Eloxatin(reg) demonstrates significant benefit over standard therapy in early stage colon cancer

Main Category: Colorectal Cancer
Article Date: 03 Jun 2004 - 15:00 PDT


Eloxatin(reg) Based Adjuvant Chemotherapy Provides 23 Percent Reduction in Risk of Colon Cancer Recurrence.

Results of an ELOXATIN (oxaliplatin for injection) adjuvant trial (MOSAIC) have been published in the current issue of the New England Journal of Medicine. The trial demonstrated that the addition of ELOXATIN(reg) to the current standard of adjuvant chemotherapy for colon cancer (5-fluorouracil/leucovorin known as 5-FU/LV) reduced the risk of recurrence of cancer by 23 percent in patients who had undergone surgical removal of their primary tumor(i).

These are the first results to demonstrate a significant benefit over 5-FU/LV alone, and provide early-stage colon cancer patients with new hope for potential cure of their disease.

The MOSAIC study is a large, international, randomized phase III trial involving 2,246 patients in 148 centers, led by Dr. de Gramont, Professor of Medicine and Director of the Oncology Department, Saint-Antoine Hospital, Paris.

The MOSAIC trial was based on the assumption that the ELOXATIN-based chemotherapy regimen, a standard treatment for patients with advanced metastatic colon cancer, would also benefit patients with early-stage disease who have had surgical removal of their tumor.

The primary objective of the trial was to demonstrate the superiority of ELOXATIN-based chemotherapy over standard therapy alone, using as a primary end-point, three-year disease-free survival (the percentage of patients alive without colon cancer three years after treatment).

The FDA's Oncologic Drugs Advisory Committee (ODAC) recently endorsed 3-year Disease Free Survival as a valid endpoint for early colon cancer treatment trials.

"The MOSAIC results show that this ELOXATIN-based therapy is the first significant development for the adjuvant management of early colon cancer in 10 years," said Dr. de Gramont(ii). "By adding ELOXATIN to standard chemotherapy, we see a significant improvement in three-year disease free survival. These results, in addition to the recent first-line approval, demonstrate the value of ELOXATIN across the continuum of care for colon cancer patients."

After a median follow-up of 37 months, 3-year disease-free survival was 72.9 % in the 5-FU/LV arm and 78.2 % in the Eloxatin/5-FU/LV arm, which corresponds to a 23% reduction in the risk of relapse. In the Eloxatin arm, the most frequently reported side effects were neutropenia (decrease in white blood cells) that was complicated by fever or infection in 1.8% of cases, diarrhea and peripheral sensory neuropathy (numbness, "pins and needles" in the extremities).

The incidence of significant sensory neuropathy was 12% during the study but this improved when patients discontinued treatment, with only 0.5% having significant symptoms 18 months later.

On the basis of the MOSAIC trial a supplemental New Drug Application (sNDA) was submitted to the FDA in the US in early 2004 as well as an extension of indication to EMEA in Europe for ELOXATIN to include the adjuvant treatment of patients with colon cancer.

"The MOSAIC data represent significant incremental gain in the comprehensive management of colon cancer. The data unequivocally demonstrate that oxaliplatin is an active agent in the adjuvant setting and suggest that oxaliplatin containing regimens should become an accepted standard of care," said Dr. Norman Wolmark, MD, Chairman, Department of Human Oncology, Allegheny General Hospital, Pittsburgh.

In the United States alone, approximately 60,000 patients present with early stage colon cancer every year.

The National Comprehensive Cancer Network (NCCN), an alliance of 19 of the world's leading cancer centers, recently updated its colon and rectal guidelines to account for the current evidence surrounding ELOXATIN-based therapies. [http://www.nccn.org]

The MOSAIC trial was supported by a grant from Sanofi-Synthelabo.

About ELOXATIN(reg)

In the U.S., ELOXATIN(reg) received marketing approval on January 9, 2004, for the first line treatment of metastatic carcinoma of the colon or rectum. This approval recommends the use of ELOXATIN(reg), in combination with infusional 5-FU/LV, for the treatment of advanced carcinoma of the colon or rectum. ELOXATIN(reg) had previously (August 2002) received approval for second line treatment of these patients.

