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


METHODS
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.
Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
Valentina
V
Pirazzoli
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.
Deborah
D
Ayeni
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Catherine B
CB
Meador
Department of Diagnostic Radiology and Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut.
Basavaraju G
BG
Sanganahalli
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.
Fahmeed
F
Hyder
Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York.
Elisa
E
de Stanchina
Department of Medicine, Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut.
Sarah B
SB
Goldberg
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.
William
W
Pao
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.
Katerina
K
Politi
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000077716:Afatinib; D000818:Animals; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004359:Drug Therapy, Combination / Q000379:methods; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000187:drug effects; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab