Phase II Study Supports Axitinib Dose Titration in Select Treatment-Naive Metastatic Renal Cell Carcinoma Patients


Key Points

  • Objective response rate was greater in patients randomly assigned to axitinib titration vs placebo titration.
  • There was no difference between randomized groups in progression-free survival.

Axitinib plasma exposure may correlate with efficacy in metastatic renal cell carcinoma, according to population pharmacokinetic data. In a phase II study reported in The Lancet Oncology, Brian I. Rini, MD, of the Cleveland Clinic, and colleagues evaluated the effects of axitinib dose titration in patients with previously untreated metastatic renal cell carcinoma. They found a higher response rate in patients receiving dose titration.

Study Details

In this double-blind multicenter study, 213 treatment-naive patients from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and the United States received axitinib at 5 mg twice daily during a 4-week lead-in period. Patients with blood pressure ≤ 150/90 mm Hg, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and ≤ 2 antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1) and randomly assigned to either masked titration with axitinib to total twice daily doses of 7 mg and then 10 mg if tolerated or placebo titration. Patients who did not meet these criteria continued on 5 mg twice daily without titration.

The axitinib dose was reduced stepwise by one dose level in patients with grade 3 adverse events or two readings of systolic blood pressure 150 mm Hg or higher or diastolic blood pressure 100 mm Hg or higher while receiving maximal antihypertensive therapy. The dose was reduced first to 3 mg twice daily and then to 2 mg twice daily. The primary objective was comparison of the proportion of patients achieving an objective response in the two randomized groups. The trial is ongoing.

Of the 213 patients, 112 were randomly assigned to the axitinib titration group (n = 56) or placebo titration group (n = 56 patients); 91 were not eligible for titration, and 10 withdrew during the lead-in period. In the overall population, median age was 62 years (range, 28–87 years), 67% were male, 76% were white, 64% had ECOG performance status of 0 (64% in axitinib titration group, 61% in placebo titration group, and 69% in nonrandomized group), and 86% had previous nephrectomy. The randomized groups and the nonrandomized group were generally well balanced for demographics and baseline characteristics, except for a greater proportion of Asian (primarily Japanese) patients in the nonrandomized group (36% vs 11% in each of the randomized groups).

Response Rates

Objective response was observed in 54% (95% confidence interval [CI] = 40%–67%) of patients in the axitinib titration group vs 34% (95% CI = 22%–48%) of patients in the placebo titration group (P = .019) and in 59% (95% CI = 49%–70%) of nonrandomized patients. In patients with tumor measurements, 84% of the axitinib titration group, 79% of the placebo titration group, and 96% of the nonrandomized group had tumor shrinkage. One patient in the axitinib titration group had a confirmed complete response. Median duration of response was not reached in the axitinib titration group, 21.2 months in the placebo titration group, and 23.3 months in the nonrandomized group.

In a subset of patients with pharmacokinetic sampling, mean axitinib drug exposure on day 15 of the lead-in period during treatment with the 5-mg twice daily dose was lower in patients eligible for dose titration than in those not eligible. All patients receiving axitinib or placebo titration had 2-mg dose increases, but fewer axitinib titration group patients had increases to 10 mg (57% vs 71%). Dose reductions to less than 5 mg were more common in the axitinib titration group (18% to 3 mg and 7% to 2 mg) than in the placebo titration group (9% to 3 mg and 0% to 2 mg). In the nonrandomized group, dose was reduced to 3 mg in 43% and 2 mg in 19%.

Progression-Free Survival

Median follow-up was 26.5 months in the axitinib titration group and 26.4 months in the placebo titration group. Median progression-free survival was 14.6 months in all patients, 14.5 months in the axitinib titration group (hazard ratio 0.85, P = .24, vs placebo titration group), 15.7 months in the placebo titration group, and 16.6 months in nonrandomized patients. Median progression-free survival was 16.6 months vs 10.3 months in patients with ECOG performance status of 0 (n = 139) vs 1 (n = 74).


Common grade 3 or higher adverse events were hypertension (18% of axitinib titration group, 9% of placebo titration group, and 49% of nonrandomized group), diarrhea (13%, 4%, and 9%), and decreased weight (7%, 5%, and 7%). Serious adverse events occurred in 27% of the axitinib titration group, 23% of the placebo titration group, and 38% of the nonrandomized group. The most common serious adverse events in all patients apart from disease progression were dehydration (4%) and diarrhea, vomiting, pneumonia, and decreased appetite (2% each). Adverse events caused dose interruptions in 57% of the axitinib titration group, 45% of the placebo titration group, and 78% of the nonrandomized group.

The investigators concluded, “The greater proportion of patients in the axitinib titration group achieving an objective response supports the concept of individual axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease.”

The study was funded by Pfizer Inc.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.