Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations

Hanako Hasegawa, Hiroyuki Yasuda, Junko Hamamoto, Keita Masuzawa, Tetsuo Tani, Shigenari Nukaga, Toshiyuki Hirano, Keigo Kobayashi, Tadashi Manabe, Hideki Terai, Shinnosuke Ikemura, Ichiro Kawada, Katsuhiko Naoki, Kenzo Soejima

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)146-152
Number of pages7
JournalLung Cancer
Volume127
DOIs
Publication statusPublished - 2019 Jan 1

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Insertional Mutagenesis
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Exons
Therapeutics
Mutation
BIBW 2992
osimertinib
Cetuximab
Investigational Therapies
Exanthema
Protein-Tyrosine Kinases
Weight Loss
Lung Neoplasms
Neoplasms

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 journalArticle

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. / Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations. In: Lung Cancer. 2019 ; Vol. 127. pp. 146-152.
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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

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