Division of Respiratory Medicine and Thoracic Oncology, Department of Medicine V, University Hospital of Munich, Thoracic Oncology Centre Munich, German Centre for Lung Research, Munich, Bavaria, Germany.
Department of Clinical Oncology, Odense University Hospital, Odense, Denmark.
J Thorac Oncol. 2020 Mar;15(3):404-415. doi: 10.1016/j.jtho.2019.11.004. Epub 2019 Nov 19.
We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase-positive NSCLC.
Patients were randomized 1:1 to take either oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (arm B), stratified by central nervous system (CNS) metastases and best response to crizotinib. The primary end point was investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included independent review committee (IRC)-assessed progression-free survival (PFS), intracranial PFS (iPFS), and overall survival (OS). Exploratory analyses included CNS versus ex-CNS target lesion response and correlation of depth of response with PFS and OS.
Among 222 randomized patients (112 and 110 in arms A and B, respectively), 59 (27%) remained on brigatinib at analysis (median follow-up: 19.6 versus 24.3 months). At baseline, 71% and 67% had brain lesions among A and B arms, respectively. Investigator-assessed confirmed objective response rate was 46% versus 56%. Median IRC-assessed PFS was 9.2 months (95% confidence interval: 7.4-12.8) versus 16.7 months (11.6-21.4). Median OS was 29.5 months (18.2-not reached) versus 34.1 months (27.7-not reached). IRC-confirmed intracranial objective response rate in patients with measurable baseline brain lesions was 50% (13 of 26) versus 67% (12 of 18); median duration of intracranial response was 9.4 versus 16.6 months. IRC-assessed iPFS was 12.8 versus 18.4 months. Across arms, median IRC-assessed PFS was 1.9, 5.5, 11.1, 16.7, and 15.6 months for patients with no, 1%-25%, 26%-50%, 51%-75%, and 76%-100% target lesion shrinkage, respectively. No new safety findings were observed with longer follow-up.
Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. Depth of response may be an important end point to capture in future targeted therapy trials.
我们报告了一项评估布加替尼治疗克唑替尼耐药间变性淋巴瘤激酶阳性非小细胞肺癌的 2 期随机研究的更新数据。
患者按 1:1 随机分为口服布加替尼 90mg 每日一次（A 组）或 180mg 每日一次，7 天导入期 90mg（B 组），按中枢神经系统（CNS）转移和对克唑替尼的最佳反应分层。主要终点为研究者评估的根据实体瘤反应评价标准 1.1 确认的客观缓解率。次要终点包括独立审查委员会（IRC）评估的无进展生存期（PFS）、颅内无进展生存期（iPFS）和总生存期（OS）。探索性分析包括 CNS 与 ex-CNS 靶病灶反应以及与 PFS 和 OS 的相关性。
在 222 例随机患者中（A 组 112 例，B 组 110 例），59 例（27%）在分析时仍在接受布加替尼治疗（中位随访：19.6 个月 vs. 24.3 个月）。基线时，A 组和 B 组分别有 71%和 67%的患者有脑部病变。研究者评估的确认客观缓解率分别为 46%和 56%。IRC 评估的中位 PFS 分别为 9.2 个月（95%置信区间：7.4-12.8）和 16.7 个月（11.6-21.4）。中位 OS 分别为 29.5 个月（18.2-未达到）和 34.1 个月（27.7-未达到）。基线时有可测量脑病变的患者 IRC 确认的颅内客观缓解率为 50%（26 例中有 13 例）和 67%（18 例中有 12 例）；颅内反应的中位持续时间分别为 9.4 个月和 16.6 个月。IRC 评估的 iPFS 分别为 12.8 个月和 18.4 个月。在各臂中，IRC 评估的中位 PFS 分别为无靶病灶缩小、1%-25%靶病灶缩小、26%-50%靶病灶缩小、51%-75%靶病灶缩小和 76%-100%靶病灶缩小的患者为 1.9、5.5、11.1、16.7 和 15.6 个月。随着随访时间的延长，未发现新的安全性发现。
布加替尼（180mg 每日一次，导入期）在克唑替尼耐药患者中继续显示出强劲的 PFS、长 iPFS 和颅内反应持续时间以及高颅内客观缓解率。反应深度可能是未来靶向治疗试验中一个重要的终点。
