Abstract
Objectives: Epidermal growth factor receptor (EGFR) mutation-positive lung cancer accounts for a significant subgroup of non-small cell lung cancers (NSCLC). Approximately 4–10% of EGFR mutations in NSCLC are EGFR exon 20 insertion mutations, which are reportedly associated with resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. NSCLC patients carrying these mutations are rarely treated with EGFR-TKIs. The purpose of this study was to evaluate the efficacy of afatinib or osimertinib plus cetuximab combination therapy in experimental NSCLC models with EGFR exon 20 insertion mutations. Materials and methods: The EGFR mutations examined in this study were A763_Y764insFQEA, Y764_V765insHH, A767_V769dupASV, and D770_N771insNPG. Ba/F3 cells constitutively expressing wild type or mutated EGFR were used to determine the efficacy of afatinib or osimertinib plus cetuximab combination therapy in vitro. To determine the efficacy of the combination therapy in vivo, female BALB/c-nu mice were injected subcutaneously with 1 million Ba/F3 cells carrying EGFR A767_V769dupASV or Y764_V765insHH. Results: We observed a mild but significant (P < 0.05) additive effect of the combination therapy against several EGFR exon 20 insertion mutations in vitro. Regarding EGFR A767_V769dupASV and EGFR Y764_V765insHH, cetuximab and afatinib single treatment did not induce significant inhibition of tumor formation; however, afatinib plus cetuximab combination treatment induced significant (P < 0.05) tumor growth inhibition without significant body weight loss or skin rash. Conclusion: The combination therapy induced a more potent inhibitory effect against several EGFR exon 20 insertion mutations than either therapy alone. Cetuximab can potentially increase the efficacy of afatinib or osimertinib in NSCLC with EGFR exon 20 insertion mutations.
| Original language | English |
|---|---|
| Pages (from-to) | 146-152 |
| Number of pages | 7 |
| Journal | Lung Cancer |
| Volume | 127 |
| DOIs | |
| Publication status | Published - 2019 Jan 1 |
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Keywords
- Afatinib
- Cetuximab
- EGFR exon 20 insertion mutations
- EGFR tyrosine kinase inhibitor
- Lung cancer
ASJC Scopus subject areas
- Oncology
- Pulmonary and Respiratory Medicine
- Cancer Research
Cite this
Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations. / Hasegawa, Hanako; Yasuda, Hiroyuki; Hamamoto, Junko; Masuzawa, Keita; Tani, Tetsuo; Nukaga, Shigenari; Hirano, Toshiyuki; Kobayashi, Keigo; Manabe, Tadashi; Terai, Hideki; Ikemura, Shinnosuke; Kawada, Ichiro; Naoki, Katsuhiko; Soejima, Kenzo.
In: Lung Cancer, Vol. 127, 01.01.2019, p. 146-152.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations
AU - Hasegawa, Hanako
AU - Yasuda, Hiroyuki
AU - Hamamoto, Junko
AU - Masuzawa, Keita
AU - Tani, Tetsuo
AU - Nukaga, Shigenari
AU - Hirano, Toshiyuki
AU - Kobayashi, Keigo
AU - Manabe, Tadashi
AU - Terai, Hideki
AU - Ikemura, Shinnosuke
AU - Kawada, Ichiro
AU - Naoki, Katsuhiko
AU - Soejima, Kenzo
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Objectives: Epidermal growth factor receptor (EGFR) mutation-positive lung cancer accounts for a significant subgroup of non-small cell lung cancers (NSCLC). Approximately 4–10% of EGFR mutations in NSCLC are EGFR exon 20 insertion mutations, which are reportedly associated with resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. NSCLC patients carrying these mutations are rarely treated with EGFR-TKIs. The purpose of this study was to evaluate the efficacy of afatinib or osimertinib plus cetuximab combination therapy in experimental NSCLC models with EGFR exon 20 insertion mutations. Materials and methods: The EGFR mutations examined in this study were A763_Y764insFQEA, Y764_V765insHH, A767_V769dupASV, and D770_N771insNPG. Ba/F3 cells constitutively expressing wild type or mutated EGFR were used to determine the efficacy of afatinib or osimertinib plus cetuximab combination therapy in vitro. To determine the efficacy of the combination therapy in vivo, female BALB/c-nu mice were injected subcutaneously with 1 million Ba/F3 cells carrying EGFR A767_V769dupASV or Y764_V765insHH. Results: We observed a mild but significant (P < 0.05) additive effect of the combination therapy against several EGFR exon 20 insertion mutations in vitro. Regarding EGFR A767_V769dupASV and EGFR Y764_V765insHH, cetuximab and afatinib single treatment did not induce significant inhibition of tumor formation; however, afatinib plus cetuximab combination treatment induced significant (P < 0.05) tumor growth inhibition without significant body weight loss or skin rash. Conclusion: The combination therapy induced a more potent inhibitory effect against several EGFR exon 20 insertion mutations than either therapy alone. Cetuximab can potentially increase the efficacy of afatinib or osimertinib in NSCLC with EGFR exon 20 insertion mutations.
AB - Objectives: Epidermal growth factor receptor (EGFR) mutation-positive lung cancer accounts for a significant subgroup of non-small cell lung cancers (NSCLC). Approximately 4–10% of EGFR mutations in NSCLC are EGFR exon 20 insertion mutations, which are reportedly associated with resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. NSCLC patients carrying these mutations are rarely treated with EGFR-TKIs. The purpose of this study was to evaluate the efficacy of afatinib or osimertinib plus cetuximab combination therapy in experimental NSCLC models with EGFR exon 20 insertion mutations. Materials and methods: The EGFR mutations examined in this study were A763_Y764insFQEA, Y764_V765insHH, A767_V769dupASV, and D770_N771insNPG. Ba/F3 cells constitutively expressing wild type or mutated EGFR were used to determine the efficacy of afatinib or osimertinib plus cetuximab combination therapy in vitro. To determine the efficacy of the combination therapy in vivo, female BALB/c-nu mice were injected subcutaneously with 1 million Ba/F3 cells carrying EGFR A767_V769dupASV or Y764_V765insHH. Results: We observed a mild but significant (P < 0.05) additive effect of the combination therapy against several EGFR exon 20 insertion mutations in vitro. Regarding EGFR A767_V769dupASV and EGFR Y764_V765insHH, cetuximab and afatinib single treatment did not induce significant inhibition of tumor formation; however, afatinib plus cetuximab combination treatment induced significant (P < 0.05) tumor growth inhibition without significant body weight loss or skin rash. Conclusion: The combination therapy induced a more potent inhibitory effect against several EGFR exon 20 insertion mutations than either therapy alone. Cetuximab can potentially increase the efficacy of afatinib or osimertinib in NSCLC with EGFR exon 20 insertion mutations.
KW - Afatinib
KW - Cetuximab
KW - EGFR exon 20 insertion mutations
KW - EGFR tyrosine kinase inhibitor
KW - Lung cancer
UR - http://www.scopus.com/inward/record.url?scp=85057535617&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85057535617&partnerID=8YFLogxK
U2 - 10.1016/j.lungcan.2018.11.039
DO - 10.1016/j.lungcan.2018.11.039
M3 - Article
VL - 127
SP - 146
EP - 152
JO - Lung Cancer
JF - Lung Cancer
SN - 0169-5002
ER -