Emerging tyrosine kinase inhibitors for the treatment of renal cancer.

BACKGROUND

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.

METHODS

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.

CONCLUSIONS

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.