Discussion讨论

Treatment Approaches治疗手段

Targeted Therapies 靶向治疗

Ceritinib 色瑞替尼

Ceritinib is approved by the FDA for patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. The approval is based on an expanded phase 1 study (ASCEND-1) showing overall response rates of 56% to ceritinib in patients (92/163) who had previously received crizotinib; the median duration of response was 8.3 months (6.8-9.7). Common grade 3 to 4 adverse events included increased alanine aminotransferase (73  [30%] patients) and increased aspartate aminotransferase (25 [10%]). Some patients with CNS lesions responded to ceritinib. Based on the study and the FDA approval, the NCCN Panel recommends ceritinib as subsequent therapy for patients with ALK-positive NSCLC who have progressed after crizotinib; patients who do not tolerant crizotinib may be switched to ceritinib or alectinib. A recent phase 2 trial (ASCEND-2) assessed ceritinib in patients who had previously received at least 2 or more treatments, had progressed on crizotinib, and had brain metastases. The overall response rate was 38%; the duration of response was 9.7 months (95% CI, 7.1–11.1 months). The intracranial overall response rate was 45.0% (95% CI, 23.1%–68.5%). FDA批准了色瑞替尼用于克唑替尼进展或不能耐受、ALK阳性的转移性NSCLC患者。批准是根据一项扩展的1期研究（ASCEND-1）显示，在既往已接受克唑替尼治疗的患者中，色瑞替尼治疗的总有效率为56%（92/163）；中位疗效持续时间是8.3个月（6.8-9.7）。常见的3-4级不良事件包括丙氨酸氨基转移酶升高（73例[30%]）及天冬氨酸转氨酶升高（25例[10%]）。某些具有CNS病变的患者对色瑞替尼应答。基于该研究和FDA的批准，研究小组建议色瑞替尼作为ALK阳性的NSCLC患者在克唑替尼进展后的后续治疗；不耐受克唑替尼的患者可以转换至色瑞替尼或阿雷替尼。最近一项2期试验（ASCEND-2）评估了色瑞替尼治疗既往曾接受过至少2个或以上治疗、克唑替尼进展并有脑转移的患者。总有效率是38%；疗效持续时间是9.7个月（95%CI，7.1-11.1个月）。颅内病变总有效率为45.0%（95%CI，23.1%-68.5%）。山东省肿瘤医院呼吸肿瘤内科张品良

A recent phase 3 trial assessed ceritinib versus platinum-based chemotherapy as first-line therapy for patients with ALK-positive metastatic NSCLC. The data show that PFS was improved when using ceritinib when compared with platinum-based chemotherapy; the median PFS was 16.6 months (95% CI, 12.6–27.2) for ceritinib and 8.1 months (CI, 5.8–11.1) for chemotherapy (hazard ratio 0.55 [95% CI, 0.42–0.73]; P<.00001). For ceritinib, common adverse events included diarrhea (85% [160/189] of patients), nausea (69% [130/189]), vomiting (66% [125/189), and an increase in alanine aminotransferase (60% [114/189]). For chemotherapy, common adverse events included nausea (55% [97/175 patients], vomiting (36% [63/175]), and anemia (35% [62/175]). For the 2017 update (Version 5), the NCCN Panel now recommends (category 1) ceritinib as first-line therapy for patients with ALK-positive metastatic NSCLC based on this phase 3 trial. 最近一项3期试验评估了色瑞替尼与以铂为基础的化疗作为ALK-阳性转移性非小细胞肺癌患者的一线治疗。数据显示，与以铂为基础的化疗相比，使用色瑞替尼延长无进展生存期；中位无进展生存期色瑞替尼是16.6个月（95%CI，12.6-27.2），化疗是8.1个月（CI，5.8-11.1）（风险比为0.55[95% CI，0.42-0.73]；P<0.00001）。色瑞替尼常见的不良反应包括腹泻（85% [160/189]）、恶心（69%[130/189]）、呕吐（66%[125/189）和丙氨酸氨基转移酶升高（60%[114/189]）。化疗常见的不良反应包括恶心（55%[97/175]）、呕吐（36%[63/175]）和贫血（35%[62/175]）。根据该3期试验，2017第5版更新，NCCN小组目前推荐（1类）色瑞替尼作为ALK阳性转移性非小细胞肺癌患者的一线治疗。