FDA Approval Summary: Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based Chemotherapy.
FDA Approval Summary: Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based Chemotherapy.
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DOI：
10.1634/theoncologist.2015-0507
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发表时间：
2016-05
期刊：
影响因子：
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通讯作者：
Pazdur R
中科院分区：
文献类型：
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作者：
Kazandjian D;Suzman DL;Blumenthal G;Mushti S;He K;Libeg M;Keegan P;Pazdur R
在CheckMate 057试验中，一项国际、多中心、开放标签、随机化试验，在铂类化疗期间或之后进展的转移性非鳞状非小细胞肺癌患者中，与多西他赛相比，nivolumab证明了总生存期和客观缓解率的改善。无进展生存期在研究的两组之间没有差异。2015年10月9日，美国食品药品监督管理局（FDA）在3.25个月的审查时间轴后，将纳武利尤单抗转移性非小细胞肺癌（NSCLC）适应症扩展至包括非鳞状NSCLC患者。批准是基于在一项国际、多中心、开放标签、随机试验中证明了在铂类化疗期间或之后进展的转移性非鳞状NSCLC患者中，nivolumab与多西他赛的总生存期（OS）改善。CheckMate 057试验招募了582名患者，他们随机（1：1）接受nivolumab或多西他赛。在预先规定的中期分析中，与多西他赛相比，纳武利尤单抗显示OS改善，风险比（HR）为0.73（p = .0015），纳武利尤单抗治疗患者的中位OS为12.2个月（95% CI：9.7-15.0个月），多西他赛治疗患者的中位OS为9.4个月（95% CI：8.0-10.7个月）。客观缓解率（ORR）也有统计学显著改善，ORR为19%（95% CI：15%-24%）和12%（95%置信区间：反应的中位持续时间在纳武单抗组中为17个月，在多西他赛组中为6个月。两组间无瘤生存率无统计学差异。一项预先设定的回顾性亚组分析表明，接受纳武单抗治疗的程序性细胞死亡配体1阴性肿瘤患者的OS与接受多西他赛治疗的患者相似。纳武利尤单抗的毒性特征与已知的免疫介导的不良事件特征一致，除了1例5级边缘系统脑炎，这导致了上市后要求研究，以更好地表征免疫介导的脑炎。根据CheckMate 057临床试验的结果，nivolumab代表了需要二线治疗转移性非小细胞肺癌患者的新治疗选择。纳武利尤单抗在致敏性表皮生长因子受体（EGFR）和间变性淋巴瘤激酶（ALK）改变患者中的作用尚不清楚。在进行专门研究以更好地表征程序性细胞死亡1（PD-1）治疗的作用和顺序之前，EGFR或ALK改变的患者在开始PD-1抑制剂治疗之前应在适当的靶向治疗中取得进展。一些肿瘤缺乏程序性细胞死亡配体1（PD-L1）表达的患者似乎也具有持久的反应。美国食品和药物管理局批准了Dako的PD-L1检测，PD-L1 IHC 28-8 pharmDx，申请人声称该检测是nivolumab使用的非必要补充诊断。
In the CheckMate 057 trial, an international, multicenter, open-label, randomized trial in patients with metastatic nonsquamous non-small cell lung cancer with progression on or after platinum-based chemotherapy, improved overall survival and objective response rates were demonstrated with nivolumab compared with docetaxel. Progression-free survival did not differ between the two arms of the study. On October 9, 2015, the U.S. Food and Drug Administration expanded the nivolumab metastatic non-small cell lung cancer (NSCLC) indication to include patients with nonsquamous NSCLC after a 3.25-month review timeline. Approval was based on demonstration of an improvement in overall survival (OS) in an international, multicenter, open-label, randomized trial comparing nivolumab to docetaxel in patients with metastatic nonsquamous NSCLC with progression on or after platinum-based chemotherapy. The CheckMate 057 trial enrolled 582 patients who were randomized (1:1) to receive nivolumab or docetaxel. Nivolumab demonstrated improved OS compared with docetaxel at the prespecified interim analysis with a hazard ratio (HR) of 0.73 (p = .0015), and a median OS of 12.2 months (95% CI: 9.7–15.0 months) in patients treated with nivolumab compared with 9.4 months (95% CI: 8.0–10.7 months) in patients treated with docetaxel. A statistically significant improvement in objective response rate (ORR) was also observed, with an ORR of 19% (95% CI: 15%–24%) in the nivolumab arm and 12% (95% CI: 9%–17%) in the docetaxel arm. The median duration of response was 17 months in the nivolumab arm and 6 months in the docetaxel arm. Progression-free survival was not statistically different between arms. A prespecified retrospective subgroup analysis suggested that patients with programmed cell death ligand 1-negative tumors treated with nivolumab had similar OS to those treated with docetaxel. The toxicity profile of nivolumab was consistent with the known immune-mediated adverse event profile except for 1 case of grade 5 limbic encephalitis, which led to a postmarketing requirement study to better characterize immune-mediated encephalitis. Based on the results from the CheckMate 057 clinical trial, nivolumab represents a new treatment option for patients requiring second-line treatment for metastatic non-small cell lung cancer. The role of nivolumab in patients with sensitizing epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) alterations is less clear. Until dedicated studies are performed to better characterize the role and sequence of programmed cell death 1 (PD-1) therapy, patients with EGFR or ALK alterations should have progressed on appropriate targeted therapy before initiating PD-1 inhibitor therapy. Some patients whose tumors lack programmed cell death ligand 1 (PD-L1) expression also appear to have durable responses. The U.S. Food and Drug Administration granted approval to Dako’s PD-L1 test, PD-L1 IHC 28-8 pharmDx, which the applicant claimed as a nonessential complementary diagnostic for nivolumab use.