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

J Thorac Oncol. 2008 Mar;3(3):258-64. doi: 10.1097/JTO.0b013e3181653d1b.


Purpose: 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.

Patients and 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.

Conclusion: 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.

Publication types

  • Clinical Trial, Phase I
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / administration & dosage*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cetuximab
  • DNA, Neoplasm / genetics
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Follow-Up Studies
  • Gefitinib
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoglobulin G / immunology
  • Immunohistochemistry
  • Infusions, Intravenous
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Male
  • Middle Aged
  • Polymerase Chain Reaction
  • Protein Kinase Inhibitors / administration & dosage*
  • Quinazolines / administration & dosage*
  • Retrospective Studies
  • Sequence Analysis, DNA
  • Treatment Outcome


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • DNA, Neoplasm
  • Immunoglobulin G
  • Protein Kinase Inhibitors
  • Quinazolines
  • ErbB Receptors
  • Cetuximab
  • Gefitinib