Lancet Oncol：CH5424802对ALK重排晚期非小细胞肺癌治疗有效

目前，克里唑蒂尼是唯一被批准用于ALK重排非细胞肺癌（NSCLC）治疗的药物。而CH5424802是现有的选择性口服ALK抑制剂，来自日本Kyushu国立医院肿瘤中心的Takashi Seto等为了研究CH5424802的有效性和安全性而设计了相关研究，他们的研究结果发表在Lancet Oncol 4月的在线期刊上。

本研究为针对CH5424802的多中心、单队列、开放式标签、1-2期临床研究，本文的研究者所纳入的是既往没有接受过ALK抑制剂治疗的ALK重排的晚期非小细胞肺癌患者，这些患者来自于日本的13个医院。在研究的1期部分中，受试者每日2次口服CH5424802治疗，剂量逐渐提升。1期研究的主要终点为剂量限制性毒性反应、患者所能耐受的最大治疗剂量和其他药代动力学相关参数。在研究的2期部分中，患者所接受1期研究所确定的推荐剂量的CH5424802治疗，同样是每日2次口服。2期研究的主要终点是对治疗存在客观反应的患者所占的比例。治疗每21天为一个疗程，持续至患者病情出现进展、出现患者所不能耐受的副反应事件或是患者要求停止治疗。研究者采用意向治疗分析法对研究结果进行分析。本研究在日本药物信息中心注册，注册号为JapicCTI-101264。

在2010年9月10日至2012年4月18日期间研究者进行受试者纳入。本文中所分析的数据的截止日期是2012年7月31日。在1期临床研究的部分中，24名患者接受的治疗剂量为每日两次20-300mg口服。即使在接受最大剂量的患者中，研究者也没有观察到剂量限制性毒性反应或4级不良反应事件的发生，因此，研究者将2期临床研究的推荐治疗剂量定为300mg每日两次口服。在2期临床研究的部分中，有46名患者接受推荐的治疗剂量进行治疗，其中的43人达到了对药物的客观反应（93.5%，95%可信区间为82.1%-98.6%），在这些受试者中，有2名患者为完全应答（4.3%，95%可信区间为0.5%-14.8%），另有41名患者达到部分应答（89.1%，95%可信区间为76.4%-96.4%）。在46名受试者中，有12人（26%）出现了与治疗相关的3级不良反应事件，其中，有2名患者出现了中性粒细胞计数降低和血肌酸磷酸激酶升高。有5名（11%）患者出现了严重不良反应事件。研究者并没有报道4级不良反应事件或死亡事件的发生。因为在研究所纳入的46名患者中，仍有40人在继续接受治疗，所以本研究仍在进行之中。

来自本文的结果指出，ALK重排的晚期非小细胞肺癌患者能较好的耐受CH5424802治疗，并且CH5424802治疗对上述患者有效。

与非小细胞肺癌相关的拓展阅读：

• Radiother Oncol：FDG-PET可评估局部晚期非小细胞肺癌同步放化疗后放疗剂量和急性食管炎的关系
• ANN SURG ONCOL：部分非小细胞肺癌无需行系统性淋巴结清扫术
• CHEST：非小细胞肺癌I期患者行亚肺叶切除术易复发
• 王绿化：非小细胞肺癌放疗的临床热点问题
• 非小细胞肺癌（NSCLC）的放疗进展
• 厄洛替尼延长非小细胞肺癌患者复发时间
更多信息请点击：有关非小细胞肺癌更多资讯

CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1—2 study
Background
Currently, crizotinib is the only drug that has been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of CH5424802, a potent, selective, and orally available ALK inhibitor.
Methods
In this multicentre, single-arm, open-label, phase 1—2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-101264.
Findings
Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20—300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93·5%, 95% CI 82·1—98·6) including two complete responses (4·3%, 0·5—14·8) and 41 partial responses (89·1%, 76·4—96·4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment.
Interpretation
CH5424802 is well tolerated and highly active in patients with advanced ALK-rearranged NSCLC.
Funding
Chugai Pharmaceutical Co, Ltd.