Agent significantly extends RCC patients' lives

Orlando, FL-An investigational agent that inhibits both Raf kinase and vascular endothelial growth factor receptor significantly prolongs progression-free survival in pa-tients with advanced renal cell carcinoma, according to results of a phase III clinical trial presented at the American Society for Clinical Oncology annual meeting here.

Following the release of the data, the manufacturers of the drug, known as sorafenib, announced that they would make sorafenib available to eligible individuals with kidney cancer through a treatment protocol.

The most common drug-related adverse effects in all patients were rash (62%), hand-foot skin reaction (61%), fatigue (56%), and hypertension (24%), which led to discontinuation of the drug in 2% of the patients. No drug-related deaths have been reported.

Exploring survival, safety

The phase III trial was conducted at 120 sites in several countries. A total of 769 participants who had been evaluated for safety were randomized one-to-one to receive twice-daily doses of either sorafenib, 400 mg, or placebo with best supportive care. Patients in both cohorts had similar demographic and prognostic characteristics. Mean age was 59 years; 82% had received prior cytokine therapy and 93% had undergone nephrectomy.

The primary endpoint of the study was overall survival. However, other factors, such as progression-free survival, overall response rate, quality of life, and safety of the drug were also considered.

Co-principal investigator Ronald Bukowski, MD, director of experimental therapeutics at The Cleveland Clinic Taussig Cancer Center, said that 343 cases of progression-free survival were reported. Median progression-free survival initially was estimated as 24 weeks for patients given sorafenib versus 12 weeks for the placebo group. As it turned out, 79% of patients receiving sorafenib and 50% on placebo experienced a 12-week progression-free rate.

Sorafenib is the first oral multi-kinase inhibitor that targets both the tumor cell and tumor vasculature, interfering with tumor cell growth and angiogenesis. Both events are crucial for cancer growth. The drug has a favorable safety profile, with only mild adverse effects reported in the phase III trial, such as rash (34% sorafenib/13% placebo), diarrhea (33%/10%), hand-foot skin reaction (27%/5%), hypertension (11%/1%), fatigue (26%/23%), and some hair loss, itching, and nausea. No deaths were attributed to sorafenib. The drug has been studied extensively in malignancies such as melanoma, and trials are ongoing in a number of solid tumors.

Available to eligible patients

The phase II trial was started in the fourth quarter of 2003 under a special protocol assessment by the FDA. In March 2004, the FDA granted sorafenib fast-track status. As a result of favorable progression-free survival data obtained in the course of the trial, the double-blind code was broken and placebo patients were allowed to cross over to treatment with sorafenib, Dr. Bukowski said.

Sorafenib is now being made available to eligible patients through qualified investigators participating in a treatment protocol at clinical sites throughout the United States. To be eligible, individuals with advanced kidney cancer may not have been treated previously with sorafenib.

The manufacturers of sorafenib expect to begin marketing the drug in the first half of 2006, pending FDA approval.