81 Updated results of the phase 3 AXIS trial: Axitinib vs sorafenib as second-line therapy for metastatic renal cell carcinoma (mRCC)

Abstract

INTRODUCTION & OBJECTIVES: Axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. This randomised, open-label trial compared the efficacy and safety of axitinib vs sorafenib as secondline therapy for mRCC. Potential associations between germline single-nucleotide polymorphisms (SNPs) in VEGF pathway genes with progression-free survival (PFS) and blood pressure (BP) endpoints were also evaluated. MATERIAL & METHODS: Eligible patients (pts) had clear-cell mRCC; measurable, RECIST-defined progressive disease after 1 prior first-line systemic therapy; and Eastern Cooperative Oncology Group performance status (PS) of 0/1. Pts were stratified by PS and prior therapy and randomised 1:1 to axitinib (5 mg twice daily [BID] starting dose, titrated to 7 mg and 10 mg BID) or sorafenib (400 mg BID). DNA samples were genotyped using Taqman allelic discrimination. Associations were assessed between SNPs in VEGF-A, VEGFR1, VEGFR2, and HIF1(alpha) with PFS, and between SNPs in VEGF-A, 1 diastolic BP [dBP] reading (greater-than or equal to)90 mmHg). RESULTS: In all, 723 pts were randomised to axitinib (n=361) or sorafenib (n=362). Prior therapies were sunitinib- (54%), cytokine- (35%), bevacizumab- (8%), and temsirolimus-based regimens (3%). Median PFS was 6.7 mo (95% confidence interval [CI] 6.3-8.6) in the axitinib vs 4.7 mo (95% CI, 4.6-5.6) in the sorafenib arm (hazard ratio 0.665; P<0.0001). PFS favoured axitinib in subgroups for prior cytokine (12.1 vs 6.5 mo; P<0.0001) and prior sunitinib (4.8 vs 3.4 mo; P=0.0107). Objective response rates (ORRs) were 19.4% for axitinib vs 9.4% for sorafenib (P=0.0001) and favoured axitinib in the prior cytokine subgroup (32.5 vs 13.6%; P<0.0002). Adverse events (AEs) more frequent for axitinib vs sorafenib included hypertension (40% vs 29%), fatigue (39% vs 32%), nausea (32% vs 22%), dysphonia (31% vs 14%), vomiting (24% vs 17%), and hypothyroidism (19% vs 8%); AEs more frequent for sorafenib vs axitinib were hand-foot syndrome (51% vs 27%), rash (32% vs 13%), alopecia (32% vs 4%), and anaemia (12% vs 4%). DNA samples from Caucasian pts (n=263, 36%) were analysed. Three VEGF-A SNPs displayed PFS differences, ie, rs1570360 (adjusted P=0.127), rs699947 (P=0.058), and rs833061 (P=0.0580); these potential PFS-genotype associations are governed mainly by PFS differences among genotypes in the axitinib arm. The SNPs examined were not associated with axitinib-related hypertension or dBP. Further updates will be presented at the 2012 meeting. CONCLUSIONS: Pts receiving axitinib demonstrated significantly longer PFS and higher ORR than pts receiving sorafenib; both agents were well tolerated. Axitinib has a distinct safety profile compared with sorafenib. Preliminary data suggest specific SNPs may account for some of the observed interpatient variability in PFS.