Chicago, IL—Upward dose titration of axitinib in patients who tolerate the starting dose may optimize drug exposure and improve the efficacy of the drug as a first-line therapy for metastatic renal-cell carcinoma (mRCC), said Brian I. Rini, MD, Associate Professor of Medicine at the Cleveland Clinic, at ASCO 2012.
Axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors with demonstrated efficacy as second-line treatment for mRCC.
Patients who receive the 5-mg twice- daily starting dosage of axitinib exhibit variable levels of drug exposure; retrospective analyses of phase 2 clinical trials indicate that higher drug exposure to axitinib enhances its efficacy. “A significant percentage of patients have exposure that is below what is considered to be a therapeutic threshold,” said Dr Rini. After upward dose titration, to 7 mg, or 10 mg twice daily, most patients achieve therapeutic drug levels.
Patients who achieved a therapeutic drug exposure in previous studies had superior progression-free survival (PFS) compared with those who did not achieve a therapeutic threshold. The improvement in PFS was nearly double in those who achieved therapeutic drug exposure, Dr Rini said. He speculated that dose titration based on tolerability may improve outcomes.
This randomized, phase 2 clinical trial evaluated the efficacy and safety of axitinib dose titration from the standard 5-mg twice-daily dose to a maximum of 10 mg twice daily.
A total of 203 patients with treatment-naive mRCC received axitinib, 5 mg twice daily, for a 4-week lead-in period (cycle 1). Of these, 112 patients with 2 consecutive weeks of blood pressure (BP) ≤150/90 mm Hg (use of ≤2 antihypertensives was allowed); no axitinib-related toxicities grade <2; and no dose reductions were randomized in a double-blind fashion to axitinib 5 mg twice daily, followed by dose titration with axitinib (arm A) or placebo (arm B). The 91 patients who did not meet the randomization eligibility criteria continued to receive ≤5 mg twice daily, based on drug tolerance (arm C).
Tumor assessments were performed at screening; at weeks 8, 16, and 24; and every 12 weeks thereafter. A subset of patients underwent ambulatory BP monitoring at baseline and again on days 4 and 15 of cycle 1.
A pooled analysis of blinded data from arms A and B (eligible for dose titration) showed an objective response rate (ORR) of 43%; the ORR in arm C (not eligible for dose titration) was 59%. The median PFS was 14.5 months in arms A and B combined, and 16.4 months in arm C.
Therapeutic drug exposure was achieved more often in arm C: the AUC12 was 234 ng·h/mL in arm C versus 99 ng·h/mL in arms A and B combined.
Median PFS in patients with drug exposure above the therapeutic threshold on day 15 was 13.4 months compared with 11.0 in those with subtherapeutic exposure. Patients with mean increases of diastolic BP ≥15 mm Hg had a higher ORR than those with diastolic BP increases <15 mm Hg. The AUC12 was generally higher in those with greater changes in BP, said Dr Rini.
The most common adverse events were hypertension, diarrhea, and fatigue.
“Axitinib is effective in the first-line treatment of metastatic renal cell carcinoma as evidenced by a long PFS and a high objective response rate,” Dr Rini said.—WK