NEWS

FDA Evaluating Oxaliplatin for Advanced Colorectal Cancer Treatment

Joyce Baldwin

Three years ago, oxaliplatin (Eloxatine) was in the headlines as the first potential breakthrough in 30 years in the treatment of advanced metastatic colorectal cancer. Results from clinical trials suggested that the addition of oxaliplatin to standard chemotherapy regimens was associated with an improvement in median progression-free survival exceeding 8 months and in median survival to nearly 16 months.

Despite these results, in April 2000 the U.S. Food and Drug Administration declined to approve the use of oxaliplatin in combination with the standard chemotherapy regimen of 5-fluorouracil and leucovorin (5-FU/LV) as a first-line therapy for advanced and metastatic colorectal cancer because the data available at that time from multi-institutional phase III trials failed to show that the drug combination had a survival advantage over 5-FU/LV. However, these trials had not been designed to directly measure improvements in survival.

But at this year’s annual meeting of the American Society for Clinical Oncology, new data from a large-scale clinical trial sponsored by the National Cancer Institute showed promising results with a drug regimen that combines oxaliplatin with infusional 5-FU/LV. Based in part on the results of this trial, oxaliplatin is now on the "fast-track" for consideration by the FDA as second-line therapy for the treatment of patients with advanced colorectal cancer.

"These data support an important role for oxaliplatin in the treatment of patients with advanced colorectal cancer, and I’m hopeful the data we collected in addition to data collected by others will support FDA approval," said Richard M. Goldberg, M.D., professor of oncology at the Mayo Clinic in Rochester, Minn.



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Dr. Richard M. Goldberg

 
Oxaliplatin was first approved as a second-line therapy in the treatment of metastatic colorectal cancer in France in April 1996. Since then, more than 50 countries have approved the drug for this indication. There are more than 30 ongoing studies of oxaliplatin in combination with other drugs for ovarian cancer, pancreatic cancer, esophageal cancer, and other malignancies.

The new drug application submitted to the FDA in June by Sanofi-Synthelabo, the French-based company that developed and manufactures oxaliplatin, is for oxaliplatin as second-line therapy. The 2000 application sought approval for the drug as first-line therapy. Goldberg explained that the earlier application was denied because the data supporting the application were from two randomized phase III trials conducted in France, both of which were based on determining time to disease progression, not overall survival. The French agency equivalent to the U.S. FDA accepted time to progression as a marker of efficacy.

"If you are looking for a time to progression end point, you need to include significantly fewer patients to meet that goal. The two trials that were done did not show a survival advantage, perhaps in part because they were underpowered in terms of the number of patients recruited," said Goldberg, who is the coordinator of the Gastrointestinal Cancer Program for the North Central Cancer Treatment Group, which coordinated the NCI-sponsored trial. "Our trial was adequately powered to demonstrate a survival advantage."

As originally designed, this study, known as N9741, included multiple treatment arms, some of which were dropped during the course of the study because of toxicity and changes in the accepted standard regimen. Eventually it was modified to include three treatment arms: a regimen known as FOLFOX4 (oxaliplatin combined with infusional 5-FU/LV), a regimen known as IFL (irinotecan combined with bolus 5-FU/LV), and a combination of oxaliplatin and irinotecan. IFL (also known as the Saltz regimen) has been the standard treatment for advanced colorectal cancer since April 2000.

Interim results from the N9741 study were so strongly in favor of the FOLFOX4 regimen compared with the IFL regimen that "when the NCCTG Data Safety Monitoring Board reviewed the results of the study in the spring of this year, it determined that all other arms of the study except the FOLFOX4 arm should be closed," said Percy Ivy, M.D., the senior investigator in the Investigational Drug Branch of NCI’s Cancer Therapy Evaluation Program who monitored and reviewed the study.

In addition to the NCI-sponsored trial, Sanofi also sponsored studies in the United States using oxaliplatin in the treatment of patients with advanced colon cancer who had been previously treated with other chemotherapy drugs. "Those data have not yet been released," Goldberg said, "but are being used by the FDA in its review."

Oxaliplatin is not yet licensed in the United States for a specific indication; however, based on the results of the N9741 study, the NCI is offering expanded access to oxaliplatin through a special treatment protocol called TRC-0201. "This program allows the NCI to release an investigational agent on protocol," said Ivy, "but it is not an extension of the N9741 trial." Since U.S. supplies of oxaliplatin are limited, patients will be selected for the new program by a lottery system. Ivy said that patient advocate groups had recommended this approach as a fair and equitable one.

NCI based its decision to offer expanded access to oxaliplatin on the preliminary analysis of data on 795 patients with previously untreated metastatic colorectal cancer who were enrolled in the N9741 trial between March 1999 and April 2001. This analysis demonstrated that patients receiving the FOLFOX4 regimen had a significantly longer time to disease progression, better overall survival, higher response rates, and lower toxicity than patients receiving IFL.

Patients in the FOLFOX4 treatment arm of the study had a median survival of 18.8 months, about 4 months longer than that seen with the standard treatment of IFL. Patients treated with the FOLFOX4 regimen had a median time to tumor progression of 8.8 months versus 6.9 months for the IFL arm and tumor response rates of 38% compared with 29% in the IFL group. The one-year survival rate was 71% for the FOLFOX4 treatment arm and 58% for the IFL arm of the study.

About half of the patients enrolled on the FOLFOX4 arm of the study went on to receive irinotecan because their disease had progressed while they were on oxaliplatin. About 17% of patients in the IFL arm went on to receive oxaliplatin—a much lower number because oxaliplatin is not widely available, Goldberg said. Ivy pointed out that treatment patients received after completing their N9741 protocol treatment could "have had an impact on the duration of survival."

Goldberg said he is hopeful that oxaliplatin will offer some improvement for patients already at an advanced stage of disease. He said that when he completed his oncology fellowship in 1983, "all we had was 5-FU, and seeing a response in a patients with metastatic colon cancer was extraordinary. It was the sort of thing you showed your colleagues. When [irinotecan] came along a response became a much more routine thing. With oxaliplatin, I have come to the point where I kind of expect patients to improve or at least stabilize rather than considering improvement or stabilization to be an exceptional event."

And with new molecularly targeted drugs in development, the challenge will be to integrate these agents into current treatment protocols and therapeutic strategies, said Axel Grothey, M.D., an oncologist at University of Halle, Germany. "These novel molecular therapeutics have very little overlapping toxicity with conventional chemotherapy and most likely have synergistic effects in terms of efficacy. Thus, I am very confident that we will soon see the first phase III trial that achieves a median overall survival of more than 24 months in patients with metastatic colorectal cancer."


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