Sequential therapy with targeted agents in patients with advanced renal cell carcinoma: optimizing patient benefit

Multiple targeted agents are now available for the treatment of patients with metastatic renal cell carcinoma (mRCC). Although targeted agents offer improvements over previous treatments and significantly prolong progression-free survival, most patients eventually experience disease progression. For these patients, sequential treatment with multiple lines of therapy may afford sustained clinical benefit. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) are recommended as first-line therapy for most patients with mRCC. Current clinical practice guidelines uniformly recommend treatment with the mammalian target of rapamycin (mTOR) inhibitor everolimus after initial VEGFr-TKI failure. Recent results of the AXIS phase 3 trial demonstrated improved efficacy with second-line axitinib compared with sorafenib in patients who progressed on a variety of first-line therapies, including the VEGFr-TKI sunitinib. Available clinical evidence, individual patient profile, and toxicity concerns should be carefully evaluated when deciding whether to administer an mTOR inhibitor or a second VEGFr-TKI after progression on a first-line VEGFr-TKI. In patients who progress on a VEGFr-TKI and an mTOR inhibitor, retrospective analyses indicate that treatment with a second VEGFr-TKI in the third-line setting provides additional clinical benefit. Recent results from a prospective phase 1/2 trial indicate that third-line therapy with the investigational TKI, dovitinib, may have promising efficacy in patients who progress on a VEGFr-TKI and an mTOR inhibitor; a phase 3 trial of dovitinib versus sorafenib in this patient population is ongoing. This review discusses and evaluates current clinical evidence for sequential therapy with targeted agents in patients with mRCC.