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)

被引：0

作者：

Uehara, Yuji ^{[1
,2
,3
]}

Izumi, Hiroki ^{[1
]}

Kobayashi, Ikei S. ^{[4
]}

Matsumoto, Shingo ^{[1
]}

Hosomi, Yukio ^{[2
]}

Okuno, Takae ^{[5
]}

Sugisaka, Jun ^{[6
]}

Takase, Naoto ^{[7
]}

Taima, Kageaki ^{[8
]}

Sasaki, Shinichi ^{[9
]}

Teranishi, Shuhei ^{[10
]}

Miyamoto, Shingo ^{[11
]}

Mori, Masahide ^{[12
]}

Nakashima, Chiho ^{[13
]}

Asano, Shuichi ^{[14
]}

Oi, Hajime ^{[1
]}

Sakai, Tetsuya ^{[1
]}

Shibata, Yuji ^{[1
]}

Udagawa, Hibiki ^{[1
]}

Sugiyama, Eri ^{[1
]}

Nosaki, Kaname ^{[1
]}

Umemura, Shigeki ^{[1
]}

Zenke, Yoshitaka ^{[1
]}

Yoh, Kiyotaka ^{[1
]}

Ikeda, Sadakatsu ^{[3
]}

Costa, Daniel B. ^{[4
]}

Kobayashi, Susumu ^{[4
,15
]}

Goto, Koichi ^{[1
]}

机构：

[1] Natl Canc Ctr Hosp East, Dept Thorac Oncol, Kashiwa, Japan

[2] Komagome Hosp, Tokyo Metropolitan Canc & Infect Dis Ctr, Dept Thorac Oncol & Resp Med, Tokyo, Japan

[3] Tokyo Med & Dent Univ, Ctr Innovat Canc Treatment, Dept Precis Canc Med, Tokyo, Japan

[4] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA

[5] Shimane Univ, Dept Internal Med, Div Med Oncol & Resp Med, Fac Med, Izumo, Japan

[6] Sendai Kousei Hosp, Dept Pulm Med, Sendai, Japan

[7] Takarazuka City Hosp, Dept Med Oncol, Takarazuka, Japan

[8] Hirosaki Univ, Grad Sch Med, Dept Resp Med, Hirosaki, Japan

[9] Juntendo Univ, Urayasu Hosp, Dept Resp Med, Urayasu, Japan

[10] Yokohama City Univ Med Ctr, Resp Dis Ctr, Yokohama, Japan

[11] Japanese Red Cross Med Ctr, Dept Med Oncol, Tokyo, Japan

[12] NHO Osaka Toneyama Med Ctr, Dept Rehabil, Toyonaka, Japan

[13] Saga Univ, Div Hematol Resp Med & Oncol, Fac Med, Saga, Japan

[14] Japan Community Hlth Care Org Chukyo Hosp, Dept Respirol, Nagoya, Japan

[15] Natl Canc Ctr, Exploratory Oncol Res & Clin Trial Ctr, Div Translat Genom, Kashiwa, Japan

来源：

LUNG CANCER | 2025年 / 202卷

关键词：

Non-small cell lung cancer; Afatinib; Osimertinib; EGFR; I740_K745dup; K745_E746insIPVAIK; MUTATIONS; OSIMERTINIB; AFATINIB; RARE;

D O I：

10.1016/j.lungcan.2025.108479

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 comutation 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 EGFR EGFRex19ins compared to other TKIs.

引用

页数：12

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