Sorafenib (BAY 43-9006) is an oral multikinase inhibitor that has been shown to target tumor cells and tumor blood vessels. Preclinical studies suggest that sorafenib primarily acts to stabilize disease by inhibiting tumor growth.OBJECTIVE
To evaluate the effects of sorafenib on tumor growth in patients with metastatic renal cell carcinoma (RCC).DESIGN
This placebo-controlled, phase II randomized discontinuation trial (RDT) enrolled patients ≥18 years old, with ≥1 measurable tumor, histologically or cytologically confirmed metastatic RCC, a life expectancy of ≥12 weeks and adequate bone marrow, liver and kidney function. Exclusion criteria included other serious medical problems or central nervous system involvement.INTERVENTION
Patients were treated with 400 mg of oral sorafenib twice daily during a 12-week run-in period. Further doses of sorafenib were determined based on patient response: patients with stable disease, defined as a <25% change in bidimensional tumor measurements (shrinkage or growth) relative to baseline, were randomly assigned to either sorafenib or placebo for an additional 12 weeks; patients with a ≥25% tumor shrinkage continued open-label sorafenib until toxicity or disease progression. Treatment was discontinued in patients with tumor growth of 25% or more.OUTCOME MEASURES
The primary endpoint was the percentage of patients who were free from disease progression at 24 weeks after the initiation of sorafenib treatment (12 weeks after the run-in period). Secondary endpoints included progression-free survival (PFS), tumor response and toxicity.RESULTS
In all, 202 patients entered the run-in period. At the end of 12 weeks, 73 patients (36%) showed ≥25% tumor shrinkage and remained on sorafenib, and 65 (32%) had stable disease and were randomly assigned to sorafenib (n = 32) or placebo (n = 33). Among the open-label sorafenib group, 8 patients showed a partial response at 12 weeks. In terms of the primary endpoint, patients treated with sorafenib were significantly more likely to be progression-free than those in the placebo group (50% vs 18%; P = 0.0077). In addition, median PFS from randomization was significantly longer in patients treated with sorafenib than in patients receiving placebo (24 weeks vs 6 weeks; P = 0.0087). Patients whose disease progressed on placebo were re-treated with sorafenib and showed subsequent stabilization of progressive disease. Overall median PFS was 29 weeks for the entire population (n = 202), and 40 weeks in those patients who had continued on sorafenib after the 12-week run-in period (n = 79). The most common treatment-related adverse events reported were fatigue, skin rash/desquamation, hand-foot skin reaction, pain and diarrhea, all of which were grade 1 to 2 in severity. In all, 9% of patients discontinued therapy because of drug-related toxicity, and no treatment-related deaths occurred.CONCLUSION
The authors conclude that treatment with sorafenib stabilizes metastatic RCC, and that chronic daily therapy is tolerable in the majority of patients.