Abstract
<div>Abstract<p><b>Purpose:</b> The EGFR tyrosine kinase inhibitors (TKIs), erlotinib and afatinib, have transformed the treatment of advanced <i>EGFR</i>-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<sup>T790M</sup>). We previously found that the combination of the EGFR TKI afatinib and the EGFR antibody cetuximab could overcome EGFR<sup>T790M</sup>-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.</p><p><b>Experimental Design:</b> 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<sup>L858R</sup>-induced lung adenocarcinomas delayed tumor relapse and drug-resistance compared with single-agent TKIs.</p><p><b>Results:</b> 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 <i>EGFR<sup>T790M</sup></i> mutation and <i>Kras</i> mutations. Experiments in cell lines and xenografts confirmed that the afatinib plus cetuximab combination does not suppress the emergence of EGFR<sup>T790M</sup>.</p><p><b>Conclusions:</b> These results highlight the potential of afatinib plus cetuximab as an effective treatment strategy for patients with TKI-naïve <i>EGFR</i>-mutant lung cancer and indicate that clinical trial development in this area is warranted. <i>Clin Cancer Res; 22(2); 426–35. ©2015 AACR</i>.</p></div>
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
