Jóri Balázs, Bundschuh Otto, Falk Markus, Heukamp Lukas C, Kluge Alexander, Tiemann Markus, Willborn Kay C, Woitzik Johannes, Griesinger Frank
Lungenkrebsmedizin, Oldenburg, Germany.
Institute for Hematopathology Hamburg, Hamburg, Germany.
Transl Lung Cancer Res. 2024 Jul 30;13(7):1749-1755. doi: 10.21037/tlcr-23-769. Epub 2024 Jul 15.
Capmatinib, a potent and selective tyrosine kinase inhibitor (TKI), holds promise as a therapeutic agent due to its potentially elevated intracranial efficacy in metastatic non-small cell lung cancer (NSCLC) patients harboring exon 14 skipping alterations in (MET Proto-Oncogene). This study aims to evaluate a targeted therapeutic approach to an exon 14 skipping (METex14) advanced NSCLC patient that progressed on Crizotinib and developed off target resistance alteration in PIK3CA.
We present a case of advanced METex14 NSCLC patient wherein central nervous system (CNS) relapse occurred post complete surgical resection and remission of the lung tumor under first-line crizotinib treatment. Subsequent disease monitoring demonstrated a profound intracranial response to capmatinib in a crizotinib-resistant brain lesion. Molecular analysis unveiled the original METex14 D1028N driver mutation and a newly arisen bypass mutation, potentially contributing to off-target resistance.
Before capmatinib was approved as a first line treatment option for metastatic NSCLC harboring somatic METex14 mutations, crizotinib conferred a potential option for targeted treatment. Switching to a selective -TKI like capmatinib with a better CNS penetration, it appears to be a promising approach for CNS metastasized NSCLC patients with METex14 mutations that failed on crizotinib. Further research is needed to more effectively understand and monitor resistance mechanisms using advanced diagnostic techniques such as DNA-based hybrid-capture (HC) next generation sequencing (NGS) to guide molecularly stratified therapy beyond the first line setting.
卡马替尼是一种强效且选择性的酪氨酸激酶抑制剂（TKI），对于携带（MET原癌基因）外显子14跳跃改变的转移性非小细胞肺癌（NSCLC）患者，因其潜在的颅内疗效提升而有望成为一种治疗药物。本研究旨在评估一种针对一名外显子14跳跃（METex14）晚期NSCLC患者的靶向治疗方法，该患者在克唑替尼治疗期间病情进展，并在PIK3CA基因发生了脱靶耐药改变。
我们报告了一例晚期METex14 NSCLC患者的病例，该患者在一线克唑替尼治疗下肺肿瘤完全手术切除并缓解后发生了中枢神经系统（CNS）复发。随后的疾病监测显示，卡马替尼对克唑替尼耐药的脑转移瘤有显著的颅内反应。分子分析揭示了最初的METex14 D1028N驱动突变和一个新出现的旁路突变，这可能导致了脱靶耐药。
在卡马替尼被批准作为携带体细胞METex14突变的转移性NSCLC的一线治疗选择之前，克唑替尼是一种潜在的靶向治疗选择。对于在克唑替尼治疗中失败的METex14突变的CNS转移NSCLC患者，改用具有更好CNS渗透性的选择性TKI（如卡马替尼）似乎是一种有前景的方法。需要进一步研究，以使用基于DNA的杂交捕获（HC）下一代测序（NGS）等先进诊断技术更有效地理解和监测耐药机制，从而指导一线治疗之外的分子分层治疗。
