title: Dual inhibition of the epidermal growth factor receptor with cetuximab, an IgG1 monoclonal antibody, and gefitinib, a tyrosine kinase inhibitor, in patients with refractory non-small cell lung cancer (NSCLC): a phase I study.
abstract: OBJECTIVE
  To determine the optimal doses of the antiepidermal growth factor receptor (anti-EGFR) monoclonal antibody cetuximab and the EGFR tyrosine kinase inhibitor gefitinib when administered as a combination for patients with advanced/metastatic non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.
  
  
  METHODS
  Patients with advanced/metastatic NSCLC treated with prior platinum-based chemotherapy received escalating doses of weekly cetuximab (100, 200, and 250 mg/m(2), IV) and fixed doses of gefitinib (250 mg/d, PO) until disease progression or unacceptable toxicity. Available tumor samples were analyzed for EGFR expression, EGFR gene copy number and mutations, and K-RAS mutations.
  
  
  RESULTS
  Thirteen patients were enrolled in three cohorts. Treatment was generally well-tolerated at all doses. One grade 3 headache, observed on the first treatment cycle was initially considered dose-limiting toxicity (DLT); this event was eventually determined to be caused by a brain metastasis, not toxicity. Three cases of grade 3/4 hypomagnesemia and 1 case of grade 3 skin rash occurred in the highest-dose cohort. Grade 1/2 infusion reactions occurred in three patients without requiring treatment discontinuation. Four patients (31%) achieved stable disease, no responses were observed. None of the patients had EGFR mutations or gene amplification in their tumor samples.
  
  
  CONCLUSIONS
  Dual EGFR inhibition with cetuximab and gefitinib is feasible; the combination can be safely administered and may have modest activity in advanced/metastatic NSCLC. Cetuximab 250 mg/m(2) weekly IV and gefitinib 250 mg/d PO is the recommended phase II dose, although the potential for late-onset hypomagnesemia warrants close monitoring of patients receiving this combined dosage.
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Ramalingam
authors.forename: Judy
authors.initials: J
authors.lastname: Forster
authors.forename: Cynthia
authors.initials: C
authors.lastname: Naret
authors.forename: Terry
authors.initials: T
authors.lastname: Evans
authors.forename: Matt
authors.initials: M
authors.lastname: Sulecki
authors.forename: Haolan
authors.initials: H
authors.lastname: Lu
authors.forename: Paola
authors.initials: P
authors.lastname: Teegarden
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weber
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000068818:Cetuximab; D004273:DNA, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D000077156:Gefitinib; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007074:Immunoglobulin G; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D000068818:Cetuximab; D000077156:Gefitinib