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2016 ESMO大会上，除了闪耀全场的免疫治疗外，针对间变性淋巴瘤激酶（ALK）的靶向治疗研究也引人瞩目。Ⅲ期临床试验ASCEND-5结果显示，对于克唑替尼治疗后病情恶化的ALK阳性非小细胞肺癌（NSCLC），色瑞替尼与化疗相比可显著延长患者无进展生存期。
主要研究者，来自意大利都灵大学的Giorgio Scagliotti教授说：“ALK阳性NSCLC患者一线应首选ALK抑制剂克唑替尼，但绝大多数患者对克唑替尼耐药后，二线方案采用化疗。ASCEND-5是首个在克唑替尼治疗失败后，比较二代ALK抑制剂色瑞替尼是否优于化疗的Ⅲ期临床研究。”
该研究纳入231例NSCLC患者，随机进入色瑞替尼治疗或化疗（培美曲塞或多西他赛）。化疗组患者如出现疾病进展可交叉进入色瑞替尼组继续治疗。主要终点是无进展生存（PFS）。
中位PFS在色瑞替尼治疗组为5.4个月，而化疗组仅有1.6个月（HR=0.49）。与化疗相比，色瑞替尼使总缓解率显著增加（39.1% vs 6.9%），但两干预组的总生存期并无明显差异。
化疗无效疾病进展，最后交叉进入色瑞替尼组治疗的患者共有75例。
Scagliotti教授表示，与化疗相比，NSCLC患者的PFS在色瑞替尼治疗下有明显延长。但并没有观察到总生存有多少提高，可能使因为交叉到色瑞替尼治疗的患者稀释了该药潜在的临床获益。
在毒性方面，该研究与之前的Ⅰ/Ⅱ期试验结果近似。最常见的3/4不良事件在色瑞替尼组是恶心（7.8%）、呕吐（7.8%）、腹泻（4.3%），在化疗组是中性粒细胞减少（15.5%）、乏力（4.4%）和恶心（1.8%）。与安慰剂相比，色瑞替尼显著提高了患者报告结局，包括肺癌特异性症状和总体健康状态。
“这项研究为克唑替尼治疗失败后的NSCLC创立了新的治疗策略。现在有理由确定给药顺序了，即先以克唑替尼为一线，耐药后过渡到色瑞替尼二线。” Scagliotti教授说道。
美国麻省总医院胸部肿瘤科主任Alice Shaw教授在评论该研究时表示：“这是第一个在ALK阳性患者二线治疗中比较二代ALK抑制剂和化疗的研究。先前的单臂试验提示，色瑞替尼和alectinib均可成为克唑替尼治疗失败后的二线治疗选择，而该Ⅲ期研究进一步证实了二代ALK抑制剂在提升PFS方面优于化疗。这将建立转移性ALK阳性肺癌克唑替尼转向色瑞替尼的治疗顺序。”
Shaw教授进一步总结道：“我们现在很期待二代ALK抑制剂在一线治疗中的试验结果，包括色瑞替尼 vs 化疗和alectinib vs 克唑替尼。后者将解决ALK阳性肺癌治疗领域最重要的问题，即谁才是ALK抑制剂的首选。”
信源：Ceritinib Provides Longer Progression-free Survival Than Chemotherapy in Phase III Trial of ALK Rearranged Lung Cancer Treatment. ESMO 2016 Press Release.
摘要原文
Abstract：LBA42
Title：Ceritinib vs chemotherapy (CT) in patients (pts) with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with CT and crizotinib (CRZ): results from the confirmatory phase 3 ASCEND-5 study
Background: The ALK inhibitor CRZ is effective in ALK+ NSCLC pts, but most develop resistance and progressive disease (PD). Ceritinib showed robust efficacy in CRZ-pretreated pts in phase 1 & 2 studies. This multicenter, open-label phase 3 study (NCT01828112) compared efficacy of ceritinib vs CT in ALK+ NSCLC pts pretreated with CT & CRZ.
Methods: ALK+ NSCLC pts pretreated with 1–2 CT regimens & CRZ were randomized to oral ceritinib 750 mg/d or CT (pemetrexed [PEM] 500 mg/m2 or docetaxel [DOC] 75 mg/m2), stratified by WHO PS (0 vs 1–2) & brain metastasis at screening. Pts discontinuing CT due to PD could crossover to ceritinib. Primary endpoint was progression-free survival (PFS), assessed by blinded independent review committee (BIRC) per RECIST v1.1.
Results: Of 231 pts (median age 54 y), 115 were randomized to ceritinib and 116 to CT (PEM, n=40; DOC, n=73; 3 not treated). Median treatment exposure was 30.3 wk for ceritinib and 6.3 wk for CT. Median follow-up duration was 16.5 mo. Ceritinib showed statistically significant improvement in PFS (BIRC: median 5.4 vs 1.6 mo, HR=0.49, P<0.001) and increased overall response rate [95% CI] (BIRC: 39.1% [30.2, 48.7] vs 6.9% [3.0, 13.1]) vs CT (Table). Of pts discontinuing CT due to PD, 75 crossed over to ceritinib. Most frequent AEs (% any grade [% grade 3/4]) were diarrhoea (72.2 [4.3]), nausea (66.1 [7.8]) & vomiting (52.2 [7.8]) with ceritinib; fatigue (28.3 [4.4]), nausea (23.0 [1.8]), alopecia (21.2 [0]) & neutropenia (20.4 [15.0]) with CT. 6 (5.2%) ceritinib- and 8 (6.9%) CT-treated pts discontinued due to AEs. Ceritinib significantly improved lung cancer-specific symptoms (LCSS & QLQ-LC13) & overall health status (EQ-5D) vs CT (P<0.05).
Conclusions: Ceritinib showed a clinically meaningful and statistically significant improvement in PFS vs CT in pretreated ALK+ NSCLC.
