Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC).

Reviewer: S. Jack Wei, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 1, 2003

Presenter: D Cunningham
Presenter's Affiliation: BOND Investigators
Type of Session: Scientific


    Cetuximab is a chimeric anti-EGFR monoclonal antibody that results in the blockade of EGF and TGF-alpha. The downstream results of this blockade results in modulation of reponse to chemotherapy, and effects on cell growth, differentiation, and apoptosis in preclinical studies. Previous trials with cetuximab have shown response rates of 20% when added to irinotecan and 10% when delivered alone. This randomized phase II study compares the effects of cetuximab with irinotecan to cetuximab alone for EGFR-positive, irinotecan-refractory MCRC.

Materials and Methods

  • 329 patients with EGFR-positive MCRC were enrolled.
  • Eligibility criteria included documented MCRC, performance status >=60, and documented disease progression within 30 days of the last dose of irinotecan.
  • Patients were randomized 2:1 to 2 arms: 1) cetuximab (400 mg/m2 x 1, then 250 mg/m2 weekly) + irinotecan at the same dose that was being delivered at initial disease progression or 2)cetuximab alone with the option to cross-over to Arm 1 in the event of disease progression.
  • 218 patients were randomized to Arm 1, 111 patients were randomized to Arm 2.


  • Arm 1 (combined arm) was superior to Arm 2 (cetuximab alone arm) with respect to disease control (55% vs. 32%, p=0.0001), response rate (23% vs. 11%, p=0.007), and median time to progression (4.1 mo vs. 1.5 mo, p<0.0001).
  • No difference was seen with regards to median survival between the 2 treatment arms.
  • The combination arm (Arm 1) had higher rates of grade 3 or 4 toxicity, particularly with regards to diarrhea and neutropenia.
  • 54 patients crossed over from Arm 2 to Arm 1 due to progressive disease.

Author's Conclusions

  • Cetuximab showed significant activity as a second-line agent both alone and in combination with irinotecan in this patient population.
  • Overall, cetuximab was well-tolerated.
  • Better response was seen with the combination of irinotecan and cetuximab compared to cetuximab alone.
  • The lack of survival benefit may be due to the high rate of cross-over between the two groups.

Clinical/Scientific Implications

    This drug has been under the microscope since the FDA did not approve the medication and the insueing Imclone scandle and SEC investigation. However, there has been strong scientific interest in this new targeted therapy throughout the controversy. The results of this study support a previous trial of C225 that was criticized for documentation and management reasons. There is much interest in this drug for its biologic targeting of a receptor that is overexpressed in a number of cancers. It is anticipated that this drug will be submitted to the FDA again for consideration of approval. A number of interesting studies with this drug are ongoing in a variety of disease sites with the results highly anticipated.

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