Sequencing of Therapeutic Agents in the Treatment of Advanced Renal Cell Carcinoma: Focus on Mechanism of Action

REVIEW ARTICLE

Stéphane Oudard^1, Alain Ravaud^2, and Bernard Escudier³

Affiliations: ¹Oncology Department, Georges Pompidou Hospital, Paris Cedex, France; ²Department of Oncology, Bordeaux University Hospital, Place Amelie Raba Léon, Bordeaux Cedex, France; and ³Institut Gustave Roussy, rue Camille-Desmoulins, Villejuif, France

ABSTRACT

INTRODUCTION
Recent introductions of numerous targeted agents (the antivascular endothelial growth factor [VEGF] monoclonal antibody bevacizumab; the VEGF receptor tyrosine kinase inhibitors [VEGFR-TKI] sorafenib, sunitinib, and pazopanib; and the mammalian target of rapamycin [mTOR] inhibitors everolimus and temsirolimus) have provided additional therapeutic options for patients with metastatic renal cell carcinoma (mRCC).

OBJECTIVES
We sought to collect evidence that may guide optimization of the therapeutic course subsequent to the inevitable progression of disease.

METHODS
We reviewed the published medical literature for data from studies of sequential targeted therapy in mRCC.

RESULTS
Due to similar safety profiles of agents with similar mechanisms of action, sequential treatment may be preferable to combination therapy because it reduces the risk of cumulative toxicity. Retrospective studies suggested that following one VEGFR-TKI with a second VEGFR-TKI could provide clinical benefit; however, prospective studies have not replicated these findings, but have evidenced increased toxicity with the second VEGFR-TKI. In contrast, targeting a different pathway with everolimus after VEGFR-TKI failure in a pivotal clinical study had clear efficacy without evidence of excess toxicity. Preliminary indications of tumor resensitization to VEGFR-TKIs after blocking mTOR activation are intriguing but must be verified in prospective studies. Future studies are focused on better understanding tumor biology and biomarkers in RCC to allow the optimal treatment sequences to be based on individual patient characteristics.

CONCLUSION
Currently, the best-supported strategy after failure of VEGFR-TKI therapy in patients with mRCC remains treatment with everolimus.

Keywords: mammalian target of rapamycin (mTOR), metastatic cancer, renal cell carcinoma, sequential therapy, tumor escape, vascular endothelial growth factor

Correspondence: Stéphane Oudard, Hôpital Européen Georges Pompidou, Service de Cancérologie Médicale, 20 rue Leblanc 75908, Paris Cedex 15, France. Tel: +33 1 56 093 003; Fax: +33 1 56 092 803; e-mail: stephane.oudard@egp.aphp.fr