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

Suresh Ramalingam, Judy Forster, Cynthia Naret, Terry Evans, Matt Sulecki, Haolan Lu, Paola Teegarden, Martin R. Weber, Chandra Belani

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

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, 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 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.

Original languageEnglish (US)
Pages (from-to)258-264
Number of pages7
JournalJournal of Thoracic Oncology
Volume3
Issue number3
DOIs
StatePublished - Jan 1 2008

Fingerprint

Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Immunoglobulin G
Monoclonal Antibodies
Platinum
Mutation
erbB-1 Genes
Drug Therapy
Gene Dosage
Growth Factor Receptors
Gene Amplification
Physiologic Monitoring
Exanthema
Headache
Disease Progression
gefitinib
Cetuximab
Neoplasms
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

@article{a754fd979d9e4161a7a062669bd27847,
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 = "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, 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 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.",
author = "Suresh Ramalingam and Judy Forster and Cynthia Naret and Terry Evans and Matt Sulecki and Haolan Lu and Paola Teegarden and Weber, {Martin R.} and Chandra Belani",
year = "2008",
month = "1",
day = "1",
doi = "10.1097/JTO.0b013e3181653d1b",
language = "English (US)",
volume = "3",
pages = "258--264",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "3",

}

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. / Ramalingam, Suresh; Forster, Judy; Naret, Cynthia; Evans, Terry; Sulecki, Matt; Lu, Haolan; Teegarden, Paola; Weber, Martin R.; Belani, Chandra.

In: Journal of Thoracic Oncology, Vol. 3, No. 3, 01.01.2008, p. 258-264.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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)

T2 - A phase I study

AU - Ramalingam, Suresh

AU - Forster, Judy

AU - Naret, Cynthia

AU - Evans, Terry

AU - Sulecki, Matt

AU - Lu, Haolan

AU - Teegarden, Paola

AU - Weber, Martin R.

AU - Belani, Chandra

PY - 2008/1/1

Y1 - 2008/1/1

N2 - 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, 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 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.

AB - 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, 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 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.

UR - http://www.scopus.com/inward/record.url?scp=43249110958&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=43249110958&partnerID=8YFLogxK

U2 - 10.1097/JTO.0b013e3181653d1b

DO - 10.1097/JTO.0b013e3181653d1b

M3 - Article

C2 - 18317068

AN - SCOPUS:43249110958

VL - 3

SP - 258

EP - 264

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

SN - 1556-0864

IS - 3

ER -