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Reviewer: Dr Lori Wood Date posted: June 21, 2007

Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: Survival and biomarker analysis Authors: Bukowski et al, ASCO 2007. Abstract: 5023. Reviewer: Dr Lori Wood Date posted: June 21, 2007. Treatment A: Sorafenib 400 mg p.o. qd. R. Treatment B:

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Reviewer: Dr Lori Wood Date posted: June 21, 2007

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  1. Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: Survival and biomarker analysisAuthors: Bukowski et al, ASCO 2007.Abstract: 5023 Reviewer: Dr Lori Wood Date posted: June 21, 2007

  2. Treatment A: Sorafenib 400 mg p.o. qd R Treatment B: Placebo Metastatic renal cell carcinoma Second-line Low or intermediate risk patients (n=903)

  3. KEY DATES NEEDED TO INTERPRET RESULTS • Primary endpoint was overall survival. • Preplanned interim analysis was done using PFS as one of the endpoints. There was a statistically significant difference in PFS and, therefore, the study was stopped and crossover was allowed. • Interim analysis: Jan 2005. • First overall survival reported: 220 events - May 2005 (ECCO 2005). • Crossover allowed due to positive PFS results: May 2005. • Overall survival 6m post crossover: 367 events - Nov 2005 (ASCO 2006). • Final overall analysis planned at 540 events: Sept 2006 (ASCO 2007). • Secondary overall survival analysis was done censoring the placebo data on June 30, 2005 as a way to minimize the crossover effect on overall survival: Sept 2006 (ASCO 2007). • p value required for the final analysis of overall survival using prespecified O’Brien-Fleming statistical boundaries is: p=0.037

  4. RESULTS *p value required to be p=0.037 due to multiple looks.

  5. STUDY COMMENTARY • This study was designed to show that Sorafenib improves PFS and overall survival in patients with metastatic RCC previously treated with cytokines. • Sorafenib increased PFS in these patients (5.5m vs 2.8m). • Final overall survival is not significantly improved (when taking in to account the O’Brien-Fleming statistical boundaries for multiple looks) likely because of crossover (48% of patients) at the first interim analysis. Therefore, perhaps looking at overall survival data with placebo patients censored at the time of crossover (the last line in the previous table) may be the most reasonable to look at. • Baseline VEGF was an independent prognostic factor for PFS and overall survival. Sorafenib benefited patients with both high and low VEGF levels.

  6. BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS • In cytokine failure patients, Sorafenib improves PFS (5.5m vs 2.8m) and likely improves overall survival; however, this cannot be shown statistically likely because of crossover. • Crossover has never been an issue before in metastatic RCC trials as there has not been particularly effective therapy in the past. • The primary endpoint in future metastatic RCC trials will likely be PFS and not overall survival (as with many other cancers). • Then the question comes up: What is a clinically meaningful improvement in PFS (To our patients? To our funding agencies?). • The question is how Sorafenib should be used in Canada: • Do we really need to treat patients with cytokines (i.e. Interferon) first and Sorafenib only in the second-line setting? • Does it have a role in first-line (see ASCO 2007 Abstract 5025)? • There is no question it works in the first-line setting in some patients. • Only patients with private insurance will have access to Sorafenib as of June 2007.

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