两项临床试验中brigatinib 治疗间变性淋巴瘤激酶阳性非小细胞肺癌伴脑转移患者的探索性分析
Exploratory Analysis of Brigatinib Activity in Patients With Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer and Brain Metastases in Two Clinical Trials.
机构信息
D. Ross Camidge, University of Colorado Cancer Center, Aurora, CO; Dong-Wan Kim, Seoul National University Hospital; Myung-Ju Ahn, Samsung Medical Center; Dae Ho Lee, Asan Medical Center, Seoul, South Korea; Marcello Tiseo, University Hospital of Parma, Parma, Italy; Corey J. Langer, University of Pennsylvania, Philadelphia, PA; Alice T. Shaw, Massachusetts General Hospital, Boston; William Reichmann, Jeff Haney, Tim Clackson, and David Kerstein, ARIAD Pharmaceuticals, Cambridge, MA; Rudolf M. Huber, University Hospital of Munich, Munich, Germany; Maximilian J. Hochmair, Otto Wagner Hospital, Vienna, Austria; Lyudmila A. Bazhenova and Kathryn A. Gold, University of California San Diego Moores Cancer Center, La Jolla; Sai-Hong Ignatius Ou, University of California Irvine School of Medicine, Irvine, CA; Howard L. West, Swedish Cancer Institute, Seattle, WA; and Scott N. Gettinger, Yale Cancer Center, New Haven, CT.
出版信息
J Clin Oncol. 2018 Sep 10;36(26):2693-2701. doi: 10.1200/JCO.2017.77.5841. Epub 2018 May 16.
Purpose In patients with crizotinib-treated, anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC), initial disease progression often occurs in the CNS. We evaluated brigatinib, a next-generation ALK inhibitor, in patients with ALK-positive NSCLC with brain metastases. Patients and Methods Patients with ALK-positive NSCLC received brigatinib (90 to 240 mg total daily) in a phase I/II trial (phI/II; ClinicalTrials.gov identifier: NCT01449461) and in the subsequent randomized phase II trial ALTA (ALK in Lung Cancer Trial of AP26113; ClinicalTrials.gov identifier: NCT02094573; patients in arm A received 90 mg once daily; patients in arm B received 180 mg once daily with 7-day lead-in at 90 mg). Primary end points (systemic objective response rates [ORRs]) were previously reported. Independent review committees assessed intracranial efficacy in patients with baseline brain metastases. Results Most patients with ALK-positive NSCLC had baseline brain metastases (50 of 79 [63%], phI/II; 80 of 112 [71%] and 73 of 110 [66%] in ALTA arms A and B, respectively), many of whom had no prior brain radiotherapy (23 of 50 [46%], phI/II; 32 of 80 [40%], ALTA arm A; 30 of 73 [41%], arm B). All patients, except four in phI/II, had received crizotinib. Among patients with measurable (≥ 10 mm) brain metastases, confirmed intracranial ORR was 53% (eight of 15; 95% CI, 27% to 79%) in phI/II, 46% (12 of 26; 95% CI, 27% to 67%) in ALTA arm A, and 67% (12 of 18; 95% CI, 41% to 87%) in arm B. Intracranial ORRs were similar in subsets without prior radiation or progression postradiation. Among patients with any baseline brain metastases, median intracranial progression-free survival (iPFS) was 14.6 months (95% CI, 12.7 to 36.8 months), phI/II; 15.6 months (95% CI, 9.0 to 18.3 months), ALTA arm A; 18.4 months (95% CI, 12.8 months to not reached), ALTA arm B. Conclusion Brigatinib yielded substantial intracranial responses and durable iPFS in ALK-positive, crizotinib-treated NSCLC, with highest iPFS in patients receiving 180 mg once daily (with lead-in).
目的 在接受克唑替尼治疗的间变性淋巴瘤激酶基因（ALK）重排的非小细胞肺癌（ALK 阳性 NSCLC）患者中，初始疾病进展通常发生在中枢神经系统（CNS）。我们评估了第二代 ALK 抑制剂布加替尼在伴有脑转移的 ALK 阳性 NSCLC 患者中的疗效。
方法 接受 ALK 阳性 NSCLC 治疗的患者在一项 I/II 期试验（phI/II；临床试验.gov 标识符：NCT01449461）和随后的随机 II 期试验 ALTA（ALK 在肺癌试验中的 AP26113；临床试验.gov 标识符：NCT02094573；臂 A 中的患者接受 90mg 每日一次；臂 B 的患者接受 180mg 每日一次，7 天的 90mg 导入期）中接受布加替尼（总剂量为 90 至 240mg 每日）。先前报道了主要终点（系统客观缓解率[ORR]）。基线时有脑转移的患者由独立审查委员会评估颅内疗效。
结果 大多数 ALK 阳性 NSCLC 患者基线时有脑转移（phI/II 中有 50 例[63%]，ALTA 臂 A 中有 80 例[71%]，臂 B 中有 73 例[66%]），其中许多患者以前没有接受过脑部放疗（phI/II 中有 23 例[46%]，ALTA 臂 A 中有 32 例[40%]，臂 B 中有 30 例[41%]）。除 phI/II 中的 4 例外，所有患者均接受过克唑替尼治疗。在有可测量（≥10mm）脑转移的患者中，phI/II 中确认的颅内 ORR 为 53%（15 例中有 8 例；95%CI，27%至 79%），ALTA 臂 A 中为 46%（26 例中有 12 例；95%CI，27%至 67%），臂 B 中为 67%（18 例中有 12 例；95%CI，41%至 87%）。无既往放疗或放疗后进展的亚组中，颅内 ORR 相似。在有任何基线脑转移的患者中，颅内无进展生存期（iPFS）的中位数为 14.6 个月（95%CI，12.7 至 36.8 个月），phI/II；15.6 个月（95%CI，9.0 至 18.3 个月），ALTA 臂 A；18.4 个月（95%CI，12.8 个月至不可评估），ALTA 臂 B。
结论 布加替尼在接受克唑替尼治疗的 ALK 阳性 NSCLC 患者中产生了显著的颅内反应和持久的 iPFS，每日接受 180mg 治疗的患者 iPFS 最高（有导入期）。
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