Sorafenib Doubles PFS in Advanced Renal Cell Ca

ASCO — In a large randomized double-blind phase III international trial in patients with previously treated metastatic renal cell cancer (RCC), the oral multikinase inhibitor sorafenib (BAY 43-9006) was well tolerated and doubled progression-free survival (PFS) vs placebo with best supportive care. Lead investigator Bernard Escudier, MD, presented interim results in 769 patients at the 41st Annual Meeting of the American Society of Clinical Oncology (LBA4510) on behalf of the BAY 43-9006 TARGETs Clinical Trial Group. The primary endpoint of the study, overall survival, has not yet been reached, he said, and will be reported at a later date.

The study, which is the largest randomized, controlled trial conducted to date in advanced RCC, concluded enrollment in mid-February of this year, with 905 patients randomized. Because of the strong PFS results in the interim analysis, the study was modified in May 2005 to allow patients to cross over from placebo to sorafenib, said Dr. Escudier, head of the Immunotherapy and Innovative Therapy Unit at Institut Gustave-Roussy, Paris, France.

Sorafenib is an oral dual-action Raf kinase and VEGFR (vascular endothelial growth factor receptor) inhibitor (see illustration) that has activity in several tumor types, suppressing tumor cell proliferation and angiogenesis through multiple pathways.

Study Design

Patients eligible for the 19-country, 120-site study had histologically or cytologically confirmed unresectable and/or metastatic RCC of clear cell histology. They had to have measurable disease and failure to respond to one prior systemic therapy in the 8 months preceding enrollment, and were required to have good organ function and performance status (ECOG 0 or 1), and no brain metastases. Patients with poor-risk Motzer criteria were excluded.

All patients were stratified by country into low- or intermediate-risk groups, according to the Memorial Sloan-Kettering Cancer Center prognostic index and Motzer criteria. Nearly all of the patients had had a nephrectomy, and the median time from diagnosis was about 2 years. The patients were randomized to receive sorafenib 400 mg twice daily or placebo.

Benefit Seen in All Subgroups

In an independently assessed PFS analysis performed 66 weeks from patient randomization, median PFS was 24 weeks (167 days) for patients randomized to sorafenib vs 12 weeks (84 days) for those in the placebo arm (hazard ratio [HR] 0.44, P < .000001).

"Interestingly the PFS benefit from sorafenib was observed in all patient subgroups," Dr. Escudier said, with similar benefits seen in patients older vs younger than 65 years of age; with low vs intermediate Motzer score; with time from diagnosis less than vs greater than 1.5 years; and regardless of prior IL-2/interferon therapy or lung/liver metastasis at baseline. Response rates were also similar in the top three enrolling countries for the study—France, Poland, and the United States, he added.

Overall, 80% of patients randomized to sorafenib had disease control, he said. Stable disease was seen in 78% of the sorafenib patients vs 55% of the placebo patients. Partial response was noted in 2% of the sorafenib group vs no patients on placebo.

"Objective response rate by independent review in the sorafenib group was much lower than expected by most of the investigators, including me," Dr. Escudier said. He pointed out that independently assessed measurements of maximum percent reduction in 574 patients, showed that "74% of the sorafenib patients had some tumor shrinkage vs 20% randomized to placebo, and obviously this explains the large change we observed in progression-free survival."

Dr. Escudier noted that tumor vascularization assessed by color Doppler ultrasound at baseline and at weeks 3 and 6 "proved to be a very useful tool to predict PFS" in conjunction with CT data in this patient population (see ASCO abstract 3069, for this ancillary study, performed in 30 patients at Institut Gustave Roussy).

Well Tolerated

Sorafenib was well tolerated in the 768 patients evaluated for safety, Dr. Escudier said. Hypertension, fatigue, diarrhea, rash, and hand-foot syndrome of all grades were more common with sorafenib, but grade 3-4 events were rare: Grade 3-4 hypertension was seen in 1% in the sorafenib group and 0% in the placebo group, grade 3-4 hand-foot skin reaction in 5% vs 0%, and grade 3-4 fatigue, diarrhea, and rash in 1% to 2% of sorafenib patients vs 1% or less with placebo. "Interestingly, fatigue is not an issue with this drug," he said.

Notably, he added, while dose reduction or interruption was more common in the sorafenib group (25% vs 14% for placebo), the rate of treatment discontinuation was actually higher in the placebo group (59% vs 38%). "In our study, disease progression was the main reason for discontinuation, and was much more frequent in the placebo arm," he said.

Bayer Pharmaceuticals Corporation and Onyx Pharmaceuticals, Inc. are currently preparing a New Drug Application for possible approval of sorafenib by the US Food and Drug Administration as a treatment for patients with advanced renal cell carcinoma. According to Bayer, discussions are also underway with regulatory agencies about registration in other territories.

The companies are making sorafenib available to eligible patients with advanced RCC through qualified investigators participating in its Advanced Renal Cell Carcinoma Sorafenib (ARCCS) protocol at clinical sites throughout the United States. Patients may not have been previously treated with sorafenib. Physicians may call 1-866-639-2827 for more information about the protocol.