■阿莱替尼在间变性淋巴瘤激酶(ALK)融合基因阳性的非小细胞肺癌(NSCLC)患者中取得了出色的治疗效果,然而,患者最终会对其产生抵抗力。探索alectinib耐药后的基因变异定位为ALK阳性晚期NSCLC的整体治疗提供了依据。本研究旨在表征ALK重排阳性的晚期NSCLC患者在一线治疗耐药后的突变特征。研究还调查了抵抗后的治疗选择和应对策略。
■收集2018年11月至2022年4月在广州医科大学附属第一医院接受一线阿来替尼治疗的晚期非小细胞肺癌患者的临床资料。此外,收集患者基线和耐药后组织的下一代测序(NGS)数据.一名患者接受了肺癌类器官培养和药物敏感性测试。
■在35名阿来替尼一线治疗的晚期非小细胞肺癌患者中,31目前处于无进展生存期(PFS;4.3-35.0个月)。四名患者经历了进行性疾病,所有患者均依次接受色瑞替尼治疗.3例患者序贯治疗前的组织NGS结果显示棘皮动物微管相关蛋白样4-ALK融合保持在原始基线,ceritinib治疗的PFS为0.5-1.3个月.一名患者在ALK蛋白激酶的结构域(V1180L和E1161D)中出现获得性抗性突变,ceritinib治疗的PFS为6.7个月.对于一名在色瑞替尼耐药进展后保持原始基线ALK重排阳性而无获得性突变的患者,肺癌样器官培养序贯布格替尼和洛拉替尼导致3.2和1.9个月的PFS,分别,与该患者的相应药物敏感性测试结果一致。
■对于ALK重排阳性患者,其他第二代酪氨酸激酶抑制剂(TKIs)或第三代氯拉替尼的盲测序可能无法保证在一线第二代ALK-TKI阿莱替尼治疗进展后,肿瘤抑制效果令人满意.在疾病进展后对患者血液或组织样本进行NGS检测可能有助于了解阿来替尼耐药的病因。肺癌样器官患者来源的药敏试验根据NGS结果选择药敏药物,为耐药后患者的后续药物治疗提供参考。特别是那些在基线时仍保持ALK重排阳性的人。
UNASSIGNED: Alectinib has achieved excellent therapeutic efficacy in anaplastic lymphoma kinase (ALK) fusion gene-positive non-small cell lung cancer (NSCLC) patients, however, patients eventually develop resistance to it. Exploring the gene variant mapping after alectinib resistance provides a basis for the whole management of ALK-positive advanced NSCLC. This study aimed to characterize the mutation profiles of real-world ALK rearrangement-positive advanced NSCLC patients after first-line alectinib treatment resistance. The research also investigated the treatment options and coping strategies after resistance.
UNASSIGNED: Clinical data of patients with advanced NSCLC who received first-line alectinib treatment in the First Affiliated Hospital of Guangzhou Medical University between November 2018 and April 2022 were collected. Moreover, next-generation sequencing (NGS) data of the patient\'s baseline and post-resistance tissues were gathered. One patient underwent lung cancer organoid culture and drug sensitivity testing.
UNASSIGNED: Out of 35 first-line alectinib-treated patients with advanced NSCLC, 31 are presently in progression-free survival (PFS; 4.3-35.0 months). Four patients experienced progressive disease, and all of them were sequentially treated with ceritinib. Tissue NGS results before sequential treatment in three patients indicated an echinoderm microtubule-associated protein-like 4-ALK fusion that remained at the original baseline, and the PFS for ceritinib treatment was 0.5-1.3 months. One patient developed acquired resistance mutations in the structural domain of ALK protein kinase (V1180L and E1161D), and the PFS for ceritinib treatment was 6.7 months. For one patient who maintained original baseline ALK rearrangement positive without acquired mutation after progression of ceritinib resistance, lung cancer-like organ culture with sequential brigatinib and lorlatinib led to a PFS of 3.2 and 1.9 months, respectively, which aligned with the corresponding drug susceptibility testing results for this patient.
UNASSIGNED: For ALK rearrangement-positive patients, blind sequencing of other second-generation tyrosine kinase inhibitors (TKIs) or third-generation lorlatinib may not guarantee satisfactory tumor suppression following first-line second-generation ALK-TKI alectinib administration for treatment progression. NGS testing of patients\' blood or tissue samples after disease progression may provide insight into the etiology of alectinib resistance. Patient-sourced drug sensitivity testing of lung cancer-like organs selects drug-sensitive medications based on NGS results and provides a reference for subsequent drug therapy for patients after drug resistance, particularly those who remain ALK rearrangement-positive at baseline.