The safety and efficacy of sorafenib in the treatment of advanced renal cell carcinoma (RCC) were studied in the following two randomized controlled clinical trials.

TARGET   


TARGET (NCT00073307) was an international, multicenter, randomized, double blind, placebo-controlled trial in patients with advanced renal cell carcinoma who had received one prior systemic therapy. Primary study endpoints included overall survival and progression-free survival (PFS). Tumor response rate was a secondary endpoint. The PFS analysis included 769 patients, per protocol, stratified by MSKCC (Memorial Sloan Kettering Cancer Center) prognostic risk category (low or intermediate) and country and randomized to sorafenib 400 mg twice daily (N=384) or to placebo (N=385).

Table 11 summarizes the demographic and disease characteristics of the study population analyzed. Baseline demographics and disease characteristics were well balanced for both treatment groups. The median time from initial diagnosis of RCC to randomization was 1.6 and 1.9 years for the sorafenib and placebo arms, respectively.

Progression-free survival, defined as the time from randomization to progression or death from any cause, whichever occurred earlier, was evaluated by blinded independent radiological review using RECIST criteria. Figure 2 depicts Kaplan-Meier curves for PFS. The PFS analysis was based on a two-sided Log-Rank test stratified by MSKCC prognostic risk category and country.

Figure 2: Kaplan-Meier Curves for Progression-free Survival - TARGET (RCC)

NOTE: HR is from Cox regression model with the following covariates: MSKCC prognostic risk category and country. P-value is from two-sided Log-Rank test stratified by MSKCC prognostic risk category and country.

The median PFS for patients randomized to sorafenib was 167 days compared to 84 days for patients randomized to placebo. The estimated hazard ratio (immediate risk of progression or death with sorafenib compared to placebo) was 0.44 (95% CI: 0.35, 0.55).  


A series of patient subsets were examined in exploratory univariate analyses of PFS. The subsets included age above or below 65 years, ECOG PS 0 or 1, MSKCC prognostic risk category, whether the prior therapy was for progressive metastatic disease or for an earlier disease setting and time from diagnosis of less than or greater than 1.5 years. The effect of sorafenib on PFS was consistent across these subsets, including patients with no prior IL-2 or interferon therapy (N=137; 65 patients receiving sorafenib and 72 placebo), for whom the median PFS was 172 days in the sorafenib arm compared to 85 days in the placebo arm.  


Tumor response was determined by independent radiologic review according to RECIST criteria. Overall, of 672 patients who were evaluable for response, 7 (2%) patients in the sorafenib and no (0%) patients in the placebo arms had a confirmed partial response. Thus the gain in PFS primarily reflects the stable disease population.  


At the time of a planned interim survival analysis, based on 220 deaths, overall survival was longer for those randomized to sorafenib compared with placebo with a hazard ratio of 0.72. This analysis did not meet the prespecified criteria for statistical significance. Additional analyses are planned as the survival data mature.  


BAY43-9006   


BAY43-9006 (NCT00101413) was a randomized discontinuation trial in patients with metastatic malignancies, including RCC. The primary endpoint was the percentage of randomized patients remaining progression-free at 24 weeks. All patients received sorafenib for the first 12 weeks. Radiologic assessment was repeated at week 12. Patients with <25% change in bi-dimensional tumor measurements from baseline were randomized to sorafenib or placebo for a further 12 weeks. Patients who were randomized to placebo were permitted to cross over to open-label sorafenib upon progression. Patients with tumor shrinkage ≥25% continued sorafenib, whereas patients with tumor growth ≥25% discontinued treatment.

A total of 202 patients with advanced RCC were enrolled into BAY43-9006, including patients who had received no prior therapy and patients with tumor histology other than clear cell carcinoma. After the initial  


12 weeks of sorafenib, 79 patients with RCC continued on open-label sorafenib, and 65 patients were randomized to sorafenib or placebo. After an additional 12 weeks, at week 24, for the 65 randomized patients, the progression-free rate was significantly higher in patients randomized to sorafenib (16/32, 50%) than in patients randomized to placebo (6/33, 18%) (p=0.0077). Progression-free survival was significantly longer in the sorafenib arm (163 days) than in the those randomized to placebo (41 days) (p=0.0001, HR=0.29).