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Sorafenib for Patients with Advanced Kidney Cancer

Development of sorafenib, sunitinib, bevacizumab, and temsirolimus has been predicated on pioneering work in molecular genetics and tumor biology of renal-cell cancer.

Advanced renal-cell carcinoma is recognized as one of the most therapy-resistant epithelial neoplasms. In the early 1980s, work with the immune modulators interferon- and interleukin-2 provided a glimmer of hope; however, except for a small subset of patients who benefit from interleukin-2, these toxic agents have not provided meaningful clinical benefit. Recent work has demonstrated that the von Hippel-Lindau tumor suppressor gene (VHL) is inactivated in most patients with clear-cell carcinoma, which is the most common histologic subtype of renal cancer. Inactivation of VHL ultimately results in increased expression of vascular endothelial growth factor (among others), thereby providing an important target for drug discovery.

Sorafenib is an orally administered small-molecule kinase inhibitor with phase II–trial evidence of activity in patients with clear-cell kidney carcinoma. In an industry-supported international trial, 903 patients with advanced renal-cell cancer whose disease had progressed within 8 months of standard treatment (most often, immune-based therapies) were assigned randomly to sorafenib (400 mg twice daily) or placebo. The primary endpoint was overall survival; median follow-up was 6.6 months.

At a planned interim analysis of progression-free survival (at 17 months), a significant advantage favoring sorafenib (5.5 months vs. 2.8 months with placebo) prompted investigators to perform an interim analysis of overall survival (and to allow crossover of placebo patients to sorafenib after this analysis was completed). Sorafenib-treated patients had a lower risk for death than did placebo recipients (P=0.02), but this difference was not statistically significant, because correction factors were required for an interim analysis. The overall response rate for sorafenib patients was 10%, versus 2% among placebo patients. Diarrhea, rash, fatigue, and skin reactions were the most common adverse effects associated with sorafenib. Hypertension and cardiac ischemia were uncommon, but they occurred with higher frequency in sorafenib-treated patients.

Comment: Results from this large, well-conducted, placebo-controlled study of previously treated patients with advanced renal-cell cancer were reported initially in 2004 and led to FDA approval of sorafenib in early 2005. Development of sorafenib, sunitinib (Journal Watch Oncology and Hematology Jan 10 2007), bevacizumab, and, more recently, temsirolimus, has been predicated on pioneering work in molecular genetics and tumor biology of renal-cell cancer. Much work remains to understand the optimal application of these new agents in advanced kidney cancer; however, dramatic progress has been made already.

— Robert Dreicer, MD, MS, FACP

Published in Journal Watch Oncology and Hematology January 10, 2007

Citation(s):

Escudier B et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007 Jan 11; 356:125-34.

• Medline abstract (Free)

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