CHICAGO—Axitinib appears to be effective in the first-line treatment of metastatic renal cell carcinoma (mRCC) as evidenced by a long progression-free survival (PFS) and a high objective response rate, according to a new study presented at the American Society of Clinical Oncology 2012 annual meeting.

Axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors that has shown efficacy in mRCC. However, some patients have sub-optimal drug exposures at the standard 5 mg twice daily dose. Prior analyses indicated higher drug exposure enhanced efficacy and it is theorized that dose titration based on individual tolerability may optimize exposure and improve outcomes. Researchers conducted a randomized phase 2 trial that evaluated the efficacy and safety of axitinib dose titration from 5 mg twice daily to a maximum of 10 mg twice daily in the first-line treatment of mRCC.

“Up to 30% of patients may be under-dosed at the standard dose,” said lead investigator Brian I. Rini, MD, Associate Professor of Medicine at Cleveland Clinic in Ohio. “The study shows that higher drug levels are associated with better outcomes.”

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In the study, patients with treatment-naïve mRCC received axitinib 5 mg twice a day for a four-week lead-in period (cycle 1). Patients with two consecutive weeks of blood pressure (BP) measurements of 150/90 mm Hg or less, no axitinib-related toxicities greater than grade 2, no dose reductions, and taking no more than two antihypertensive medications were then randomized in a double-blind fashion to axitinib 5 mg twice a day plus dose titration with either axitinib (arm A) or placebo (arm B). Patients ineligible for randomization continued with the same dose (arm C). The primary endpoint of the study was objective response rate (ORR).

In all, 213 patients were accrued and 112 were randomized to arms A or B, and 91 to arm C.  The mean age of the patients was 61 years (range 28-87 years) and 143 were male (67%). All patients had clear-cell histology and no prior systemic therapy for mRCC.

In a blinded pooled analysis of data from arms A and B, the ORR was 43%; the ORR in arm C was 59%. The median progression-free survival (mPFS) was 14.5 months in arms A and B combined and 16.4 months in arm C. Patients with drug exposure above therapeutic threshold on day 15 of cycle 1 had longer mPFS and higher ORR than those with sub-therapeutic exposure (mPFS 13.9 vs. 11 months). Patients with mean increases of diastolic BP of 15 mm Hg or higher as measured by ambulatory BP monitoring had a higher ORR than those with diastolic BP increases less than 15 mm Hg (60% vs. 51%).

The most common adverse events were hypertension in 135 patients (63%), diarrhea in 123 (58%), and fatigue in 102 (48%).

“It is a very effective drug for kidney cancer and we need to get smarter about how we dose this drug in our patients,” Dr. Rini told Renal & Urology News. “I think a significant number are being under dosed and it may be true for other oral agents for renal cell carcinoma.”