Cetuximab (IMC-C225) plus Weekly Irinotecan (CPT-11), Fluorouracil (5FU), and Leucovorin (LV) in Colorectal Cancer (CRC) that Expresses the Epidermal Growth Factor Receptor (EGFR)

Reviewer: Mary Kara Bucci, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 19, 2002

Presenter: Arthur Rosenberg
Presenter's Affiliation: The Bendheim Cancer Center of Greenwich Hospital, Connecticut
Type of Session: Poster

Background

Previous studies have shown that increased expression of Epidermal Growth Factor Receptor (EGFR) conveys an unfavorable prognosis in multitude of cancers, including colorectal cancer. Cetuximab (IMC-C225) is a humanized monoclonal antibody that binds selectively to EGFR, thereby inhibiting the binding of the Epidermal Growth Factor to this receptor. A previous trial demonstrated a 22.5 % response rate to Cetuximab plus Irinotecan (CPT-11) in 120 patients with CPT-11 refractory, EGFR-positive colorectal cancer. This response appeared independent of EGFR over-expression. This current study builds upon those findings by combining Cetuximab with weekly CPT-11, 5FU, and LV, a standard regimen, for metastatic colorectal cancer with expression of EGFR.

Materials and Methods

29 patients with measurable metastatic colorectal cancer and immunohistochemical evidence of EGFR expression were enrolled on this trial.
Patients were treated with a combination of weekly CPT-11, 5FU, and LV on the first 4 weeks of a six week cycle. Cetuximab was given weekly for all 6 weeks.
The initial dose of Cetuximab was 400 mg/m2 infused over 120 minutes. Subsequent doses were 250 mg/m2 and were infused over 60 min.
CPT-11, 125 mg/m2, was given 1 hour after the Cetuximab infusion. This was immediately followed by LV, 20 mg/m2, and 5FU, 500 mg/m2. All drugs were given intravenously.
After the first 6 patients were enrolled on this trial, new guidelines for the administration of CPT-11/5FU/LV were published (Saltz, N Eng J Med. 2000;343:905-14), outlining recommendations for dose reductions according to patient toxicity. Doses in this study were reduced according to these guidelines.

Results

7 patients reported serious adverse events that were considered to be related to Cetuximab, including thrombophlebitis (7%), gastroenteritis (3%), neutropenia (3%), dehydration (3%), pulmonary embolus (3%), and acute renal failure (3%).
Adverse events most frequently reported, regardless of relation to Cetuximab, were: acne (76%), nausea (69%), diarrhea (69%), mucositis (59%), neutropenia (59%), asthenia (55%), vomiting (45%), weight loss (35%), fever (35%) and anorexia (35%).
Grade 3-4 adverse events included diarrhea (28%), neutropenia (28%), acne (21%), asthenia (10%), and dehydration (10%).
One patient died from sepsis during the study.
9 patients were discontinued from the study due to progressive disease, one patient was discontinued due to a serious adverse effect, and one was discontinued for an unknown reason. 17 patients are undergoing continuing treatement.
14 of 29 patients (48%) have had a partial response
12 patients have had stable disease (3 pts, 10%) or a minor response (9 pts, 31%), and 2 patients (7%) have progessed. One patient is not evaluable.

Author's Conclusions

The authors conclude that addition of Cetuximab to CPT-11/5FU/LV is safe and tolerable, with vigilant monitoring.
Most patients required a dose reduction of CPT-11.
The authors recommend further investigation of Cetuximab, with reduced doses of CPT-11 (100 mg/m2) and 5FU (400 mg/m2).

Clinical/Scientific Implications

This study is one of several presented at this meeting demonstrating the relative safety and efficacy of Cetuximab in a variety of cancers with EGFR expression. The size of this study was limited and dose reductions were required, however the 48% response rate is encouraging. Further investigation is indicated.

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