STUDIES EVALUATING ELOXATIN®-BASED REGIMENS IN GASTROINTESTINAL CANCERS PRESENTED AT THE 42nd ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY (ASCO)

Atlanta, GA, June 5, 2006 Sanofi–aventis announced today key results from three studies evaluating Eloxatin® (oxaliplatin injection) in various gastrointestinal tumor types (colorectal, pancreatic and gastric cancers). These results were presented at the 42nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Atlanta, Georgia. Final analysis of TREE-study demonstrates that Eloxatin®-based chemotherapy combined with bevacizumab provided significant improvement in overall survival (OS) for patients with advanced colorectal cancer. Results from this study evaluating the use of Eloxatin®-based regimens plus bevacizumab demonstrate a greater than two year median overall survival (OS) among patients with metastatic colorectal cancer, the longest survival results seen to date in this patient population. The research findings were presented on Monday, June 5, during an oral scientific presentation. In the TREE-study, two successive cohorts (TREE-1 and TREE-2) were investigated. The TREE-1 study contained three arms, evaluating Eloxatin® combined with three different ways to deliver fluoropyrimidine chemotherapy (intravenous infusion, intravenous bolus and oral). TREE-2 evaluated the same three regimens in combination with the vascular epithelial growth factor inhibitor bevacizumab. The two cohorts of patients were included from the same centers and investigators, and the inclusion and exclusion criteria, as well as the base cytotoxic chemotherapy regimens were identical in each cohort. The median overall survival results from the TREE-1 cohort, 18.2 months [95% C.I.14.5 – 21.6 months] are in line with previous studies looking at Eloxatin® in combination with fluropyrimidine alone1. The median overall survival in the TREE-2 cohort was 24.4 months [21.4–26.8 months]. The safety results revealed no unexpected toxicity, and are also in line with previously presented data on the combination of Eloxatin®-based chemotherapy and bevacizumab2. Overall, the incidence of any grade 3/4 severe toxicity (TREE-1 vs. TREE-2 respectively) were as follows: FOLFOX 75% vs. 66%, bFOL 42% vs.59%, CapeOx 73% vs. 54%. The addition of bevacizumab in TREE2 caused more grade 3/4 hypertension, impaired wound healing, and bowel perforation in each arm. “The results of this study demonstrate for the first time that median survival for patients with advanced colorectal cancer can extend beyond two years,” said Howard S. Hochster, M.D., FACP, principal investigator and professor at the New York University School of Medicine. “Oxaliplatin-based chemotherapy is already the standard treatment for these patients, and now the TREE-2 results show that adding bevacizumab to this regimen delivers increased overall survival for these patients.” About TREE-2 The randomized multicenter TREE-2 (A Randomized, Prospective Study Comparing Three Regimens of oxaliplatin Plus Fluoropyrimidine and Bevacizumab for Evaluation of Safety and Tolerability in First-Line Treatment of Patients with Advanced Colorectal Cancer) is the first study evaluating the safety and tolerability of bolus, infusional, and oral fluoropyrimidine + oxaliplatin-based regimens combined with bevacizumab for the first-line treatment of metastatic colorectal cancer. In the TREE-2 study, 213 adults aged 18 or older with metastatic colorectal cancer were treated with one of three oxaliplatin-containing chemotherapy regimens: oxaliplatin plus infusional 5-fluorouracil/leucovorin (FOLFOX), oxaliplatin plus bolus 5FU (bFOL), and oxaliplatin plus Capecitabine (CapeOx), all used in combination with bevacizumab. 1Goldberg R, et al. J Clin Oncol 2004;22:23–30. 2Giantonio B, et al. ASCO 2005 (Abstract 2) ECOG 6201 study shows non-statistically significant survival increase when using fixed dose rate (FDR) gemcitabine (GEM) or a combination of gemcitabine with Eloxatin® (oxaliplatin injection) (GemOx) compared to the standard gemcitabine regimen in patients with locally advanced or metastatic pancreatic cancer. Results from a study of advanced pancreatic cancer patients were presented on Sunday, June 4, during a scientific oral presentation. The study evaluated three regimens including a standard gemcitabine regimen, (1000 mg/m² IV over 30 minutes once weekly for 7 weeks followed by one week of rest for course one only). In all subsequent courses, patients received gemcitabine IV over 30 minutes on days 1, 8 and 15, with courses repeating every 4 weeks in the absence of disease progression or unacceptable toxicity.); a fixed dose rate (FDR) gemcitabine regimen (gemcitabine 1500mg/m² IV over 150 minutes on days 1, 8, and 15. Courses repeated every 4 weeks in the absence of disease progression or unacceptable toxicity.); or the GemOx regimen (gemcitabine 1000mg/m² IV over 100 minutes on day 1 and oxaliplatin100mg/m² IV over 120 minutes on day 2. Courses repeated every 2 weeks in the absence of disease progression or unacceptable toxicity.) Overall survival results for the three regimens evaluated in the study were 4.9 months, 6.0 months and 5.9 months, respectively (95% CI: 4.5-5.6, 5.4-6.9, 5.1-6.8 respectively ). The findings show that changing the gemcitabine mode of administration or combining gemcitabine with oxaliplatin does not provide a significant clinical benefit in this patient population. About ECOG 6201 This multi-institutional trial included patients with measurable and non-measurable advanced, unresectable pancreatic cancer, normal organ function and performance status (PS) 0-2. Patients had not previously received chemotherapy. Patients were stratified by PS 0-1 versus 2 and locally advanced versus metastatic disease (cancer that has spread beyond the original tumor). The study was designed to detect a 33% difference in median survival (hazard ratio 1.33) with 81% power while maintaining a significance level of 2.5% in a two-sided test for each of the two primary comparisons, assuming exponential failure and median survival of 6 months for the standard gemcitabine regimen, and 8 months for the experimental regimens. The primary endpoint was overall survival of the two experimental arms versus the standard arm. Secondary endpoints were the evaluation of toxicity, response, patterns of failure, progression-free survival and quality of life. Median follow up was 12.2 months. Eight hundred and thirty two patients were randomized (53% men, 88% PS 0-1, 88% metastatic). The most common side effects were grade ¾ severe myelosuppression (decrease in blood cell count) and fatigue. REAL 2 trial shows improved overall survival in advanced stomach cancer with Eloxatin®-capecitabine combination. Results of the Real 2 study evaluating four regimens for the treatment of advanced stomach cancer were presented on Monday, June 5, during a scientific oral presentation. The randomised multi-center phase III study evaluated the replacement of fluorouracil with capecitabine and of cisplatin with oxaliplatin in patients with advanced gastric (stomach) cancer. The results of the REAL 2 trial showed that a chemotherapy regimen including Eloxatin® and capecitabine (EOX) significantly improves median overall survival (OS) over a traditional standard regimen of epirubicin, cisplatin and 5-FU (ECF) in patients with advanced gastric (stomach) cancer. The efficacy advantage of the EOX combination was associated with less grade 3/4 neutropenia: 28% for EOX regimen versus 42% for the ECF regimen (p