Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC).

Reviewer: Christopher Dolinsky, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 14, 2005

Presenter: B. Escudier
Presenter's Affiliation: Institut Gustave Roussy, Villejuif, France
Type of Session: Scientific


-         Sorafenib (BAY 43-9006) is an oral inhibitor of a number of tyrosine kinases including Raf kinase.
-         Sorafenib has been demonstrated to inhibit angiogenesis and tumor cell growth in animal models.
-         This molecule has been studied in a variety of tumors, including renal cell carcinoma (RCC).
-         Promising phase II data on sorafenib for metastatic renal cell carcinoma showed a 70% progression free response rate at 12 weeks.

Materials and Methods

-         A phase III, double-blind placebo controlled multi-institution trial randomized 905 patients with metastatic renal cell carcinoma to either 400 mg twice a day of sorafenib or placebo.
-         Patients all had histologically confirmed clear cell tumors, ECOG 0-1 performance status, absence of brain metastases, and prior treatment with one systemic regimen.
-         At the time of this publication, 769 patients were available for statistical analysis.
-         The two groups were well balanced in terms of a variety of demographic and disease related factors including: age, performance status, number of metastatic sites, prior nephrectomy, and prior radiation therapy.
-         Patients were stratified into low or intermediate risk groups based on the Memorial Sloan Kettering Cancer Center prognostic index.
-         The primary endpoint for the trial is overall survival, and secondary endpoints include progression free survival and quality of life measures.
-         Progression free survival analysis was presented in this abstract.
-         Progression free survival was judged by independent review of post-treatment imaging studies.


-         Median progression free survival for the sorafenib arm was 24 weeks compared to 12 weeks for the placebo arm (hazard ratio 0.44, p<0.00001).
-         The 12 week progression free rate for the sorafenib arm was 79% compared to 50% for the placebo arm.
-         The dose of medication was either reduced or interrupted in 25% of patients in the sorafenib arm and 14% of patients in the placebo arm.
-         Medication was discontinued in 38% of patients in the sorafenib arm and 59% of patients in the placebo arm, and the most common reason for medication to be discontinued was disease progression.
-         The most common adverse effects that were greater in the sorafenib arm than the placebo arm were hypertension (11% vs 1%), rash (34% vs 13%), hand-foot syndrome (27% vs 5%) and diarrhea (33% vs 10%).
-         The rates of fatigue between the two arms were similar (26% sorafenib, 23% placebo).

Author's Conclusions

-         Tumor shrinkage was noticed in the majority of patients treated with sorafenib.
-         Sorafenib was well tolerated amongst the majority of patients studied.
-         Progression free survival was notably improved in the sorafenib arm.
-         Further analyses will be performed as the data matures.

Clinical/Scientific Implications

The authors presented an early analysis of a well designed phase III multi-institutional randomized double blind placebo controlled trial. The results of this trial are exciting and important in that such a profound result was returned using a targeted therapy without any major toxicity.  Recently, a number of biologic therapies have arisen for renal cell carcinoma, but this data represents the largest and most mature experience with any of these molecules.  Further research will most likely seek to integrate this medication at earlier stages of this disease.  Because this is an inhibitor of a variety of different kinases, laboratory research needs to be continued to further characterize the pathways inhibited by this molecule.  New directions of research with this compound will include using it in combination with other agents that have proven efficacy in this disease.  The oncology community eagerly awaits the final analyses of this trial including its primary endpoint, overall survival.