Emerging tyrosine kinase inhibitors for the treatment of renal cancer

Abstract

Introduction: Since both cytotoxic and cytokine therapy were not able to improve the prognosis of advanced renal cell carcinoma (RCC), this tumor has been a good model for the development of new biological agents in the past decade. Five VEGF receptor (VEGFR) and two mammalian target of rapamycin (mTOR) inhibitors are currently available for treatment of this disease but several issues need to be resolved such as a better definition of prognosis, the overcome of resistance and the best therapy for less frequent histologies.

Areas covered: This review focuses on new tyrosine kinase inhibitors (TKIs) under investigation in these patients. Study design, phase of investigation, result and emerging toxicities were reported for each molecule. Combination trials involving TKIs with other strategies such as immunotherapy were also covered.

Expert opinion: Despite the development of more potent and more specific VEGFR TKIs, all tumors ultimately develop resistance to therapy and a plateau has been reached in terms of overall survival. Current research effort to develop new agents aims at overcoming both the primary and the acquired resistance to anti-VEGFR TKIs focusing on new molecular pathways. The ultimate goal is not only to improve patient outcome but to achieve durable complete remission. Several pitfalls that have been responsible for failure of other compounds remain, especially the lack of strong predictive biomarkers and the use of inappropriate tumor assessment criteria that may not accurately capture response to these new therapies.

Keywords:

• anaplastic lymphoma kinase
• angiogenesis
• clinical trials
• MET
• mammalian target of rapamycin
• papillary renal cell carcinoma
• renal cell carcinoma
• tyrosine kinase inhibitors
• VEGF receptor

Declaration of interest

R Iacovelli has acted in a consulting or advisory role for Bayer and Pfizer. L Albiges has acted in a consulting or advisory role for Pfizer, Novartis, Sanofi and Amgen and has received research funding from Pfizer and Novartis. B Escudier has acted in a consulting or advisory role for Bayer, Pfizer and Novartis and has received honoraria from Bayer, Roche, Pfizer, Genentech, Novartis, Aveo and GlaxoSmithKline. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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