Third generation tyrosine kinase inhibitors and their development in advanced renal cell carcinoma - PubMed (original) (raw)

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

Ronald M Bukowski. Front Oncol. 2012.

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-α 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.

Keywords: renal cell carcinoma; tyrosine kinase inhibitors.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Molecular structures and chemical data for two third generation tyrosine kinase inhibitors, axitinib (Hu-Lowe et al., 2008), and tivozanib (Gupta and Fishman, 2011).

Figure 2

Figure 2

Phase 3 pivotal trial (AXIS and TIVO-1) designs for studies of axitinib or tivozanib vs sorafenib.

Similar articles

Cited by

References

    1. Bhargava P., Esteves B., Al-Adhami M., Nosov D. A., Lipatov O. N., Lyulko A. A., Anischenko A. A., Chacko R. T., Doval D. C., Slichenmyer W. (2010). Activity of tivozanib (AV-951) in patients with renal cell carcinoma (RCC): subgroup analysis from a phase II randomized discontinuation trial (RDT). J. Clin. Oncol. 28(Suppl.), 15s.10.1200/JCO.2009.24.9326 - DOI - PubMed
    1. Bhargava P., Robinson M. O. (2011). Development of second-generation VEGFR tyrosine kinase inhibitors: current status. Curr. Oncol. Rep. 13, 103–11110.1007/s11912-011-0154-3 - DOI - PMC - PubMed
    1. Bukowski R. M. (2009). Tyrosine kinase inhibitors in advanced renal cell carcinoma: the evolving treatment paradigm. Clin. Genitourin. Cancer 7, 9–1010.3816/CGC.2009.n.001 - DOI - PubMed
    1. Cella D., Escudier B., Rini B. I., Chen C., Bhattacharyya H., Tarazi J. C., Rosbrook B., Kim S., Motzer R. J. (2011). Patient-reported outcomes (PROs) in a phase III AXIS trial of axitinib versus sorafenib as second-line therapy for metastatic renal cell carcinoma (mRCC). J. Clin. Oncol. 29(Suppl.), abstr. 4504
    1. Choueiri T. K., Hutson T. E., Bukowski R. M. (2003). Evolving role of pegylated interferons in metastatic renal cell carcinoma. Expert Rev. Anticancer Ther. 3, 823–82910.1586/14737140.3.6.823 - DOI - PubMed

LinkOut - more resources