Massachusetts General Hospital, Boston, MA, USA.
Seoul National University Hospital, Seoul, Korea.
Lancet Oncol. 2017 Jul;18(7):874-886. doi: 10.1016/S1470-2045(17)30339-X. Epub 2017 Jun 9.
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.
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 or docetaxel 75 mg/m [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.
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<0·0001). Serious adverse events were reported in 49 (43%) of 115 patients in the ceritinib group and 36 (32%) of 113 in the chemotherapy group. Treatment-related serious adverse events were similar between groups (13 [11%] in the ceritinib group vs 12 [11%] in the chemotherapy group). The most frequent grade 3-4 adverse events in the ceritinib group were increased alanine aminotransferase concentration (24 [21%] of 115 vs two [2%] of 113 in the chemotherapy group), increased γ glutamyltransferase concentration (24 [21%] vs one [1%]), and increased aspartate aminotransferase concentration (16 [14%] vs one [1%] in the chemotherapy group). Six (5%) of 115 patients in the ceritinib group discontinued because of adverse events compared with eight (7%) of 116 in the chemotherapy group. 15 (13%) of 115 patients in the ceritinib group and five (4%) of 113 in the chemotherapy group died during the treatment period (from the day of the first dose of study treatment to 30 days after the final dose). 13 (87%) of the 15 patients who died in the ceritinib group died because of disease progression and two (13%) died because of an adverse event (one [7%] cerebrovascular accident and one [7%] respiratory failure); neither of these deaths were considered by the investigator to be treatment related. The five (4%) deaths in the chemotherapy group were all due to disease progression.
These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population.
Novartis Pharmaceuticals Corporation.
塞瑞替尼是一种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，具有强大的抗肿瘤活性，同时具有颅内活性。在 1 期和 2 期研究中，塞瑞替尼在接受化疗（主要是多线治疗）后进展的ALK 抑制剂初治和ALK 抑制剂预处理的患者中表现出高度的活性。在这项研究中，我们比较了塞瑞替尼与单药化疗在先前接受克唑替尼和铂类双药化疗后进展的晚期ALK 重排非小细胞肺癌患者中的疗效和安全性。
这是一项随机、对照、开放标签、3 期临床试验，我们从 20 个国家的 99 个中心招募了至少 18 岁的 ALK 重排的 IIIB 或 IV 期非小细胞肺癌（至少有一个可测量的病变）患者，他们接受过先前的化疗（一线或二线，包括铂类双联）和克唑替尼治疗，随后疾病进展。其他纳入标准包括世界卫生组织（WHO）表现状态 0-2、足够的器官功能和实验室检查结果、至少 12 周的预期寿命以及从先前的抗癌治疗相关毒性中恢复。我们将患者（1:1；使用阻塞[阻塞大小为 4]；按 WHO 表现状态[0 与 1-2]和是否存在脑转移分层）随机分配至每天口服 750mg 塞瑞替尼空腹（21 天治疗周期）或化疗（静脉注射培美曲塞 500mg/m2 或多西他赛 75mg/m2[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到塞瑞替尼组。主要终点是无进展生存期，由盲法独立审查委员会使用实体瘤反应评估标准 1.1 在意向治疗人群中评估，每 6 周评估一次，直到第 18 个月，此后每 9 周评估一次。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT01828112，正在进行中，但不再招募患者。
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；115 名（50%）接受塞瑞替尼治疗，116 名（50%）接受化疗（40 名[34%]接受培美曲塞，73 名[63%]接受多西他赛，3 名[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，塞瑞替尼显著改善了中位无进展生存期（塞瑞替尼组为 5.4 个月[95%CI 4.1-6.9]，化疗组为 1.6 个月[1.4-2.8]；风险比 0.49[0.36-0.67]；p<0.0001）。塞瑞替尼组 115 名患者中有 49 名（43%）和化疗组 113 名患者中有 36 名（32%）发生严重不良事件。两组之间的治疗相关严重不良事件相似（塞瑞替尼组 13 例[11%]，化疗组 12 例[11%]）。塞瑞替尼组最常见的 3-4 级不良事件是丙氨酸氨基转移酶浓度升高（24 例[21%]，113 例中有 2 例[2%]）、γ-谷氨酰转移酶浓度升高（24 例[21%]，1 例[1%]）和天冬氨酸氨基转移酶浓度升高（16 例[14%]，1 例[1%]）。塞瑞替尼组有 6 名（5%）患者因不良事件停药，而化疗组有 8 名（7%）患者停药。塞瑞替尼组有 15 名（13%）患者和化疗组有 5 名（4%）患者在治疗期间死亡（从首次研究治疗剂量到最后一剂后 30 天）。塞瑞替尼组死亡的 15 名患者中（13%）有 13 名（87%）死于疾病进展，2 名（13%）死于不良事件（1 例[7%]脑卒中和 1 例[7%]呼吸衰竭）；研究者均认为这些死亡与治疗无关。化疗组的 5 例死亡均因疾病进展所致。
这些发现表明，在克唑替尼治疗后进展的患者中，一种更有效的 ALK 抑制剂可显著提高患者的临床获益，并且在该患者人群中，与化疗相比，塞瑞替尼是一种更有效的治疗选择。
诺华制药公司。
