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Dual Inhibition of the Epidermal Growth Factor Receptor Pathway with Cetuximab and Erlotinib: A Phase I Study in Patients with Advanced Solid Malignancies

^aHelen F. Graham Cancer Center, Christiana Care, Newark, Delaware, USA; ^bThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA; ^cBristol-Myers Squibb Company, Princeton, New Jersey, USA; ^dOSI Oncology, Melville, New York, USA; ^eBristol-Myers Squibb Company, Wallingford, Connecticut, USA

Key Words. Cetuximab • Erlotinib • Phase I • Solid malignancies

Correspondence: Correspondence: Michael J. Guarino, M.D., Medical Oncology Hematology Consultants, PA, Helen F. Graham Cancer Center, 4701 Ogletown-Stanton Road, Suite 2200, Newark, Delaware 19713, USA. Telephone: 302-366-1200; Fax: 302-366-1700; e-mail: mguarino{at}cbg.org

Received May 29, 2008; accepted for publication December 1, 2008.

Disclosures: Michael J. Guarino: None; Charles J. Schneider: None; Martha A. Hosford: None; Julie R. Brahmer: Consultant/advisory role: Abbott, Cephalon, Genentech, Eli Lilly, AstraZeneca; Charles M. Rudin: Consultant/advisory role: CTI Pharmaceuticals, Amgen; Research funding/contracted research: Pharmion; Friedrich Graf Finckenstein: Employment/leadership position: Bristol-Myers Squibb; Ownership interest: Bristol-Myers Squibb; Robyn E. Philip-Norton: Employment/leadership position: OSI Pharmaceuticals; Haolan Lu: Employment/leadership position: Bristol-Myers Squibb; Martin R. Weber: Employment/leadership position: Bristol-Myers Squibb; Ownership interest: Bristol-Myers Squibb; David S. Ettinger: Consultant/advisory role: AstraZeneca, Bristol-Myers Squibb; Eli Lilly, GlaxoSmithKline, Merck, MGI Pharma, Pfizer, Sanofi-Aventis; Research funding/contracted research: Bayer, Genentech, Pharmion.

Purpose. To determine the optimal dose of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab that can be safely administered in combination with a standard daily dose of erlotinib in patients with advanced solid malignancies.

Patients and Methods. Patients with advanced solid malignancies who had failed standard chemotherapies received escalating doses of cetuximab without a loading dose (100, 200, 250 mg/m² i.v. weekly) in combination with a fixed dose of erlotinib (150 mg daily orally) until disease progression or unacceptable toxicity.

Results. Twenty-two patients were treated, including 14 patients (64%) with non-small cell lung cancer. Twenty patients received combination treatment at the highest dose level for a median of 5.5 weeks (range, 1–31 weeks). One dose-limiting toxicity was observed: grade 3 skin rash. Overall, the most common adverse events (any grade, grade 3/4) were consistent with the safety profiles of the individual drugs: acneform rash (100%, 9%), diarrhea (77%, 5%), and hypomagnesemia (59%, 12%). Seven of 18 evaluable patients (38.9%) had stable disease lasting for a median of 16.6 weeks (range, 6.1–25.1 weeks).

Conclusion. Dual EGFR inhibition with cetuximab and erlotinib is feasible; the observed toxicities were manageable and consistent with the safety profiles of the individual drugs. The recommended doses for phase II studies are 250 mg/m² i.v. weekly for cetuximab and 150 mg daily orally for erlotinib.