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【WCLC2016】ASCEND-4结果公布：色瑞替尼冲击ALK阳性NSCLC一线治疗

2016年12月08日

来源：医脉通

2016年12月4日-7日，第17届世界肺癌大会（WCLC）在奥地利维也纳盛大召开。在当地时间12月6日上午的全体会议中，圣保罗国家癌症研究所的Gilberto De Castro Jr教授，以“First–line Ceritinib Versus Chemotherapy in Patients With ALK–rearranged(ALK+)NSCLC:A Randomized,Phase 3 Study(ASCEND–4)”为题，报告了ALK重排（ALK+）NSCLC一线靶向和化疗的对比（ASCEND–4）。

研究背景

ALK融合基因发生于3%~7%的NSCLC患者，临床上常见于不吸烟的年轻腺癌患者，通常与EGFR或KRAS突变的发生互相排斥。2015年色瑞替尼得到FDA批准上市，在ALK重排（ALK+）阳性的NSCLC中取得较好的治疗效果。在2016WCLC上，研究者报告了一线色瑞替尼对比传统化疗治疗晚期ALK阳性NSCLC的研究结果。

研究内容

研究入组的376例患者为未接受过治疗，免疫组化证实为ALK阳性的晚期非鳞NSCLC，中位年龄54岁。

按1:1比例将患者随机分配进色瑞替尼治疗组（n=189）和传统化疗组（n=187）。

◆色瑞替尼治疗组给药：色瑞替尼750 mg/天；其中有59例存在脑转移；

◆化疗组给药：培美曲塞500mg/m2+顺铂75mg/m2或卡铂AUC 5-6，四周期后培美曲塞维持治疗。

按照WHO PS、脑转移和继往新辅助/辅助化疗情况将患者分层。若化疗出现疾病进展可允许患者交叉进入色瑞替尼组（交叉治疗n=80）。

研究结果

色瑞替尼组的中位药物暴露时间为66.4周，而化疗组仅有26.9周。

中位随访持续时间19.7个月（自随机化至截止日），研究实现了主要目的。经盲化独立中心评审（BIRC）分析，色瑞替尼组患者与化疗组相比中位PFS明显改善，分别为16.6 vs 8.1个月（HR=0.55）。

期中分析只完成了42.3%的需要事件，OS数据未成熟（HR=0.73,P=0.056）。

经BIRC分析，与化疗相比色瑞替尼治疗的客观缓解率（ORR）和缓解持续时间（DOR）均更高，其中ORR分别为26.7%vs 72.5%；中位DOR分别为11.1 vs 23.9个月。

对于基线脑转移可测量以及≥1次基线后评估的患者，色瑞替尼治疗的颅内ORR（BIRC，修正的RECIST v1.1标准）也比化疗高，分别为72.7%vs 27.3%。

最常见的不良事件（>50%）在色瑞替尼组为腹泻（84.7%）、恶心（68.8%）、呕吐（66.1%）以及ALT（60.3%）和AST升高（52.9%）。总体而言，色瑞替尼组和化疗组分别有5.3%和11.4%的患者因疑似药物相关的不良事件而中断治疗。

结论

对于ALK阳性晚期NSCLC患者，与化疗（包括维持治疗）相比，色瑞替尼单药一线方案在统计学和临床两方面都取得了显著的改善（PFS），使疾病进展风险降低约45%。

此外，对于存在脑转移的NSCLC患者，色瑞替尼治疗达到了高效、持续的系统缓解以及较高的颅内缓解。安全特性与之前的研究报道相一致。

原文：

ASCEND-4

First-line Ceritinib Versus Chemotherapy in Patients With ALK-rearranged (ALK+) NSCLC: A Randomized, Phase 3 Study

Background: Here, we report results of ceritinib versus chemotherapy as first-line treatment for advanced ALK+ NSCLC.

Methods: Untreated ALK+ (IHC confirmed), advanced, nonsquamous NSCLC patients (N=376; median age, 54 years) were randomized (1:1) to ceritinib 750 mg/day (n=189 [59 with brain metastases (BM)]) or chemotherapy (n=187 [62 with BM]; [pemetrexed 500 mg/m[2] plus cisplatin 75 mg/m[2] or carboplatin AUC 5-6] for 4 cycles followed by maintenance pemetrexed), stratified by WHO PS (0 vs 1-2), BM at screening, and prior neo-/adjuvant chemotherapy. Crossover from chemotherapy to ceritinib was allowed at progression (n=80 crossed-over).

Results: Median treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy. Median follow-up duration was 19.7 months (randomization to cut-off date). The study met its primary objective, with ceritinib demonstrating statistically significant improvement in BIRC PFS (RECIST 1.1; median, 16.6 [12.6, 27.2] vs 8.1 months [5.8, 11.1], HR=0.55, P<0.001) versus chemotherapy. OS was immature (HR, 0.73 [0.50, 1.08]; P=0.056) with 42.3% of required events at interim analysis. ORR (BIRC, 72.5% vs 26.7%) and DOR (BIRC, median, 23.9 vs 11.1 months) were also higher with ceritinib versus chemotherapy. Among patients with measurable baseline BM and ≥1 postbaseline assessment, intracranial ORR (BIRC neuroradiologist; modified RECIST v1.1) was higher with ceritinib (72.7% [49.8, 89.3] vs 27.3% [10.7, 50.2]) versus chemotherapy (Table). Most common AEs (>50%) with ceritinib were diarrhea (84.7%), nausea (68.8%), vomiting (66.1%), ALT increase (60.3%), and AST increase (52.9%). Overall, 5.3% ceritinib- and 11.4% chemotherapy-treated patients discontinued due to AEs suspected to be drug-related.

Conclusion: First-line ceritinib achieved statistically significant and clinically meaningful improvement in median PFS with an estimated 45% risk reduction in advanced ALK+ NSCLC versus chemotherapy including maintenance. Moreover, ceritinib achieved high and durable systemic responses and high OIRR in patients with measurable BM. Safety profile of ceritinib is consistent with previously reported.