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Clin Cancer Res. 2016 Jan 15;22(2):426-35. doi: 10.1158/1078-0432.CCR-15-0620. Epub 2015 Sep 4.

Afatinib plus Cetuximab Delays Resistance Compared to Single-Agent Erlotinib or Afatinib in Mouse Models of TKI-Naïve EGFR L858R-Induced Lung Adenocarcinoma.

Author information

1
Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
2
Experimental Pathology Graduate Program, Graduate School of Arts and Sciences, Yale University, New Haven, Connecticut. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
3
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
4
Department of Diagnostic Radiology and Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut.
5
Department of Diagnostic Radiology and Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut. Department of Biomedical Engineering, Yale University School of Engineering and Applied Science, New Haven, Connecticut.
6
Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Department of Medicine, Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.
8
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
9
Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. Department of Medicine, Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut. katerina.politi@yale.edu.

Abstract

PURPOSE:

The EGFR tyrosine kinase inhibitors (TKIs), erlotinib and afatinib, have transformed the treatment of advanced EGFR-mutant lung adenocarcinoma. However, almost all patients who respond develop acquired resistance on average approximately 1 year after starting therapy. Resistance is commonly due to a secondary mutation in EGFR (EGFR(T790M)). We previously found that the combination of the EGFR TKI afatinib and the EGFR antibody cetuximab could overcome EGFR(T790M)-mediated resistance in preclinical models. This combination has shown a 29% response rate in a clinical trial in patients with acquired resistance to first-generation TKIs. An outstanding question is whether this regimen is beneficial when used as first-line therapy.

EXPERIMENTAL DESIGN:

Using mouse models of EGFR-mutant lung cancer, we tested whether the combination of afatinib plus cetuximab delivered upfront to mice with TKI-naïve EGFR(L858R)-induced lung adenocarcinomas delayed tumor relapse and drug-resistance compared with single-agent TKIs.

RESULTS:

Afatinib plus cetuximab markedly delayed the time to relapse and incidence of drug-resistant tumors, which occurred in only 63.6% of the mice, in contrast to erlotinib or afatinib treatment where 100% of mice developed resistance. Mechanisms of tumor escape observed in afatinib plus cetuximab resistant tumors include the EGFR(T790M) mutation and Kras mutations. Experiments in cell lines and xenografts confirmed that the afatinib plus cetuximab combination does not suppress the emergence of EGFR(T790M).

CONCLUSIONS:

These results highlight the potential of afatinib plus cetuximab as an effective treatment strategy for patients with TKI-naïve EGFR-mutant lung cancer and indicate that clinical trial development in this area is warranted.

PMID:
26341921
PMCID:
PMC4715986
DOI:
10.1158/1078-0432.CCR-15-0620
[Indexed for MEDLINE]
Free PMC Article

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