Targeting Renal Cell Carcinoma

Recent discovery and clinical development of targeted agents have expanded treatment options in renal cell carcinoma (RCC) and have improved prognosis for patients with RCC metastases. Because RCC displays nearly universal resistance to chemotherapy, it has long been considered a model tumor for studying drug resistance. Cytokine therapy has been the mainstay of RCC systemic treatment for the past two decades. However, few patients respond to interferon-alfa or interleukin-2, and median overall survival with these agents ranges from 10 to 15 months. Recently, an improved understanding of RCC biology, combined with targeted drug-directed research, has contributed to dramatic progress. Clear cell is the predominant RCC cell type, characterized by mutations in the von Hippel-Lindau gene, which plays a key role in regulating angiogenesis through a hypoxia-driven pathway. Targets for drugs within this pathway include vascular endothelial growth factor (VEGF) and its receptor (VEGFr), and hypoxia inducible factor (HIF). Therefore, early drug research with sorafenib and other targeted agents focused on RCC. In this issue of Journal of Clinical Oncology, Escudier et al report the survival analysis of a phase III randomized trial of sorafenib versus placebo as second-line therapy for metastatic clear cell RCC. At a preplanned interim independent assessment, progression-free survival was significantly longer in patients treated with sorafenib versus patients randomly assigned to placebo. The median interim progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio [HR], 0.44; P .0001). After interim analysis, patient treatment was unblinded, and those on the placebo arm were offered sorafenib. In the final analysis, the median overall survival was comparable in both arms. However, treatment with sorafenib was associated with an improved survival when censoring patients randomly assigned to placebo who crossed over to sorafenib (17.8 v 14.3 months; HR, 0.78; P .0287). The prolongation of progression-free survival observed with sorafenib is the relevant outcome. This phase III trial by Escudier et al, as well as five other trials, has established a benefit for targeted agents in metastatic RCC (Table 1). Sunitinib, temsirolimus, and bevacizumab (combined with interferon-alfa) have been compared with interferon-alfa alone in first-line therapy. Everolimus was compared with placebo after progression to VEGFr tyrosine kinase inhibitors (TKI) therapy (sunitinib and/or sorafenib). The eligibility criteria for sunitinib and bevacizumab phase III trials allowed inclusion of all three Memorial Sloan-Kettering Cancer Center (MSKCC) risk groups, but trial accrual largely comprised patients with an intermediate or favorable prognosis. In an interim analysis, patients treated with sunitinib showed significant improvement in progression-free survival compared with interferon-alfa, meeting the primary end point of the trial. Overall survival was assessed as a secondary end point, and was longer with sunitinib than with interferon-alfa. The degree of difference in overall survival between the two arms was influenced by the number of patients in the interferon-alfa arm who crossed over to sunitinib at the time of progression. Nevertheless, the trial outcome resulted in a paradigm shift from cytokine therapy to targeted agents in first-line treatment of metastatic RCC. Moreover, the median survival of more than 2 years in the sunitinib arm is a milestone for RCC treatment, compared with the short survival previously achieved with cytokine therapies. Likewise, significant improvements in progression-free survival were observed in European and US cooperative group phase III trials with a combination of bevacizumab plus interferon-alfa compared to interferon-alfa alone. The targeted agent temsirolimus, a mammalian target of rapamycin inhibitor, was compared with interferon-alfa in a phase III trial of first-line therapy, where it was shown to prolong overall survival. Only patients with poor-prognosis features (expanded from MSKCC risk criteria) were eligible for this trial. Objective responses were infrequent with temsirolimus ( 10%) in this group of patients with a poor prognosis. However, the trial showed a statistically significant improvement for targeted therapy over interferon-alfa in an analysis of overall survival as a primary end point. Recently, everolimus, an orally administered mTOR inhibitor, was studied in patients who progressed on therapy with VEGFr TKI. The outcome of this trial indicated an advantage in progression-free survival. Everolimus was the first and only agent to show benefit in a phase III trial of patients who had progressed on VEGFr TKI therapy. As a result of these trials, the US Food and Drug Administration approved sorafenib (December 2005), sunitinib (January 2006, with phase II trial), and temsirolimus (May 2007) for the treatment of advanced RCC. Bevacizumab plus interferon-alfa has been approved by regulatory agencies in Europe (December 2007); the US outcome of a review by the US Food and Drug Administration is pending. Everolimus was recently approved (March 2009) by the US Food and Drug Administration for patients with advanced RCC after progression to treatment with sunitinib or sorafenib. The 2009 National Comprehensive Cancer Network (NCCN) treatment recommendations offer guidelines for management of metastatic clear cell RCC. According to these guidelines, a category 1 recommendation is based on high-level evidence (eg, randomized controlled trials) and uniform NCCN consensus.