Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall efficacy and pharmacokinetic (PK) analyses from a randomized phase II study.

Abstract

4503 Background: Axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors with efficacy in mRCC. Due to PK and pharmacodynamic variability, some patients have sub-optimal drug exposures at the standard 5-mg twice daily (BID) dose. Prior analyses indicated higher drug exposure enhanced efficacy; thus, dose titration based on individual tolerability may optimize exposure and improve outcomes. A randomized phase II trial evaluated the efficacy and safety of axitinib dose titration from 5 mg BID to a maximum of 10 mg BID in first-line mRCC. Methods: Patients with treatment-naïve mRCC received axitinib 5 mg BID for a 4-week lead-in period (cycle 1). Then, patients with 2 consecutive weeks of blood pressure (BP) ≤150/90 mmHg, no axitinib-related toxicities >grade 2, no dose reductions, and ≤2 antihypertensive medications were randomized in a double-blind fashion to axitinib 5 mg BID + dose titration with either axitinib (arm A) or placebo (arm B); those ineligible for randomization continued with same dose (arm C). Primary endpoint is objective response rate (ORR). Serial 6-hr PK sampling and 24-hr ambulatory BP monitoring (ABPM) were performed on cycle 1 day 15 in a subset of patients. Results: In all, 203 patients were accrued; 112 randomized to arms A or B, and 91 in arm C. As of July 1, 2011, ORR (95% confidence interval [CI]) was 40.2% (31.0, 49.9) in A+B (blinded pooled analysis) and 56.0% (45.2, 66.4) in C. Median progression-free survival (mPFS) (95% CI) was 13.7 mo (9.2, not estimable [NE]) in A+B and 12.2 mo (8.6, 16.7) in C. Patients with drug exposure above therapeutic threshold (AUC 24 ≥300 ng·h/mL; n=27) on cycle 1 day 15 had longer mPFS and higher ORR than those with sub-therapeutic exposure (n=25) (mPFS [95% CI]: 13.9 mo [12.2, NE] vs 8.3 mo [5.5, NE]; ORR: 59% vs 48%). Patients with mean increases of diastolic BP (ΔdBP) ≥15 mmHg (n=18) per ABPM had higher ORR than those with ΔdBP <15 mmHg (n=36) (61% vs 53%). Conclusions: Axitinib is effective in first-line treatment of mRCC, with high ORR and mPFS >1 yr. Preliminary results suggest therapeutic drug exposure and ΔdBP ≥15 mmHg on cycle 1 day 15 may be associated with better outcomes.