Introduction: Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is a first‐line treatment for ALK translocation–positive advanced non–small cell lung cancer (NSCLC); however, patients eventually progress. Immunotherapies, including the programmed death‐1 inhibitor nivolumab, have resulted in durable responses and long‐term overall survival in patients with NSCLC. We hypothesized that combining targeted therapy with immunotherapy could result in more patients with responses and/or more durable responses. Herein we report data from a study assessing nivolumab plus crizotinib in patients with previously untreated advanced ALK translocation–positive NSCLC. Methods: Group E in CheckMate 370 was a single‐arm cohort designed to evaluate the safety of first‐line nivolumab (240 mg every 2 weeks) plus crizotinib (250 mg twice daily) in patients with ALK translocation–positive NSCLC. The primary endpoint of safety would be met if ≤20% of patients discontinued treatment due to treatment‐related adverse events by week 17. Objective response rate was a secondary endpoint. A planned safety review occurred in November 2016; the data cutoff was May 26, 2017. Results: Of the first 13 patients treated with nivolumab plus crizotinib, 5 (38%) developed severe hepatic toxicities leading to the discontinuation of the combination. Of these, two patients died and the presence of severe hepatic toxicities may have contributed to death. Enrollment was closed and combination treatment discontinued due to observed grade ≥3 hepatic toxicities. Five patients (38%) had a partial response. Conclusions: These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily.

中文翻译：

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纳武单抗加克唑替尼一线治疗 ALK 易位阳性晚期非小细胞肺癌的安全性和耐受性的 1/2 期研究 (CheckMate 370)

简介：克唑替尼是一种间变性淋巴瘤激酶 (ALK) 抑制剂，是 ALK 易位阳性晚期非小细胞肺癌 (NSCLC) 的一线治疗药物；然而，患者最终会进展。免疫疗法，包括程序性死亡 1 抑制剂纳武单抗，已在非小细胞肺癌患者中产生持久的反应和长期的总生存期。我们假设将靶向治疗与免疫治疗相结合可能会导致更多患者出现反应和/或更持久的反应。在此，我们报告了一项评估纳武单抗联合克唑替尼治疗既往未经治疗的晚期 ALK 易位阳性 NSCLC 患者的研究数据。方法：CheckMate 370 中的 E 组是一个单臂队列，旨在评估一线纳武单抗（每 2 周 240 毫克）加克唑替尼（250 毫克，每天两次）在 ALK 易位阳性 NSCLC 患者中的安全性。如果在第 17 周前≤ 20% 的患者因治疗相关不良事件而停止治疗，则将达到安全性的主要终点。客观反应率是次要终点。2016 年 11 月进行了计划中的安全审查；数据截止日期为 2017 年 5 月 26 日。 结果：在接受纳武单抗加克唑替尼治疗的前 13 名患者中，5 名 (38%) 出现了严重的肝毒性，导致联合用药终止。其中，两名患者死亡，严重肝毒性的存在可能导致死亡。由于观察到 ≥ 3 级肝毒性，招募已结束并停止联合治疗。五名患者 (38%) 有部分反应。结论：这些发现不支持对纳武单抗 240 mg 每 2 周加克唑替尼 250 mg 每天两次的进一步评估。