Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial
Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial
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DOI：
10.1016/s1470-2045(17)30339-x
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发表时间：
2017-07-01
期刊：
影响因子：
51.1
通讯作者：
Felip, Enriqueta
中科院分区：
文献类型：
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作者：
Shaw, Alice T.;Kim, Tae Min;Felip, Enriqueta
Ceritinib是下一代间变性淋巴瘤激酶（ALK）抑制剂，在ALK重排的非小细胞肺癌患者中显示出稳健的抗肿瘤疗效，沿着颅内活性。在I期和II期研究中，ceritinib已被证明在化疗后进展的ALK前药和ALK前药患者（主要是多线）中具有高度活性。在这项研究中，我们比较了塞瑞替尼与单药化疗在晚期ALK重排非小细胞肺癌患者中的疗效和安全性，这些患者先前在克唑替尼和铂类药物双重化疗后进展。我们招募了至少18岁的ALK重排IIIB或IV期非小细胞肺癌患者，（至少有一处可测量病灶）既往接受过化疗（一线或二线，包括铂双联）和克唑替尼，随后发生疾病进展的患者，来自20个国家的99个中心。其他入选标准包括WHO体力状态评分为0-2分、器官功能和实验室检查结果良好、预期寿命至少为12周、已从既往抗癌治疗相关毒性中恢复。我们将患者随机分配（1：1;区组[区组大小为4];按WHO体力状态[0 vs 1-2]和有无脑转移分层）至口服塞瑞替尼750 mg/天空腹（21天治疗周期）或化疗（静脉注射培美曲塞500 mg/m（2）或多西他赛75 mg/m（2）[研究者选择]，每21天一次）。因疾病进展而停止化疗的患者可以交叉至ceritinib组。主要终点是无进展生存期，由设盲的独立审查委员会使用实体瘤疗效评价标准1.1在意向治疗人群中进行评估，每6周一次评估，直至第18个月，此后每9周一次。本试验已在ClinicalTrials注册。在2013年6月28日至2015年11月2日期间，我们随机分配了231名患者;塞瑞替尼组115例（50%），化疗组116例（50%）（培美曲塞组40例[34%]，多西他赛组73例[63%]，3例[3%]在接受治疗前停药）。中位随访时间为16.5个月（IQR 11.5-21.4）。与化疗相比，塞瑞替尼显示出中位无进展生存期的显著改善（塞瑞替尼5.4个月[95%CI 4.1-6.9] vs化疗1.6个月[1.4-2.8];风险比0.49 [0.36-0.67]; p
Background Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor, which has shown robust anti-tumour efficacy, along with intracranial activity, in patients with ALK-rearranged non-small-cell lung cancer. In phase 1 and 2 studies, ceritinib has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed after chemotherapy (mostly multiple lines). In this study, we compared the efficacy and safety of ceritinib versus single-agent chemotherapy in patients with advanced ALK-rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy.Methods In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged at least 18 years with ALK-rearranged stage IIIB or IV non-small-cell lung cancer (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression, from 99 centres across 20 countries. Other inclusion criteria were a WHO performance status of 0-2, adequate organ function and laboratory test results, a life expectancy of at least 12 weeks, and having recovered from previous anticancer treatment-related toxicities. We randomly allocated patients (1:1; with blocking [block size of four]; stratified by WHO performance status [0 vs 1-2] and presence or absence of brain metastases) to oral ceritinib 750 mg per day fasted (in 21 day treatment cycles) or chemotherapy (intravenous pemetrexed 500 mg/m(2) or docetaxel 75 mg/m(2) [investigator choice], every 21 days). Patients who discontinued chemotherapy because of progressive disease could cross over to the ceritinib group. The primary endpoint was progression-free survival, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumors 1.1 in the intention-to-treat population, assessed every 6 weeks until month 18 and every 9 weeks thereafter. This trial is registered with ClinicalTrials. gov, number NCT01828112, and is ongoing but no longer recruiting patients.Findings Between June 28, 2013, and Nov 2, 2015, we randomly allocated 231 patients; 115 (50%) to ceritinib and 116 (50%) to chemotherapy (40 [34%] to pemetrexed, 73 [63%] to docetaxel, and three [3%] discontinued before receiving treatment). Median follow-up was 16.5 months (IQR 11.5-21.4). Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5.4 months [95% CI 4.1-6.9] for ceritinib vs 1.6 months [1.4-2.8] for chemotherapy; hazard ratio 0.49 [0.36-0.67]; p