(CHICAGO, IL) — Axitinib, a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors, is effective in the first-line treatment of metastatic renal cell carcinoma (RCC), according to a study presented at the 2012 American Society of Clinical Oncology Annual Meeting.

Results of this randomized, phase 2 study demonstrated a high objective response rate (ORR) and median progression-free survival (PFS) of more than 1 year. “Preliminary results suggest therapeutic drug exposure and mean increases of diastolic blood pressure (BP) ≥15 mmHg on cycle 1, Day 15 may be associated with better outcomes,” according to study lead Brian I. Rini, MD, of the Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, and colleagues.

Previously, due to pharmacokinetic and pharmacodynamic variability, patients have had suboptimal drug exposures at the standard axitinib 5mg twice-daily dose, and analyses have indicated higher drug exposure to axitinib has enhanced efficacy. Therefore, this study evaluated efficacy and safety of axitinib dose titration from 5mg twice daily to a maximum of 10mg twice daily. The primary end point was ORR.

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In a 4-week lead-in period (cycle 1), 213 patients with treatment-naïve metastatic RCC received axitinib 5mg twice daily. In a subset of patients, serial 6-hour pharmacokinetic sampling and 24-hour ambulatory blood pressure monitoring were performed on cycle 1, Day 15. Mean age of the patients was 61 years and 67% were male.

A total of 112 patients with 2 consecutive weeks of blood pressure ≤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 5mg twice daily plus dose titration with either axitinib (Arm A) or placebo (Arm B); 91 patients ineligible for randomization continued with the same dose (Arm C).

In all of the patients, median PFS was 14.5 months and ORR, 48%. Median PFS was 14.5 months in Arms A+B and 16.4 months in Arm C; ORR was 43.0% in Arms A+B (blinded pooled analysis) and 59.0% in Arm C. Median progression-free survival (PFS) for patients with ≥150 ng·h/mL axitinib exposure was 13.9 months vs 11.0 months for those <150 ng·h/mL. In the ≥150 ng·h/mL group, 59 patients had a partial response and 26, stable disease, compared with 40 partial responses and 36 stable disease in the <150 ng·h/mL group. Patients with diastolic BP ≥90 mmHg (n=17) had higher ORR than those with diastolic BP <90 mmHg (n=46), 65% vs 50%; median PFS was 22.5 months and 13.7 months, respectively. On Day 15 of cycle 1, patients in Arms A+B had an AUC of 99 vs AUC 234 in Arm C (P<0.0001).

Most common grade 3 or 4 adverse events were hypertension (29%), diarrhea (17%), and fatigue (6%).

“Therapeutic drug exposure and elevated blood pressure on cycle 1, Day 15, are associated with better clinical outcome,” Dr. Rini said. “Unblinding and comparison of patients dose titrated with axitinib vs placebo will provide further insight into the clinical benefits in metastatic RCC.”