FDA Approval Summary: Crizotinib for the Treatment of Metastatic Non-Small Cell Lung Cancer With Anaplastic Lymphoma Kinase Rearrangements
FDA Approval Summary: Crizotinib for the Treatment of Metastatic Non-Small Cell Lung Cancer With Anaplastic Lymphoma Kinase Rearrangements
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DOI：
10.1634/theoncologist.2014-0241
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发表时间：
2014-10-01
期刊：
影响因子：
5.8
通讯作者：
Pazdur, Richard
中科院分区：
文献类型：
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作者：
Kazandjian, Dickran;Blumenthal, Gideon M.;Pazdur, Richard
2011年8月26日，克唑替尼获得加速批准，用于治疗经美国FDA批准的ALK阳性的局部晚期或转移性非小细胞肺癌（NSCLC）患者。S.美国食品药品监督管理局（FDA）。批准是基于两项单臂试验，证明客观缓解率（ORR）为50%和61%，中位缓解持续时间为42周和48周。2013年11月20日，克唑替尼在研究A8081007（一项在347例既往接受过一种含铂方案的ALK阳性晚期NSCLC患者中进行的随机试验）中获得了基于临床获益确认的常规批准。患者被分配（1：1）接受克唑替尼250 mg口服，每日2次或标准治疗（多西他赛或培美曲塞）。主要终点是由独立放射学审查确定的无进展生存期（PFS）;次要终点是ORR和总生存期（OS）。克唑替尼组的PFS显著更长，克唑替尼和化疗组的中位PFS分别为7.7和3.0个月，中期分析时，治疗组间的ORR绝对增加46%，但OS无差异。克唑替尼治疗患者中最常见的药物不良反应（>25%）为视力障碍、恶心、腹泻、呕吐、便秘、水肿、转氨酶升高和疲乏。克唑替尼最严重的毒性为肝毒性、间质性肺病或肺炎和QT间期延长。克唑替尼的快速临床开发项目（从在NSCLC亚组中发现ALK重排到获得FDA全面批准，历时6年）是分子靶向肿瘤治疗新时代高效药物开发的典范。
On August 26, 2011, crizotinib received accelerated approval for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK-positive as detected by a test approved by the U. S. Food and Drug Administration (FDA). Approval was based on two single-arm trials demonstrating objective response rates (ORRs) of 50% and 61% and median response durations of 42 and 48 weeks. On November 20, 2013, crizotinib received regular approval based on confirmation of clinical benefit in study A8081007, a randomized trial in 347 patients with ALK-positive advanced NSCLC who had previously received one platinum-containing regimen. Patients were assigned (1:1) to receive crizotinib 250 mg orally twice daily or standard of care (docetaxel or pemetrexed). The primary endpoint was progression-free survival (PFS) determined by independent radiology review; secondary endpoints were ORR and overall survival (OS). PFS was significantly longer in the crizotinib arm, with median PFS of 7.7 and 3.0 months in the crizotinib and chemotherapy arms, respectively, and a 46% absolute increase in ORR but no difference in OS between treatment arms at the interim analysis. The most common adverse drug reactions (>25%) in crizotinib-treated patients were vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue. The most serious toxicities of crizotinib were hepatotoxicity, interstitial lung disease or pneumonitis, and QT-interval prolongation. Crizotinib's rapid clinical development program (6 years from identification of ALK rearrangements in a subset of NSCLC to full FDA approval) is a model of efficient drug development in this new era of molecularly targeted oncology therapy.