Promising preliminary data for axitinib in metastatic kidney cancer

Jun 12 2012

By Laura Cowen

Preliminary study data show that axitinib may be an effective first-line treatment for metastatic renal cell carcinoma (mRCC), particularly in patients with high therapeutic drug exposure and a rise in blood pressure during the first 2 weeks of treatment, researchers report.

Brian Rini (Cleveland Clinic, Ohio, USA) reported at the American Society of Clinical Oncology's Annual Meeting, held in Chicago, Illinois, USA, that between 40% and 56% of patients with treatment-naïve mRCC experienced an objective response following treatment with axitinib.

The researchers explain that axitinib is a potent selective vascular endothelial growth factor receptor inhibitor, but pharmacokinetic and phramcodynamic variability can mean that some patients have suboptimal drug exposures at the standard 5 mg twice daily dose.

Rini and team hypothesized that dose titration based on individual tolerability may optimize exposure and improve outcomes.

To test this hypothesis, the researchers initially treated 203 mRCC patients with axitinib 5 mg twice daily for a 4-week lead-in period (cycle 1).

Then, patients with blood pressure (BP) at or below 150/90 mmHg for 2 consecutive weeks, no axitinib-related toxicities above grade 2, no dose reductions, and two or fewer antihypertensive medications were randomly assigned to receive axitinib 5 mg twice daily plus dose titration with either axitinib to a maximum of 10 mg twice daily (arm A) or placebo (arm B). Those ineligible for randomization continued with the same dose (arm C).

In all, 112 patients were randomly assigned to arms A or B, and 91 to arm C.

Rini reported that the objective response rate (ORR) was 40.2% in arms A+B combined and 56.0% in C. Median progression-free survival (mPFS) was 13.7 months in arms A+B and 12.2 months in arm C.

He said that it is currently unknown whether the lower ORR was driven by the patients assigned to placebo titration. This question will be answered in the final analysis of study data.

A subanalysis performed on day 15 of cycle 1 showed that patients with drug exposure above therapeutic threshold (area under the curve at 24 hours ≥300 ng/h per mL; n=27) had significantly longer mPFS and higher ORR than those with sub-therapeutic exposure (n=25), at 13.9 versus 8.3 months, and 59% versus 48%, respectively.

In addition, patients with mean diastolic BP (DBP) increases of 15 mmHg or more (n=18) per ambulatory BP measurement had higher ORR than those with mean DBP increases below 15 mmHg (n=36), at 61% versus 53%.

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