Safety, Pharmacokinetics, and Activity of ABX-EGF, a Fully Human Anti–Epidermal Growth Factor Receptor Monoclonal Antibody in Patients With Metastatic Renal Cell Cancer

To determine the antitumor activity of ABX-EGF, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFr), in previously treated patients with metastatic renal cell carcinoma, and to characterize its toxicity, immunogenicity, pharmacokinetics, and pharmacodynamics. The antitum...

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Bibliographic Details
Published in:	Journal of clinical oncology Vol. 22; no. 15; pp. 3003 - 3015
Main Authors:	ROWINSKY, Eric K, SCHWARTZ, Garry H, ARENAS, Rosalin, FOON, Kenneth A, SCHWAB, Gisela, DUTCHER, Janice, GOLLOB, Jared A, THOMPSON, John A, VOGELZANG, Nicholas J, FIGLIN, Robert, BUKOWSKI, Ronald, HAAS, Naomi, LOCKBAUM, Pamela, LI, Yu-Ping
Format:	Journal Article
Language:	English
Published:	Baltimore, MD American Society of Clinical Oncology 01-08-2004 Lippincott Williams & Wilkins
Subjects:	Alkaline Phosphatase - blood Antibodies, Anti-Idiotypic - blood Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal - immunology Antibodies, Monoclonal - pharmacokinetics Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal - toxicity Biological and medical sciences Carcinoma, Renal Cell - drug therapy Carcinoma, Renal Cell - metabolism Drug Eruptions - etiology Female Follow-Up Studies Hemoglobins - analysis Humans Immunohistochemistry Kidney Neoplasms - drug therapy Kidney Neoplasms - metabolism Kidneys Male Medical sciences Middle Aged Neoplasm Metastasis Nephrology. Urinary tract diseases Safety Tumors Tumors of the urinary system Kidney disease Human Urinary system disease Activity Malignant tumor Monoclonal antibody Metastasis Epidermal growth factor receptor Growth factor receptor Cancerology Epidermal growth factor Kidney cancer Advanced stage Pharmacokinetics Tumor cell
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Summary:	To determine the antitumor activity of ABX-EGF, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFr), in previously treated patients with metastatic renal cell carcinoma, and to characterize its toxicity, immunogenicity, pharmacokinetics, and pharmacodynamics. The antitumor activity, as well as the toxicity, pharmacokinetics, pharmacodynamics, and immunogenicity of ABX-EGF, were assessed. Eighty-eight patients were treated with ABX-EGF doses of 1.0, 1.5, 2.0, or 2.5 mg/kg weekly with no loading dose. EGFr immunostaining was performed on 76 tumor biopsy specimens (86%), and 69 (91%) scored positive. Major responses occurred in three patients, and two patients had minor responses. Forty-four patients (50%) also had stable disease at their first 8-week assessment, and the median progression-free survival (PFS) was 100 days (95% CI, 58 to 140 days). Low hemoglobin and high alkaline phosphatase predicted for short PFS. The principal toxicity, an acneiform rash, occurred in 68%, 95%, 87%, and 100% of patients who received at least three doses of ABX-EGF at 1.0, 1.5, 2.0, and 2.5 mg/kg/wk, respectively. A trend indicated that the severity of the rash may relate to PFS. No human antihuman antibodies were detected. ABX-EGF pharmacokinetics fit a model that incorporated both linear and saturable EGFr-mediated clearance mechanisms, and interindividual variability was low. At 2.5 mg/kg/wk, ABX-EGF concentrations throughout treatment exceeded those estimated to saturate nonlinear clearance and inhibit xenograft growth by 90%. ABX-EGF was generally well tolerated. The objective response rate was low in previously treated patients with metastatic renal cell carcinoma. Although skin rash may be a pharmacodynamic marker of drug action, its potential as a surrogate marker of clinical benefit requires further evaluation.
ISSN:	0732-183X 1527-7755
DOI:	10.1200/JCO.2004.11.061