Introduction: The second‐generation anaplastic lymphoma kinase (ALK) inhibitor alectinib recently showed superior efficacy compared to the first‐generation ALK inhibitor crizotinib in advanced ALK‐rearranged NSCLC, establishing alectinib as the new standard first‐line therapy. Brigatinib, another second‐generation ALK inhibitor, has shown substantial activity in patients with crizotinib‐refractory ALK‐positive NSCLC; however, its activity in the alectinib‐refractory setting is unknown. Methods: A multicenter, retrospective study was performed at three institutions. Patients were eligible if they had advanced, alectinib‐refractory ALK‐positive NSCLC and were treated with brigatinib. Medical records were reviewed to determine clinical outcomes. Results: Twenty‐two patients were eligible for this study. Confirmed objective responses to brigatinib were observed in 3 of 18 patients (17%) with measurable disease. Nine patients (50%) had stable disease on brigatinib. The median progression‐free survival was 4.4 months (95% confidence interval [CI]: 1.8–5.6 months) with a median duration of treatment of 5.7 months (95% CI: 1.8–6.2 months). Among 9 patients in this study who underwent post‐alectinib/pre‐brigatinib biopsies, 5 had an ALK I1171X or V1180L resistance mutation; of these, 1 had a confirmed partial response and 3 had stable disease on brigatinib. One patient had an ALK G1202R mutation in a post‐alectinib/pre‐brigatinib biopsy, and had progressive disease as the best overall response to brigatinib. Conclusions: Brigatinib has limited clinical activity in alectinib‐refractory ALK‐positive NSCLC. Additional studies are needed to establish biomarkers of response to brigatinib and to identify effective therapeutic options for alectinib‐resistant ALK‐positive NSCLC patients.

中文翻译：

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Brigatinib 在艾乐替尼难治性 ALK 阳性非小细胞肺癌患者中的应用：一项回顾性研究

简介：第二代间变性淋巴瘤激酶 (ALK) 抑制剂艾乐替尼最近在晚期 ALK 重排 NSCLC 中显示出优于第一代 ALK 抑制剂克唑替尼的疗效，确立了艾乐替尼作为新标准一线治疗的地位。Brigatinib 是另一种第二代 ALK 抑制剂，在克唑替尼难治性 ALK 阳性 NSCLC 患者中显示出显着的活性；然而，其在艾乐替尼难治性环境中的活性尚不清楚。方法：在三个机构进行了一项多中心、回顾性研究。如果患者患有晚期、艾乐替尼难治性 ALK 阳性 NSCLC 并接受布加替尼治疗，则符合条件。审查医疗记录以确定临床结果。结果：22 名患者符合本研究的条件。在 18 名患有可测量疾病的患者中有 3 名 (17%) 观察到对布加替尼的确认客观反应。9 名患者 (50%) 在接受布加替尼治疗后病情稳定。中位无进展生存期为 4.4 个月（95% 置信区间 [CI]：1.8-5.6 个月），中位治疗持续时间为 5.7 个月（95% CI：1.8-6.2 个月）。在本研究中接受艾乐替尼后/布加替尼前活检的 9 名患者中，5 名具有 ALK I1171X 或 V1180L 耐药突变；其中，1 人证实部分缓解，3 人接受布加替尼治疗后病情稳定。一名患者在艾乐替尼后/布加替尼前活检中具有 ALK G1202R 突变，并且疾病进展是对布加替尼的最佳总体反应。结论：布加替尼在艾乐替尼难治性 ALK 阳性 NSCLC 中的临床活性有限。