Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer.

Abstract

PURPOSE:

This preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC).

PATIENTS AND METHODS:

The activity and mechanism of action of the combination of cetuximab plus erlotinib were investigated in vitro in colorectal cancer cell lines. In the clinical study, patients with chemotherapy-refractory mCRC were treated with cetuximab 400 mg/m(2) as a loading dose and then weekly cetuximab 250 mg/m(2) with erlotinib 100 mg orally daily. The primary end point was response rate (RR), which was evaluated separately in KRAS wild-type (WT) versus KRAS mutant tumors. Secondary end points included toxicity, progression-free survival (PFS), and overall survival. Target accrual was 50 patients, with a one-stage design.

RESULTS:

Preclinical studies demonstrated synergistic activity of cetuximab and erlotinib cotreatment on growth inhibition of colon cancer cell lines both as a result of enhanced inhibition of the epidermal growth factor receptor pathway and differential effects on STAT3. In the clinical study, 50 patients were enrolled, with 48 patients evaluable for response. The overall RR was 31% (95% CI, 26% to 57%), with a median PFS of 4.6 months (95% CI, 2.8 to 5.6 months). RR was 41% (95% CI, 26% to 57%) in KRAS WT tumors, with a median PFS of 5.6 months (95% CI, 2.9 to 5.6 months). There was no response in 11 patients with KRAS mutations. Frequent grade 3 and 4 toxicities were rash (48%), hypomagnesaemia (18%), and fatigue (10%).

CONCLUSION:

The combination of cetuximab and erlotinib synergistically inhibits growth of colon cancer cell lines, achieves promising efficacy in patients with KRAS WT mCRC, and merits evaluation in further randomized studies.

• Authors: Andrew J Weickhardt, Tim J Price, Geoff Chong, Val Gebski, Nick Pavlakis, Terrance G Johns, Arun Azad, Effie Skrinos, Kate Fluck, Alexander Dobrovic, Renato Salemi, Andrew M Scott, John M Mariadason, Niall C Tebbutt
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 30 Issue 13 Pg. 1505-12 (May 01 2012) ISSN: 1527-7755 [Electronic] United States
• PMID: 22412142 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• KRAS protein, human
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Quinazolines
• STAT3 Transcription Factor
• STAT3 protein, human
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins p21(ras)
• ras Proteins
• Cetuximab

Topics

• Adult
• Aged
• Aged, 80 and over
• Analysis of Variance
• Antibodies, Monoclonal (administration & dosage)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Australia
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cetuximab
• Colorectal Neoplasms (drug therapy, enzymology, genetics, mortality, pathology)
• Disease-Free Survival
• Drug Resistance, Neoplasm
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Erlotinib Hydrochloride
• Female
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Molecular Targeted Therapy
• Mutation
• Protein Kinase Inhibitors (administration & dosage)
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins p21(ras)
• Quinazolines (administration & dosage)
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction (drug effects)
• Time Factors
• Transfection
• Treatment Outcome
• ras Proteins (genetics)