論文No4139
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,Hiroki Izumi,Ikei S. Kobayashi,...Daniel B. Costa,Susumu S Kobayashi,Koichi Goto
LUNG CANCER, Volume 202,108479, April 2025
要約
本研究は、まれなEGFRエクソン19挿入変異（EGFRex19ins）を有する非小細胞肺がん（NSCLC）患者の臨床ゲノム学的特徴とEGFRチロシンキナーゼ阻害薬（TKIs）の治療成績を、多施設共同前向き研究LC-SCRUM-Asiaのデータを用いて評価しました。
EGFRex19insはNSCLCの0.1%に認められ、主な亜型はEGFR-K745_E746insIPVAIKでした。
共存変異としてはTP53が最も頻繁でした。
臨床試験では、EGFR-TKIs治療を受けた患者の奏効率は42%であり、世代別に見ると第2世代TKIsで最も高い奏効率（80%）と比較的長い無増悪生存期間（中央値14.7ヶ月）が示されました。
前臨床試験においても、EGFR-K745_E746insIPVAIKを発現する細胞は第2世代TKIsに対して最も高い感受性を示し、構造解析の結果もこれを支持しました。
これらの結果から、EGFRex19insに対しては第2世代EGFR-TKIsが他の世代のTKIsよりも有効である可能性が示唆されました。
Take Home Message
まれなEGFRエクソン19挿入変異（特にEGFR-K745_E746insIPVAIK）を有する非小細胞肺がん患者に対しては、第2世代EGFRチロシンキナーゼ阻害薬が第1世代や第3世代の薬剤と比較して、より高い治療効果（奏効率と無増悪生存期間）を示す可能性が、臨床試験と前臨床試験の両面から示唆されました。
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.