Key predictive factors of axitinib (AG-013736)-induced proteinuria and efficacy: A phase II study in Japanese patients with cytokine-refractory metastatic renal cell Carcinoma
Introduction
Renal cell carcinoma (RCC) is the most common form of kidney cancer,1 accounting for 2–3% of adult malignancies worldwide2 and increasing at a rate of 2–3% per decade.1 Approximately 30% of RCC patients have metastatic disease (mRCC) at the time of diagnosis.1, 3, 4, 5 Although the overall incidence of RCC is lower in Asian countries than in North America and Europe, it is particularly high among Japanese males.5 In 2008, the incidence rate (per 100,000 persons at risk) for kidney cancer was 17.7, 13.6 and 2.0 in North America, Europe and Asia, respectively; the rate among Japanese males was 16.2.6 Surgical removal of primary tumours is widely recommended,2 but systemic therapy is needed for mRCC patients. Furthermore, mRCC is resistant to traditional cancer treatments, e.g. chemotherapy and radiation. Until recently, cytokine treatment with interferon-α (IFN-α) and/or interleukin-2 (IL-2) was the standard of care for mRCC.4, 7 However, these therapies offer modest clinical benefit.4
Rising rates of RCC, prevalence of metastatic cases and limited efficacy of available therapies highlight the need for novel treatment options. Pathways leading to angiogenesis, which is essential for tumour progression and metastasis, are key targets of current research. Most clear-cell RCC, which accounts for 75% of mRCC cases,8 exhibit loss of function of the von Hippel Lindau gene.9, 10 This leads to acceleration of the vascular endothelial growth factor (VEGF) pathway and promotion of angiogenesis.9
Axitinib, an oral, selective and potent inhibitor of vascular endothelial growth factor (VEGF) receptors (VEGFR)-1, 2 and 3,11 demonstrated clinical efficacy in phase II studies of various tumour types.12, 13, 14, 15, 16, 17 Single-agent axitinib is active and well tolerated as second-line treatment for mRCC.12, 15 Objective response rates (ORR) for axitinib were 44.2% and 22.6% in phase II studies of patients with cytokine-refractory12 and sorafenib-refractory mRCC,15 respectively, conducted in Western countries.
The present phase II study investigated the efficacy, safety and biomarkers of axitinib in Japanese patients with cytokine-refractory mRCC. This was the first study to investigate the activity and safety of axitinib for mRCC in Asian patients.
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Study design and end-points
This was an open-label, multicentre phase II study. The primary end-point was ORR. Secondary end-points included progression-free survival (PFS), duration of response (DR), safety and changes in the plasma concentrations of potential biomarkers (soluble VEGFR [sVEGFR]-1, 2, 3; VEGF and soluble stem cell factor receptor [sKIT]). Exploratory analyses evaluated the relationship between changes in plasma concentration profiles of biomarkers and efficacy end-points. Potential predictive factors of
Patient characteristics and treatment exposure
Sixty-four patients were enrolled (Table 1). Median duration of treatment with axitinib was 326 days (range, 13–696) with a mean daily dose of 7.1 mg (range, 1.6–16.4). Axitinib dosing was titrated >5 mg BID in five patients (8%), and reduced to <5 mg BID in 42 patients (66%). In all, 37 patients discontinued the study, 13 due to treatment-related AEs and 24 due to disease progression. As of the analysis cut-off date, 27 patients (42%) were still receiving axitinib.
Efficacy
A summary of axitinib efficacy is
Discussion
In this study, axitinib was well tolerated and demonstrated significant clinical activity as second-line treatment for Japanese patients with cytokine-refractory mRCC. Moreover, tumour shrinkage was observed in the majority of patients. This clinical benefit is encouraging and warrants further investigation of axitinib in this population. Final analysis of efficacy data from this study, including overall survival, is awaited.
Common treatment-related AEs were hypertension, hand–foot syndrome,
Japan Axitinib Phase II Study Group
The following investigators and investigational sites also participated in this study: S. Nagai (National Cancer Center Hospital East, Department of Oncology/Hematology, Chiba, Japan), T. Fujioka (Iwate Medical University School of Medicine, Department of Urology, Iwate, Japan), M. Niwakawa (Shizuoka Cancer Center, Department of Urology, Shizuoka, Japan), T. Nakamura (Kyoto Prefectural University of Medicine, Department of Urology, Kyoto, Japan), T. Shuin (Kochi University, Kochi Medical
Conflict of interest statement
Y. Tomita, H. Uemura, H. Kanayama, N. Shinohara and S. Ozono have received speaker honoraria from Pfizer. H. Fujimoto has nothing to disclose. H. Nakazawa, S. Naito and H. Akaza have received speaker honoraria, and consultant or advisory fees from Pfizer. K. Imai and Y. Umeyama are employees of Pfizer and own stock in Pfizer.
Acknowledgements
We thank the patients and families who participated in this study, the physicians who referred them and the study coordinators. Editorial support was provided by Joanna Bloom, PhD, of UBC Scientific Solutions and was funded by Pfizer Inc. We would like to thank Gamal ElSawah, MD, Pfizer Medical Affairs, for his review of the manuscript. This study was sponsored by Pfizer Japan Inc., Tokyo, Japan. Pfizer Japan Inc. involved in the study design, interpretation of data and the writing of the
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Current address: The University of Tokyo, Research Center for Advanced Science and Technology, Tokyo, Japan.