AACR: Cetuximab Shows Survival Edge as Third-Line Colorectal Cancer Therapy

April 17, 2007

LOS ANGELES -- Cetuximab (Erbitux) extended median survival by about six weeks as a third-line monotherapy for refractory metastatic colorectal cancer, but did not extend survival when used as a second-line agent in combination with irinotecan (Camptosar).

LOS ANGELES, April 17 -- Cetuximab (Erbitux) extended median survival by about six weeks as a third-line monotherapy for refractory metastatic colorectal cancer.

But as a second-line therapy in combination with irinotecan (Camptosar), the addition of centuximab but did not extend survival over irinotecan monotherapy.

Those results, reported at the American Association for Cancer Research meeting here, emerged from a pair of phase III trials in patients with epidermal growth factor receptor (EGFR)-positive disease.

The FDA approved cetuximab on the basis of phase II data, but required that phase III trials be done, said Larry Norton, M.D., of Memorial Sloan-Kettering Cancer Center in New York. These two trials -- both of which had overall survival as FDA-mandated primary endpoints -- are the result of that order. Dr. Norton moderated the session.

Among patients who failed 5-FU or capecitabine therapy as well as irinotecan and oxaliplatin (Eloxatin), cetuximab on top of best supportive care was associated with a median survival of 6.1 months versus 4.6 months those randomized to the best medical care arm (HR of 0.77, 95% CI 0.64 to 0.92; P=0.005), said Derek J. Jonker, M.D., of the University of Ottawa.

He said the findings confirm "cetuximab as the first biologic targeted therapy that -- as a single agent -- demonstrated improvement in both time to progression and overall survival in patients with chemotherapy-refractory colorectal cancer."

In the 1,298-patient Eribitux Plus Irinotecan in Colorectal Cancer (EPIC) trial, which assessed cetuximab as second line therapy in combination with irinotecan versus irinotecan monotherapy, there were highly significant improvements in progression-free survival and a quadrupling of the response rate -- but no improvement in the primary endpoint, which was overall survival.

Alberto F. Sobrero, M.D., of Hospital San Marino in Genoa, Italy, made no attempt to mask his frustration with the results as he commented: "Ugh," when he displayed the overall survival data.

Dr. Sobrero said the lack of an overall survival benefit was most likely due to the high crossover rate after the trial ended. Fifty-seven percent of placebo patients crossed over to cetuximab "and so they are getting the survival benefit of cetuximab that was found in the Canadian study."

He said that a post hoc analysis that removed the crossover patients from equation found there was a significant survival benefit. But even as he reported that benefit, Dr. Sobrero cautioned that a post hoc analysis "while relevant is not really good and should only be considered hypothesis-generating."

Richard Goldberg, M.D., of the University of North Carolina said the real take home message from EPIC was the increase in progression-free survival (3.98 months versus 2.56 months P

EPIC randomized 648 patients to cetuximab (400 mg/m2 loading dose of cetuximab followed by week infusion of 250 mg/m2) plus irinotecan 350 mg/m2 once every three weeks and 650 patients to irinotecan 350 mg/m2 once every three weeks.

Among the findings:

  • 76.3% of the cetuximab patients developed acneiform rash, which is associated with response, Dr. Sebrero said only 4% of 5% patients without rash respond to cetuximab while 55% of patients with rash respond.
  • Cetuximab patients had more cycles of therapy -- an average of five cycles versus three cycles and also had more toxicitities.
  • The cetuximab/irinotecan therapy was associated with a 16.36% response rate versus 4.15% response for irinotecan monotherapy (P