Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial

Abstract

Summary Background Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. Methods In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) 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 without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. This ongoing trial is registered with ClinicalTrials.gov, number NCT00835978. Findings Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40–67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22–48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49–70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten [18%] of 56 in the axitinib titration group vs five [9%] of 56 in the placebo titration group vs 45 [49%] of 91 in the non-randomised group), diarrhoea (seven [13%] vs two [4%] vs eight [9%]), and decreased weight (four [7%] vs three [5%] vs six [7%]). One or more all-causality serious adverse events were reported in 15 (27%) patients in the axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each [4%]), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each [2%]). Interpretation 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 ...

Alternate sunitinib schedules in patients with metastatic renal cell carcinoma

“…Another prospective, multicenter phase II study is being conducted in Canada, which looks at the potential of dose escalation beyond 50 mg/day in patients who are able to tolerate the drug, and schedule adjustment before dose reduction in those who experience treatment-related toxicity (NCT01499121) [17]. In a phase II trial evaluating dose titration of axitinib, the majority of the patients who underwent dose titration received a greater ORR, although no PFS benefit was seen, thereby keeping the question of benefit to dose escalation open at this time [20]. Trials that explore individual dose escalation for patients on sunitinib will yield further insights on maximizing objective response and duration of PFS in mRCC patients.…”

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

“…In total, 122 RCC patients were randomized to either axitinib or placebo dose titration. The axitinib dose titration group showed an increased ORR compared to the placebo group ( P = 0.019)43, but this did not result in improved OS ( P = 0.162) 44. One small study ( n = 24) also found a relationship between axitinib C min >5 ng/mL and tumor response and the occurrence of hypertension, hyperthyroidism, and proteinuria 45.…”

“…Diastolic blood pressure (dBP) ≥90 mmHg has been associated with increased probability of response, PFS, and OS in RCC patients 41, 42. Based on these results, a randomized phase II trial to individualize axitinib dose based on dBP has been performed 43. In total, 122 RCC patients were randomized to either axitinib or placebo dose titration.…”

Individualized Dosing with Axitinib: Rationale and Practical Guidance

“…Treatment-naïve patients with mRCC received axitinib 5 mg b.i.d. (Figure 3 [8,9] [9]. In the nonrandomized group, 54 (59%; 95% CI: 49-70) patients had an OR, suggesting that patient selection criteria based on tolerability correctly indicated which patients had adequate axitinib exposure levels at 5 mg b.i.d.…”

“…Because of the interpatient variability in half-life and exposure seen with axitinib, it is not possible to predict the exact exposure level a patient will have. However, Rini et al demonstrated that increasing the axitinib dose leads to increased exposure [9]. Patients who, based on tolerability criteria, were eligible for subsequent dose escalation up to 7 mg b.i.d.…”