell carcinoma to derive optimal benefit from the drug as second-line therapy, according to a secondary analysis of a large international, randomized trial.

The primary results from AXIS, which were reported previously, found a significantly longer PFS with axitinib versus sorafenib ([Nexavar] mean: 6.7 vs. 4.7 months; hazard ratio: 0.665) as second-line treatment in patients with metastatic RCC.

The trial included 723 patients (median age: 61 years; 72% men, 76% Caucasian) with clear-cell metastatic RCC who had measureable disease (per Response Evaluation Criteria in Solid Tumors) and who had progressed despite prior therapy with either sunitinib ([Sutent] 54%), cytokines (35%), bevacizumab ([Avastin] 8%), or temsirolimus-based regimens ([Torisel] 3%).

Patients were randomized to axitinib at a starting dosage of 5 mg, twice daily, or 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 mmHg without antihypertensive medication). The dosage of axitinib could be reduced in dose-titrated patients for toxicity at the discretion of the investigator.

Thirty-seven percent of patients assigned to axitinib met the criteria for dose escalation and were able to be titrated to >5 mg, twice daily. Of the 37%, about half were titrated to 7 mg, twice daily and half to 10 mg, twice daily. Twenty percent who had their dose titrated had to have it reduced subsequently.

Subtherapeutic exposure of axitinib was defined as an area under the curve at 12 hours (AUC12) <150 ng•h/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, associate professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland.

"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."

Progression-free survival was roughly equivalent in those who did and did not have dose escalation of axitinib, both of which were superior to 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.

Duration of prior therapy influences PFS

Another finding from the secondary analysis was that PFS on prior sunitinib therapy appears to influence PFS on second-line vascular endothelial growth factor receptor tyrosine kinase inhibitors (ie, axitinib, sorafenib). Axitinib-treated patients who were previously treated with sunitinib for 9 months or longer had a median PFS of 6.3 months, while axitinib-treated patients who had previously taken sunitinib for less than 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.

Dr. Rini and several of his co-authors are consultants/advisers, employees, and/or receive honoraria and/or research funding from Pfizer, Inc.