Targeted therapy is now accepted as the main stream treatment of patients with metastatic renal cell carcinoma (mRCC). In Japan, four agents are currently in use, namely sunitinib, sorafenib, everolimus and temsirolimus. A further two agents are expected to be available within a few years.
To maximize their effectiveness, it is postulated that the use of these agents one after another may overcome the unresponsiveness of the previous agents, and prolong patient survival. This is the concept of ‘sequential therapy’. At present, sunitinib, a VEGFR-TKI, is the first choice for patients with good and intermediate risk, according to the treatment algorithm proposed by several guidelines. Next, everolimus, an mTOR inhibitor, is recommended as second line therapy. Progression free survival (PFS) with everolimus has been found to be only 4.9 months in patients who had been refractory to the first tyrosine kinase inhibitor, but a tumor shrinkage was obtained in 47% of these patients. It is has been argued that the agents which follow should have a different mode of action from the agents which preceded them. However, axitinib, another VEGFR-TKI, has been recently reported to show similar PFS to everolimus in those patients with sunitinib failure (4.8 versus 3.9 months). This suggests that a VEGFR-TKI still can show some benefit in the patients refractory to a different VEGFR-TKI. This may be due to the fact that each VEGFR-TKI has different patterns of kinase inhibition. Thus, it remains unclear whether the following agent should be one with a different mode of action in the second line setting. The selection of agents is even more chaotic in the third line setting since there has been no evidence on which to base the choice.
In this presentation, we summarize the present situation of sequential therapy using targeted therapy in patients with mRCC. In addition, we discuss the future perspectives of this therapy.