Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California.
J Thorac Oncol. 2018 Oct;13(10):1530-1538. doi: 10.1016/j.jtho.2018.06.005. Epub 2018 Jun 20.
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.
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.
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.
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.
第二代间变性淋巴瘤激酶（ALK）抑制剂阿来替尼（alectinib）在晚期ALK 重排的非小细胞肺癌（NSCLC）中较第一代 ALK 抑制剂克唑替尼（crizotinib）显示出更好的疗效，确立了阿来替尼作为新的标准一线治疗药物。另一种第二代 ALK 抑制剂布加替尼（brigatinib）在克唑替尼耐药的ALK 阳性 NSCLC 患者中显示出显著的活性；然而，其在阿来替尼耐药环境中的活性尚不清楚。
在三个机构进行了一项多中心、回顾性研究。符合条件的患者为晚期、阿来替尼耐药的ALK 阳性 NSCLC 患者，且接受了布加替尼治疗。对病历进行了回顾，以确定临床结局。
本研究共有 22 名患者符合条件。在可测量疾病的 18 名患者中，有 3 名（17%）确认对布加替尼有客观缓解。9 名（50%）患者在布加替尼治疗时疾病稳定。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），中位治疗时间为 5.7 个月（95%CI：1.8-6.2 个月）。在本研究中，9 名接受阿来替尼后/布加替尼前活检的患者中，有 5 名存在 ALK I1171X 或 V1180L 耐药突变；其中，1 名患者对布加替尼有确认的部分缓解，3 名患者疾病稳定。1 名患者在阿来替尼后/布加替尼前活检中存在 ALK G1202R 突变，对布加替尼的最佳总体反应为疾病进展。
布加替尼在阿来替尼耐药的ALK 阳性 NSCLC 中临床活性有限。需要进一步的研究来确定对布加替尼反应的生物标志物，并为阿来替尼耐药的ALK 阳性 NSCLC 患者确定有效的治疗选择。
