Third generation tyrosine kinase inhibitors and their development in advanced renal cell carcinoma

Abstract

Angiogenesis in general and the vascular endothelial growth factor (VEGF) signaling axis in particular is a validated target in renal cell carcinoma (RCC). Clear-cell carcinoma of the kidney is now recognized as a malignancy that is sensitive to inhibitors of the VEGF pathway. Treatment options for patients with metastatic renal cell carcinoma have evolved in dramatic fashion over the past 6 years, and a new paradigm has developed. The cytokines interferon-a and interleukin-2 were previously utilized for therapy, but since December 2005, six new agents have been approved in the United States for the treatment of advanced RCC. Two are tyrosine kinase inhibitors (TKI's) including sunitinib and recently pazopanib, and the multikinase inhibitor sorafenib. The current review examines the evolving data with the next generation of TKI's, axitinib and tivozanib being developed for the treatment of advanced RCC. These agents were synthesized to provide increased target specificity and enhanced target inhibition. The preclinical and clinical data are examined, an overview of the development of these TKI's is provided, and discussion plus speculation concerning their potential roles as RCC therapy is provided. Treatment of patients with metastatic renal cell carcinoma (mRCC) has changed dramatically during the past 5 years, and a new paradigm has evolved. Interferon-a (INF-α) and interleukin-2 (IL-2) were previously utilized (McDermott, 2009) but since December 2005, a series of targeted agents have been approved in the United States for the treatment of mRCC, including the three multi-targeted tyrosine kinase inhibitors (TKI's) sunitinib, sorafenib, and pazopanib (Bukowski, 2009). The first generation of TKI's included sunitinib, which has emerged as the standard of care for treatment-naïve mRCC patients. The recent approval of pazopanib, a second generation agent with increased specificity for vascular endothelial growth factor (VEGF) receptors (VEGFR), provided another option for frontline therapy. This review will focus on several third generation TKI's under investigation, axitinib and tivozanib, and explore their current development as therapy for mRCC. The number of agents approved within a very short time, raises a series of questions, such as, do we need another tyrosine kinase inhibitor for this patient population, if yes, what should its characteristics and clinical activity be, and finally, how should these novel agent be studied in the future? © 2012 Bukowski.