Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2025 Apr:202:108479.
doi: 10.1016/j.lungcan.2025.108479. Epub 2025 Mar 5.

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)

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
Multicenter Study

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)

Yuji Uehara et al. Lung Cancer. 2025 Apr.

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

    1. Uehara Y, Takeyasu Y, Yoshida T, Tateishi A, Torasawa M, Hosomi Y, Masuda K, Shinno Y, Matsumoto Y, Okuma Y, Goto Y, Horinouchi H, Yamamoto N, Ohe Y, Real-world outcomes of treatment strategy between first-line osimertinib, first/second-generation EGFR-TKIs followed by osimertinib and without osimertinib in advanced EGFR-mutant NSCLC, ESMO Real World Data Digit. Oncol 5 (2024) 100058. 10.1016/j.esmorw.2024.100058. - DOI
    1. Soria J-C, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su W-C, Gray JE, Lee S-M, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS, Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer, N. Engl. J. Med 378 (2018) 113–125. 10.1056/NEJMoa1713137. - DOI - PubMed
    1. Wu Y-L, Tsuboi M, He J, John T, Grohe C, Majem M, Goldman JW, Laktionov K, Kim S-W, Kato T, Vu H-V, Lu S, Lee K-Y, Akewanlop C, Yu C-J, de Marinis F, Bonanno L, Domine M, Shepherd FA, Zeng L, Hodge R, Atasoy A, Rukazenkov Y, Herbst RS, Osimertinib in Resected EGFR-Mutated Non–Small-Cell Lung Cancer, N. Engl. J. Med 383 (2020) 1711–1723. 10.1056/NEJMoa2027071. - DOI - PubMed
    1. Uehara Y, Izumi H, Taki T, Sakai T, Udagawa H, Sugiyama E, Umemura S, Zenke Y, Matsumoto S, Yoh K, Kubota S, Aokage K, Sakamoto N, Sakashita S, Kojima M, Nagamine M, Hosomi Y, Tsuboi M, Goto K, Ishi G, Solid predominant histology and high podoplanin expression in cancer-associated fibroblast predict primary resistance to osimertinib in EGFR-mutated lung adenocarcinoma, JTO Clin. Res. Rep (2024) 100779. 10.1016/j.jtocrr.2024.100779. - DOI - PMC - PubMed
    1. Uehara Y, Tan AC, The Butterfly effect—will the MARIPOSA-2 study alter the trajectory of EGFR mutated non-small cell lung cancer (NSCLC), AME Clin. Trials Rev 2 (2024). 10.21037/actr-24-7. - DOI

Publication types

MeSH terms