NEW YORK—Because pivotal studies failed to show a survival advantage, oxaliplatin(Drug information on oxaliplatin) did not receive FDA approval as first-line therapy of metastatic colorectal cancer last year.
New US trials may move this drug closer to a regulatory go-ahead, Daniel G. Haller, MD, of the University of Pennsylvania Cancer Center, said at the Chemotherapy Foundation Symposium XVIII. A US Intergroup trial, he said, is comparing the standard treatment—the Saltz regimen, which combines fluorouracil(Drug information on fluorouracil) (5-FU), leucovorin, and irinotecan(Drug information on irinotecan) (Camptosar)—with the de Gramont regimen of 5-FU, leucovorin, and oxaliplatin. The trial also includes a third arm of oxaliplatin plus irinotecan without 5-FU.
Oxaliplatin is a platinum derivative that is effective in cisplatin(Drug information on cisplatin)-resistant cell lines. In phase I trials, oxaliplatin’s dose-limiting toxicity was neurotoxicity, primarily peripheral neuropathy that is short-lived and related to cold. No nephrotoxicity or ototoxicity has been seen.
With oxaliplatin monotherapy, response rates up to 27% have been reported in chemotherapy-naïve patients, and up to 10% in patients who previously received a 5-FU-based regimen. "These data are consistent with those seen with single-agent irinotecan," Dr. Haller said.
A French study that directly compared regimens containing either oxaliplatin or irinotecan found similar response rates and progression-free survival for both regimens. These results were reported at the American Society of Clinical Oncology (ASCO) 2000 annual meeting in New Orleans.
Dr. Haller noted that a survival advantage may be seen in one treatment or the other upon longer follow-up.
As reported by de Gramont et al (J Clin Oncol 18:2938-2947, 2000), 5-FU/leucovorin plus oxaliplatin was superior to 5-FU/leucovorin alone in the primary endpoint of progression-free survival (9.0 months vs 6.2 months, P = .0003); a significantly improved response rate was also seen (50.7% vs 22.3%, P = .0001).
However, this did not translate into an improvement in overall survival, which was a median of 16.2 months in the oxaliplatin arm vs 14.7 months in the comparator (P = .12).
Another oxaliplatin trial presented to the FDA in March 2000, looking at chronomodulated 5-FU and leucovorin with or without oxaliplatin, showed no significant survival advantage for oxaliplatin.
"Overall survival has been the gold standard for regulatory approval of oncologic drugs," Dr. Haller said. Thus, results of the comparative trial of the Saltz and de Gramont regimens are awaited.
Oxaliplatin may also have a role as salvage therapy for patients who progress on first-line therapy with the Saltz regimen, which is now being used in 30% to 40% of patients with metastatic colorectal cancer, according to Dr. Haller. He mentioned two new trials of oxaliplatin as second-line therapy, both sponsored by Sanofi-Synthelabo Inc, the company that is developing oxaliplatin. In the first study, patients who have failed the Saltz regimen will be randomized to the de Gramont bolus/infusion regimen of 5-FU/leucovorin, oxaliplatin alone, or the de Gramont regimen of 5-FU/leucovorin plus oxaliplatin. In the second study, patients who have failed 5-FU/leucovorin will be randomized to receive oxaliplatin plus irinotecan or irinotecan alone.
"Oxaliplatin has shown consistent activity as salvage treatment for patients with colorectal cancer, primarily in patients who have progressed following 5-FU/leucovorin, not the Saltz regimen," Dr. Haller said. "It would be of interest to evaluate each of these strategies in a definitive way."
