Elsevier

The Lancet

Volume 378, Issue 9807, 3–9 December 2011, Pages 1931-1939
The Lancet

Articles
Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial

https://doi.org/10.1016/S0140-6736(11)61613-9Get rights and content

Summary

Background

The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer.

Methods

We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392.

Findings

A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544–0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm.

Interpretation

Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma.

Funding

Pfizer Inc.

Introduction

Renal cell carcinoma is diagnosed in about 170 000 people worldwide annually, resulting in 72 000 deaths.1 Many patients present with advanced or unresectable disease, and up to 30% of patients who have initially localised disease will eventually relapse.2 Renal cell carcinoma is often resistant to chemotherapy and cytokines such as interleukin 2 and interferon-alfa.3

Loss of function of the von Hippel-Lindau (VHL) gene in renal cell carcinoma leads to dysregulation of the vascular endothelial growth factor (VEGF) pathway, VEGF protein overexpression, and increased tumour angiogenesis. Antiangiogenic drugs targeting the VEGF pathway with proven benefit in renal cell carcinoma include inhibitors of VEGF receptor (VEGFR; sunitinib, sorafenib, and pazopanib) and bevacizumab.4, 5, 6, 7 All these drugs have been approved on the basis of randomised trials comparing the targeted drug to either cytokine therapy or placebo. To date, no phase 3 study comparing two targeted drugs has been reported.

Axitinib is a potent, selective, second-generation inhibitor of VEGFR 1, 2, and 3 that blocks VEGFRs at sub-nanomolar drug concentrations.8 Relative potency of axitinib is 50–450 times greater than that of the first-generation VEGFR inhibitors.9 Additionally, first-generation inhibitors block other targets, such as platelet-derived growth factor receptors (PDGFR), b-RAF, KIT, and FLT-3, which are not substantially inhibited by axitinib.10, 11, 12 These off-target activities might contribute to the adverse effects of the first-generation inhibitors, suggesting that more specific inhibitors of VEGFR such as axitinib might have an enhanced therapeutic window.

In a phase 2 study13 of patients with cytokine-refractory renal cell carcinoma, the objective response rate with axitinib was 44%, with a median time to progression of 15·7 months and an overall survival of 29·9 months.13 The 5-year survival rate was 20·6% (95% CI 10·9–32·4).14 In Japanese patients with cytokine-refractory renal cell carcinoma, the objective response rate with axitinib was 55%, with a median progression-free survival (PFS) of 12 months.15 In patients with sorafenib-refractory renal cell carcinoma, the objective response rate with axitinib was 23%, with a median PFS of 7·4 months.16 These phase 2 data suggested that axitinib could be an effective second-line treatment in patients with advanced renal cell carcinoma. This randomised phase 3 trial (AXIS) was designed to directly compare the efficacy and safety of axitinib versus sorafenib in patients with advanced renal cell carcinoma who had disease progression after initial systemic therapy.

Section snippets

Study design and participants

In this multicentre phase 3 randomised controlled trial, we enrolled patients 18 years or older with histologically or cytologically confirmed renal cell carcinoma with a clear-cell component. All patients had measurable disease by Response Evaluation Criteria in Solid Tumours (RECIST, version 1.0)17 and RECIST-defined progressive disease as assessed by investigators after one previous systemic first-line regimen with a sunitinib-based, bevacizumab plus interferon-alfa-based,

Results

Between Sept 15, 2008, and July 23, 2010, 723 patients with advanced renal cell carcinoma coming from 175 sites (hospitals and outpatient clinics) in 22 countries were randomly assigned to axitinib or sorafenib. Of these, 389 (54%) patients had previously received sunitinib, 251 (35%) cytokines, 59 (8%) bevacizumab, and 24 (3%) temsirolimus. Demographics and baseline characteristics were typical of a population with advanced renal cell carcinoma and were well balanced between the axitinib and

Discussion

This randomised phase 3 study directly compared two VEGFR tyrosine kinase inhibitors, axitinib and sorafenib, in patients with metastatic renal cell cancer following failure of one previous systemic therapy (panel). Axitinib led to a statistically significant and clinically meaningful increase in the primary efficacy endpoint of PFS compared with sorafenib. These results are notable since an active agent, sorafenib, was used as the comparator rather than placebo. These data also support the

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