PARIS -- Sanofi-Synthelabo, a member of the Sanofi-Aventis Group announced that the U.S. Food and Drug Administration (FDA) has approved ELOXATIN™, in combination with conventional chemotherapy (infusional 5-fluorouracil/leucovorin, known as 5-FU/LV), for the adjuvant (postsurgical) treatment of patients with stage III colon cancer who have undergone complete resection of the primary tumor. This is the first new chemotherapy approval for the adjuvant treatment of colon cancer in over a decade1, offering patients new hope for potential cure of this disease, one of the nation’s deadliest forms of cancer.
“The FDA approval of ELOXATIN™ in this setting provides colon cancer patients with access to a potentially lifesaving treatment,” said John L. Marshall, MD, associate professor of medicine, director of development therapeutics and GI oncology for the Lombardi Cancer Center at Georgetown University. “Early postsurgical treatment with this ELOXATIN™-based regimen offers patients the greatest opportunity of living longer without recurrence of their disease. This approval marks the beginning of a promising new era of benefit for patients with colon cancer.”
The American Cancer Society estimates that in 2004, 106,370 new cases of colon cancer will have been diagnosed in the United States.2 Most patients will undergo surgery to remove their primary tumor, but many of these patients will still be at risk for recurrence. This latest approval of ELOXATIN™ provides these patients with another potent option, helping to decrease the risk of cancer recurrence and spread.3
The FDA based its decision on results from the MOSAIC study, a large, international, randomized Phase III trial involving 2,246 patients in 146 centers. At a median follow-up of four years, there was a statistically significant improvement in the primary end point, disease-free survival (DFS), for the ELOXATIN™ combination compared with infusional 5-FU/LV, both in the overall study population (four-year DFS: 76 percent vs. 69 percent; p=0.0008) and in the subgroup with stage III disease (four-year DFS: 70 percent vs. 61 percent p=0.002). Survival data were not mature at the time of the analysis. No statistical difference in overall survival was shown between the treatment arms in the overall study population or in stage III patients. No statistical difference was observed either in DFS or survival in stage II patients.
These results demonstrated that the addition of ELOXATIN™ (oxaliplatin for injection) to conventional adjuvant chemotherapy for colon cancer (5-FU/LV) reduced the risk of recurrence of cancer by 24 percent in the overall patient population who had undergone surgery to remove their primary tumor.3
This approval is an important milestone in the postsurgical treatment of colon cancer and further reinforces the status of ELOXATIN™ as a cornerstone of the treatment of colon cancer.
“This is a major step forward in treating this disease,” said Kevin Lewis, co-founder and chairman of the Colon Cancer Alliance. “It’s exciting that the FDA has made another option available to patients following surgery, particularly since early screening is increasing the number of people being diagnosed before the cancer has spread. This could offer a potentially lifesaving option to thousands of patients.”
About ELOXATIN
In the United States, ELOXATIN™ received approval on January 9, 2004, for the first-line treatment of advanced carcinoma of the colon or rectum (i.e., first therapy for patients with metastatic colorectal cancer). This approval is for the use of ELOXATIN™, in combination with infusional 5-FU/LV, for the treatment of advanced carcinoma of the colon or rectum. This same ELOXATIN™ combination had previously (August 2002) received approval for second-line treatment of this patient population (i.e., therapy for already treated patients with metastatic colorectal cancer).
ELOXATIN™ received approval in France for the second-line treatment of metastatic colorectal cancer in April, 1996, and as a first-line treatment in April, 1998. In July 1999, ELOXATIN™ was approved for the first-line treatment indication in major European countries, through the mutual recognition procedure, France being the Reference Member State.
ELOXATIN™ successfully completed a mutual recognition procedure in Europe in December, 2003, which allowed the product to be indicated for the indication: “treatment of metastatic colorectal cancer in combination with 5-fluorouracil and folinic acid” (i.e., in first- and second-line treatment).
In September 2004, the European indication was extended to include use of ELOXATIN™ in the adjuvant setting: “Adjuvant treatment of stage III (Dukes’ C) colon cancer after complete resection of primary tumor.”
ELOXATIN™ is currently marketed by sanofi-aventis in more than 60 countries for the treatment of metastatic colorectal cancer and developed in association with Debiopharm S.A.
Adjuvant Colon Cancer Setting
The incidence of grade 3 or grade 4 events was 70 percent and 31 percent on the ELOXATIN combination arm and infusional 5-FU/LV arm, respectively. Granulocytopenia, paresthesia, diarrhea, vomiting, and nausea were the most common grade 3 or 4 adverse events. Paresthesia was seen in 92 percent of patients on the ELOXATIN combination; 21 percent had residual paresthesia at 18-month follow-up. Three percent and 0.5 percent had grade 2 and 3 paresthesias, respectively, at 18-month follow-up. Grade 3 or 4 hypersensitivity was noted in 3 percent and may require discontinuation of therapy. Hepatotoxicity, evidenced by increase in transaminases (57 percent vs 34 percent) and alkaline phosphatases (42 percent vs. 20 percent), was observed more commonly in the ELOXATIN arm. The incidence of increased bilirubin was similar on both arms. Hepatic vascular disorders should be considered and investigated if abnormal liver function tests or portal hypertension are present and cannot be explained by liver metastases or other known etiologies.
Advanced Colorectal Cancer Setting
Fatigue, neuropathy, nausea, vomiting, diarrhea, stomatitis, neutropenia, and thrombocytopenia were the more common adverse events. Neither febrile neutropenia nor requirement for platelet transfusion was increased as compared to treatment with irinotecan plus bolus 5-FU/LV. Eloxatin™ (oxaliplatin for injection) has been associated with pulmonary fibrosis (<1 percent of study patients), which may be fatal. There have been reports while on study from clinical trials and from postmarketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received ELOXATIN plus 5-FU/LV while on anticoagulants. Patients requiring oral anticoagulants may require closer monitoring. Hypersensitivity has been observed (<2 percent grade 3/4) in clinical studies and trials. It was usually managed with standard epinephrine, corticosteroid, and antihistamine therapy, and may require discontinuation of ELOXATIN therapy.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications, is available at http://www.fda.gov/cder/foi/label/2004/021492s004lbl.pdf.