Sorafenib significantly improves progression-free survival in patients with advanced clear-cell renal-cell carcinoma, according to results from a phase 3, randomized, double-blind, placebo-controlled trial.
Sorafenib significantly improves progression-free survival in patients with advanced clear-cell renal-cell carcinoma, according to results from a phase 3, randomized, double-blind, placebo-controlled trial reported in the New England Journal of Medicine (NEJM).
Fewer than 10% of patients with metastatic renal-cell carcinoma survive for 5 years. Available treatments include high-dose interleukin-2, which rarely induces a durable complete response, and interferon alfa, which is associated with a modest survival advantage. Sorafenib is a multikinase inhibitor that affects tumor cell proliferation and tumor angiogenesis. Sorafenib also inhibits vascular endothelial growth factor receptors-1, -2, and -3; platelet-derived growth factor receptor-beta; FMS-like tyrosine kinase-3; c-Kit protein; and RET receptor tyrosine kinases. Sorafenib has demonstrated antitumor activity in animal models, and in a phase 2 clinical trial, sorafenib prolonged progression-free survival versus placebo in patients with metastatic renal-cell carcinoma. Most patients responding to sorafenib had the more aggressive and prevalent clear-cell type of the disease.
This phase 3 trial included 903 patients with confirmed metastatic clear-cell renal-cell carcinoma that had progressed despite 1 systemic treatment during the previous 8 months. These patients were randomized to receive sorafenib 400 mg twice daily (n=451) or placebo (n=452) administered in 6-week cycles for the first 24 weeks and in 8-week cycles thereafter. Safety was assessed every 3 weeks for the first 24 weeks and every 4 weeks thereafter; tumor response was evaluated within the last 10 days of each cycle. Patients were treated and followed until disease progression, study withdrawal due to adverse events, or death. The primary end point was overall survival, and the secondary end point was progression-free survival.
The first interim analysis of overall survival, conducted in May 2005 at a median follow-up of 6.6 months, demonstrated that sorafenib reduced the risk of death compared with placebo (HR=0.72; P=.02), but this benefit was not statistically significant. Partial responses were reported as the best response in 10% of sorafenib patients and in 2% of placebo patients (P<.001). Among the 451 sorafenib patients, 1 patient had a complete response, 43 had a partial response, and 333 had stable disease. Among the 452 placebo patients, none had a complete response, 8 had a partial response, and 239 had stable disease.
Six months after 216 of the 452 placebo patients switched to sorafenib, the median overall survival was 19.3 months for sorafenib patients and 15.9 months for placebo patients. The authors reported that this difference did not reach statistical significance.
The most common adverse events were diarrhea, rash, fatigue, hand-foot skin reactions, alopecia, and nausea. Hypertension was more frequent among sorafenib patients but led to discontinuation in <1% of these patients. Cardiac ischemia or infarction occurred in 3% of sorafenib patients and in <1% of placebo patients (P=.01).
In an accompanying editorial, James Brugarolas, MD, PhD, stated that although sorafenib caused clinically significant toxic effects, the agent improved progression-free survival. Additionally, even though a significant increase in overall survival was not observed, a final survival analysis has not yet been reported. Dr Brugarolas noted that understanding the various molecular pathways through which sorafenib and other new agents inhibit tumor growth is important for the development of the next generation of drugs.
SOURCES Escudier B, Eisen T, Stadler WM, et al; for the TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–134.
Brugarolas J. Renal-cell carcinoma-Molecular pathways and therapies [editorial]. N Engl J Med. 2007;356:185–187.