BETHESDA, MdPharmacia & Upjohns Camptosar (irinotecan hydrochloride injection) found smooth sailing through the often roiling waters of the FDAs Oncologic Drugs Advisory Committee (ODAC).
In a little more than 2 hours, the panel heard and discussed presentations by the company and a Food and Drug Administration medical reviewer, and voted unanimously to recommend that the FDA approve Camptosar for a new indication as a component of the first-line treatment of metastatic colorectal cancer.
About 130,200 new cases of colorectal cancer are anticipated in the United States this year. Of these, about 20% of patients will have metastatic disease at diagnosis, and 40% of all the new cases will ultimately develop metastases, according to Langdon Miller, MD, Pharmacia & Upjohns vice president for Clinical Research Oncology for the Americas.
Camptosar is a topoisomerase I inhibitor whose mode of action is to prevent the growth of cancer cells. The drug is being developed and marketed worldwide by a collaboration of four pharmaceutical houses. Camptosar won accelerated approval from the FDA in 1996 and full approval in 1998 for the treatment of metastatic colon or rectal cancer that recurs or progresses after fluorouracil(Drug information on fluorouracil) (5-FU) therapy.
To support its application for a first-line indication for the drug, Pharmacia & Upjohn presented two phase III randomized, multicenter trials, both of which compared Camptosar plus 5-FU/leuco-vorin to 5-FU/leucovorin alone.
Study V303 treated 385 patients at 83 centers, mostly in Europe. Study 0038 involved 683 patients (226 of whom received Camptosar plus 5-FU/leucovorin for efficacy and safety evaluation only) who were treated at 71 centers in the United States, Canada, Australia, and New Zealand. Endpoints in both studies were time to tumor progression (primary in 0038), tumor response rate (primary in V303), survival, safety, and quality of life.
Of some significance to the FDA was the fact that the two trials used three different regimens in delivering the combination arms.
In V303, Camptosar plus 5-FU/leucovorin proved significantly superior to 5-FU/leucovorin only in median survival time (17.4 months vs 14.1 months), overall tumor response rate (49% vs 31%), and median time to tumor progression (6.7 months vs 4.4 months).
Similar advantages for the drug combination over 5-FU/leucovorin were found in study 0038: median survival time (14.8 months vs 12.6 months), overall tumor response rate (50% vs 28%), and median time to tumor progression (7.0 months vs 4.3 months).
Data from both studies indicate that first-line combination treatment with Camptosar5-FU/leucovorin offers a significant benefit, even though patients in the control groups received second-line therapy, Dr. Miller commented.
The FDA analysis yielded very similar numbers to that of the company, although the FDA found somewhat lower response rates in both studies35% vs 22% in study V303 and 39% vs 21% in study 0038. Nonetheless, comparison of the Camptosar combination arms to the 5-FU/LV arms demonstrated statistically significant differences in survival, time to tumor progression, and response rates in favor of Camptosar in both studies, the agency said.
The safety data presented by the company showed mixed results. In study V303, 17% of the combination patients suffered grade 3 late diarrhea, compared with 7% of patients receiving 5-FU/leucovorin alone. In study 0038, the numbers were 15% for the combination arm and 6% for 5-FU/leucovorin alone.
Grade 3-4 mucositis percentages were the same in study V303 (3%), but in study 0038, significantly more patients in the 5-FU/leucovorin-only arm experienced grade 3-4 mucositis (17% vs 2%). Also, patients in study 0038 who received only 5-FU/leucovorin experienced more grade 4 neutropenia (43% vs 24%) and neutropenic fever (15% vs 7%).
However, the sponsor said adverse events associated with the combination treatment were reversible, noncumulative, generally predictable, and manageable. The combination arm showed relatively little difference between younger and older patients, Dr. Miller said.
Dropouts in both studies due to adverse events were acceptably low, and, as categorized by the investigators, the incidence of treatment-related deaths was less than 1%, he added. Most importantly, first-line combination treatment was associated with significant survival.
During the ODAC meeting, Pharmacia & Upjohn proposedand the committee agreedthat two of the three regimens used in the two trials should be included in the dosage and administration section of the new labeling for Camptosar.
One is a regimen developed in the United States that uses 125 mg/m² of Camptosar, 500 mg/m² of 5-FU, and 20 mg/m² of leucovorin once a week for 4 weeks every 6 weeks.
The other regimen, developed in France, gives 180 mg/m² of Camptosar on day 1 every 2 weeks; a 400 mg/m² IV bolus of 5-FU followed by 600 mg/m² continuous infusion on days 1 and 2 every 2 weeks; and 200 mg/m2 of leucovorin on days 1 and 2 every 2 weeks.
The committee also discussed the issue of whether sponsors should be expected to use the Camptosar5-FU combination as the control arm in future trials of drugs aimed at the front-line treatment of metastatic colorectal cancer.
Most committee members generally felt that they did not have a firm basis on which to make a recommendation either way.
George W. Sledge, Jr, MD, professor of medicine and pathology, Indiana University, argued that the difference in benefit found between the two studies examined by the committee was insufficient for the drug combination to replace 5-FU/leucovorin as a new gold standard.
His view quickly won the agreement of Kim A. Margolin, MD, of the City of Hope National Medical Center. I dont think we can or should try to answer this question, she said.