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).
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.
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.
Oncolink's ASCO Coverage made possible by an unrestricted Educational Grant from Bristol-Myers Squibb Oncology.
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