ELOXATIN(reg) received approval in France for the 2nd line treatment of metastatic colorectal cancer in April 1996, and as a 1st line treatment in April 1998. In July 1999, ELOXATIN(reg) was approved for the 1st line treatment indication in major European countries, through the mutual recognition procedure, France being the Reference Member State.

ELOXATIN(reg) has successfully completed a Mutual Recognition Procedure in Europe in December 2003, which will allow the product to be indicated for the full indication: "Treatment of Metastatic Colorectal Cancer in combination with 5-fluorouracil and folinic acid" (i.e., 1st line and 2nd line treatment).

ELOXATIN(reg) is currently marketed by Sanofi-Synthelabo in more than 60 countries for the treatment of metastatic colorectal cancer and developed in association with Debiopharm S.A.

Colorectal Cancer Leading Cause of Death

About one million new cases of colorectal cancer are diagnosed worldwide every year, and about 150,000 new cases in the U.S. According to the American Cancer Society, colorectal cancer is the second leading cause of malignancy-related death in the U.S., accounting for 10 to 15% of all cancer death. Over a lifetime, about one in 18 people develop colorectal cancer, and, each year, about 56,000 people die from it in the U.S.

Further development in other types of cancer

An extensive worldwide clinical development program is ongoing to explore the benefit of ELOXATIN(reg) in other types of cancer.

Clinical Considerations about Eloxatin(reg) in the United States

In the United States, ELOXATIN(reg) (oxaliplatin for injection), used in combination with infusional 5-fluorouracil (5-FU) and leucovorin (LV), is indicated for the treatment of advanced carcinoma of the colon or rectum.

ELOXATIN(reg) should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

Anaphylactic-like reactions to ELOXATIN(reg) have been reported, and may occur within minutes of ELOXATIN(reg) administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.

ELOXATIN(reg) should not be administered to patients with a history of known allergy to ELOXATIN(reg) or other platinum compounds.

Women of childbearing potential should be advised not to become pregnant while receiving treatment with ELOXATIN(reg).

ELOXATIN(reg) is associated with pulmonary toxicity, which may be fatal, and with two types of primarily peripheral sensory neuropathy: an acute, reversible type of early onset and a persistent type (>14 days). Paresthesias (all grades) occurred in 77% of previously untreated patients. Acute and persistent neuropathies occurred in 56% and 48% (all grades) of previously treated patients, respectively. An acute syndrome of pharyngolaryngeal dysesthesia seen in 1%-2% (grade 3/4) of patients, characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing), may also occur.

Both 5-FU and ELOXATIN(reg) are associated with gastrointestinal and hematologic adverse events. When ELOXATIN(reg) is administered in combination with 5-FU, the incidence of these events is increased.

Full prescribing information including boxed warning is available upon request.

About Sanofi-Synthelabo

Sanofi-Synthelabo is a major global research-based pharmaceutical group with 33,000 employees in more than 100 countries. The company is headquartered is Paris, and listed in Paris (Euronext: SAN) and in New York (NYSE: SNY). With consolidated sales of EUR 8 billion in 2003, Sanofi-Synthelabo ranks 7th in Europe and among the world's top 20 pharmaceutical companies. With an R&D portfolio of 56 compounds in development, Sanofi-Synthelabo is focused on a core group of four therapeutic areas: cardiovascular disease and thrombosis; diseases of the central nervous system; oncology; and internal medicine.

(i) de Gramont A, Banzi, M, Navarro, M, et al. Oxaliplatin/5-FU/LV in adjuvant colon cancer: results of the international randomized MOSAIC trial [abstract]. Prol Am Soc Clin Oncol. 2003; 22:253. Abstract 1015.

(ii) FDA Background for Colon Cancer Endpoints Workshop. Available at: http://www.fda.gov/cder/drug/cancer_endpoints/BackgroundColon1003.pdf. 2003.

In accordance with article 7 of the COB rule no. 2002-04, this press release was transmitted to the Autorite des marches financiers (AMF) before its publication.

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