Cetuximab (C225) Plus Irinotecan (CPT-11) Plus Infusional 5FU/Folinic Acid (FA) is Safe and Active in Metastatic Colorectal Cancer (MCRC) that Expresses Epidermal Growth Factor Receptor (EGFR)

Reviewer: Thomas Dilling, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 18, 2002

Presenter: P. Schoffski
Presenter's Affiliation: Hannover Medical School (Hannover, Germany)
Type of Session: Poster


  • EGFR is a transmembrane glycoprotein receptor overexpressed in many human solid tumors.
  • EGFR is a mediator of intracellular signals involved in cancer growth/metastatic spread.
  • C225 is one of a few monoclonal antibodies directed against the extracellular domain of EGFR.
  • Data presented at ASCO 2001 demonstrated that C225 and irinotecan (CPT-11) achieved objective response in some patients who were CPT-11-refractory.
  • These German researchers performed a phase I/II study of C225, utilizing a chemotherapy regime commonly employed in Europe.

Materials and Methods

  • A total of 27 patients have so far been enrolled at a total of 3 centers. Of these, 21 patients had tumors which were found to be EGFR-positive.
  • Two of these 21 patients were later excluded from the study secondary to treatment protocol violations.
  • Data on the remaining 19 patients are presented here.
  • Patients had histologically confirmed metastatic colorectal cancer and were chemotherapy naive, except for adjuvant 5-FU-based therapy if it was terminated >6 months prior to enrollment in this study.
  • Median Karnofsky Performance Status (KPS) was listed as 100, with a range of 70-100.
  • Prior treatment with monoclonal antibodies was an exclusion criterion.
  • The initial treatment regimen employed was as follows: patients received a bolus infusion of C225 (400 mg/m2), CPT-11 (80 mg/m2), and folinic acid (500 mg/m2).
  • Patients were then randomized to 5-FU (low-dose of 1500 mg/m2 over 24 hours) or high-dose (2000 mg/m2 over 24 hours).
  • C225 continued with weekly infusions.
  • CPT-11 was given on days 1,8,15,22,29, and 36, q7 weeks.
  • Patients were evaluated for dose-limiting toxicities at the end of one of these cycles of treatment.
  • Dose limiting toxicities (DLT) were defined as grade 4 leukopenia or neutropenia; grade 3 leukopenia or neutropenia with complications (fever); grade 3 thrombocytopenia; grade 4 skin toxicity; or grade 3 diarrhea, mucositis, or hepatotoxicity.


  • The low-dose 5-FU patients have undergone a median of 4 cycles of treatment, and the high-dose 5-FU patients have undergone a median of 2 cycles.
  • 2/6 patients in the low-dose group received dose modifications after cycle 1, though no patients in the low-dose group had dose-limiting events.
  • Similarly, 7/13 patients in the high-dose 5-FU group required dose reductions, though only 3 are listed as having dose-limiting toxicities.
  • "Characteristic toxicities" for the low-dose group included grade 3/4 diarrhea in 0 patients and skin grade 3/4 for 1 patient.
  • In the high-dose arm, "characteristic toxicities" included grade 3/4 diarrhea in 3 patients and grade 3/4 skin toxicities in 2 patients.
  • The skin toxicity was a peculiar, though previously-described and anticipated, acneiform skin eruption, related to Cetuximab.
  • Patients have been evaluated for response. Thus far, 1/19 patients has had a complete response and 8/19 have partial response (all as based on imaging studies). 3/19 have had a clinical partial response, though imaging studies are still pending.
  • Overall response in the low-dose gorup is 5/6 patients, and 7/13 in the high-dose group (if the nonconfirmed partial responses are included).

Author's Conclusions

  • C225 and CPT-11 with infusional 5-FU/FA is safe and feasible in patients with EGFR-positive metastatic colorectal cancer.
  • Patients in the high-dose group had greater incidence of dose reduction/treatment delays.
  • The DLT was diarrhea.
  • Skin toxicity related to C225 was common, though predominantly mild (grade 1/2).
  • Based upon the safety profile, the authors recommend the low-dose arm for further evaluation.

Clinical/Scientific Implications

  • This study shows an overall objective response rate of 63% for all patients.
  • The author states that this chemo regime alone (without use of C225) has published results of 30-40% objective response.
  • The KPS of these patients with metastatic colon cancer was extremely high, however, reflecting a carefully selected subgroup of patients. It is unclear whether these data could be generalized to all patients with metastatic colon cancer.
  • For this reason, a phase III trial should be done, to determine whether C225 leads to improvement in response rate or survival in patients. Such trials are currently under consideration.

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