Axitinib with or without dose titration as first-line therapy for metastatic renal cell carcinoma (mRCC).

Abstract

TPS235 Background: Axitinib is a potent, selective inhibitor of VEGFRs 1, 2, 3 that demonstrated significant activity in 2 phase II trials of patients (pts) with refractory mRCC (objective response rate [ORR] 23 and 44%; median progression-free survival [PFS] 7.4 and 15.7 mo; median overall survival [OS] 13.6 and 29.9 mo, respectively). In these trials treatment-induced diastolic blood pressure (dBP) ≥90 mmHg correlated with significantly longer median OS and ORR vs dBP <90 mmHg (30 vs. 9.8 mo; 50.8 vs. 10.2%). Further, increases in dBP and higher AUC were independently associated with increased probability of partial response, larger reductions in tumor size, and longer OS. Axitinib dose escalation was permitted in these studies; similar safety profiles were observed with titrated and untitrated doses. We hypothesize that axitinib dose titration in mRCC pts who tolerate and do not experience dBP ≥90 mmHg at the standard starting dose may increase efficacy by optimizing AUC and pharmacodynamic effects without significantly increasing toxicity. Methods: A prospective randomized phase II trial is enrolling ∼200 treatment- naïve mRCC pts to evaluate axitinib ± dose titration and relationships among AUC, dBP, and efficacy. Following an initial 4-week cycle at the standard starting dose (5 mg BID), 70 pts who meet randomization criteria will be randomized 1:1 to receive axitinib+axitinib dose titration or axitinib+placebo dose titration using a prespecified dose titration scheme; the dose titration portion is blinded. Randomization criteria include: systolic BP ≤150 mmHg, dBP ≤90 mmHg, no grade 3/4 axitinib-related toxicities, no dose reduction in the first cycle, and ≤2 concurrent antihypertensive medications. Pts not meeting these criteria will continue axitinib without dose titration in a third arm. Crossover is not permitted. Treatment will continue until disease progression or unacceptable toxicity. The primary end point is ORR between the 2 dose titration arms; secondary end points are PFS, OS, response duration, safety, pharmacokinetics, BP, and biomarker correlations. This study has ≥80% power (1-sided type I error 10%) to detect a ≥25% absolute improvement in ORR in pts receiving axitinib titration vs. placebo titration. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Genentech, Novartis, Pfizer Pfizer Bayer, Novartis, Onyx, Wyeth Pfizer