2. Academic Validation
  3. Efficacy of EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer with EGFR exon 19 insertions: clinical-genomic, preclinical analysis through LC-SCRUM-Asia (multi-institutional genomic screening registry)

Efficacy of EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer with EGFR exon 19 insertions: clinical-genomic, preclinical analysis through LC-SCRUM-Asia (multi-institutional genomic screening registry)

  • Lung Cancer. 2025 Apr:202:108479. doi: 10.1016/j.lungcan.2025.108479.
Yuji Uehara 1,  Hiroki Izumi 2,  Ikei S Kobayashi 3,  Shingo Matsumoto 4,  Yukio Hosomi 5,  Takae Okuno 6,  Jun Sugisaka 7,  Naoto Takase 8,  Kageaki Taima 9,  Shinichi Sasaki 10,  Shuhei Teranishi 11,  Shingo Miyamoto 12,  Masahide Mori 13,  Chiho Nakashima 14,  Shuichi Asano 15,  Hajime Oi 4,  Tetsuya Sakai 4,  Yuji Shibata 4,  Hibiki Udagawa 4,  Eri Sugiyama 4,  Kaname Nosaki 4,  Shigeki Umemura 4,  Yoshitaka Zenke 4,  Kiyotaka Yoh 4,  Sadakatsu Ikeda 16,  Daniel B Costa 3,  Susumu S Kobayashi 17,  Koichi Goto 4
Affiliations

Affiliations

  • 1 Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan; Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan; Department of Precision Cancer Medicine, Center for Innovative Cancer Treatment, Tokyo Medical and Dental University, Tokyo, Japan.
  • 2 Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: hiroizum@east.ncc.go.jp.
  • 3 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
  • 4 Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
  • 5 Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
  • 6 Division of Medical Oncology & Respiratory Medicine, Department of Internal Medicine, Shimane University Faculty of Medicine, Izumo, Japan.
  • 7 Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan.
  • 8 Department of Medical Oncology, Takarazuka City Hospital, Takarazuka, Japan.
  • 9 Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
  • 10 Department of Respiratory Medicine, Juntendo University Urayasu Hospital, Urayasu, Japan.
  • 11 Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan.
  • 12 Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo, Japan.
  • 13 Department of Thoracic Oncology, NHO Osaka Toneyama Medical Center, Toyonaka, Japan.
  • 14 Division of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine, Saga University, Saga, Japan.
  • 15 Department of Respirology, Japan Community Health Care Organization Chukyo Hospital, Nagoya, Japan.
  • 16 Department of Precision Cancer Medicine, Center for Innovative Cancer Treatment, Tokyo Medical and Dental University, Tokyo, Japan.
  • 17 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States; Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan. Electronic address: skobayas@bidmc.harvard.edu.
PMID: 40088581 DOI: 10.1016/j.lungcan.2025.108479
Abstract

Background: EGFR exon 19 insertions (EGFRex19ins) are rare EGFR mutations. Their clinical-genomic characteristics and outcomes with EGFR-tyrosine kinase inhibitors (TKIs) remain uncertain.

Methods: We evaluated the clinical-genomic characteristics and outcomes of EGFR-TKIs for EGFRex19ins in the multi-institutional prospective lung Cancer genomic screening project (LC-SCRUM-Asia). We also studied preclinical Ba/F3 models expressing EGFR-K745_E746insIPVAIK (Ba/F3-IPVAIK) to investigate their sensitivity to 1st-, 2nd-, 3rd-generation, and EGFR exon 20 insertion-active TKIs.

Results: In LC-SCRUM-Asia, 16,204 NSCLC patients were enrolled from March 2015 to December 2023. EGFRex19ins were detected in 13 samples (0.1 % of NSCLC). The median age was 72 years (range, 38-80); most patients were female (77 %), had adenocarcinoma (92 %), and were never-smokers (62 %). Twelve patients (93 %) had EGFR-K745_E746insIPVAIK, while one (7 %) had EGFR-K745_E746insVPVAIK. The most frequent co-mutation was TP53 (62 %); no patients had Other driver alterations. Six patients (46 %) tested positive for EGFR exon 19 deletions with PCR-based Cobas EGFR test, likely due to cross-reactivity arising from sequence homology. Twelve patients received EGFR-TKIs; five (42 %) experienced partial response. In the preclinical study, Ba/F3-IPVAIK showed the highest sensitivity to 2nd-generation EGFR-TKIs compared to Other EGFR-TKIs. Structural studies supported these consistent results. When broken down by EGFR-TKI generations, response rates for 1st-, 2nd-, and 3rd-generation TKIs were 50 % (1/2), 80 % (4/5), and 0 % (0/5), respectively. The median PFS for 1st-, 2nd-, and 3rd-generation TKIs were 8.7 (95 % CI, 7.4-NR), 14.7 (95 % CI, 8.0-NR), and 4.4 (95 % CI, 3.4-NR) months, respectively.

Conclusion: Our preclinical, structural, and clinical findings indicate 2nd-generation EGFR-TKIs are more effective for EGFRex19ins compared to Other TKIs.

Keywords

Afatinib; EGFR; I740_K745dup; K745_E746insIPVAIK; Non-small cell lung cancer; Osimertinib.

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