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桓兴医讯 Nivolumab联合Ipilimumab治疗高肿瘤突变负荷肺癌
文章来源:北京市朝阳区桓兴肿瘤医院 点击数: 发布时间:2018-04-18 16:50
《新英格兰杂志》2018-4-16在线先发
Nivolumab联合Ipilimumab治疗高肿瘤突变负荷肺癌
背景
Nivolumab联合ipilimumab在1期试验中显示出治疗非小细胞肺癌(NSCLC)有前景的功效,并且肿瘤突变负荷已经成为有益的潜在生物标志物。 在这项开放标签,多部分,3期临床试验,我们检测nivolumab联合ipilimumab相比化疗治疗高肿瘤突变负荷(≥10个突变/百万个碱基)患者的无进展生存期。
方法
我们招募了既往未接受过化疗的IV期或复发性NSCLC患者。 那些肿瘤程序性死亡配体1(PD-L1)表达水平至少为1%的患者以1:1:1的比例随机分配,分别接受nivolumab联合ipilimumab,nivolumab单药疗法或化疗; 那些肿瘤PD-L1表达水平低于1%的患者以1:1:1的比例随机分配,接受nivolumab联合ipilimumab,nivolumab联合化疗或化疗。 FoundationOne公司的CDx仪器确定肿瘤突变负荷。
结果
nivolumab联合ipilimumab治疗高肿瘤突变负荷患者的无进展生存期显著长于化疗。 nivolumab联合ipilimumab 1年无进展生存率为42.6%,化疗为13.2%,且中位无进展生存期为7.2个月(95%置信区间[CI],5.5至13.2),相对化疗5.5个月(95 %CI,4.4-5.8)(疾病进展或死亡风险比,0.58; 97.5%CI,0.41-0.81; P <0.001)。 nivolumab联合ipilimumab的客观有效率为45.3%,化疗为26.9%。 nivolumab联合ipilimumab对化疗的益处在亚组内广泛一致,包括PD-L1表达水平至少为1%的患者和水平低于1%的患者。 Nivolumab联合ipilimumab组3或4级治疗相关不良事件的发生率为31.2%,化疗组发生率为36.1%。
结论
无论是否存在PD-L1表达水平,nivolumab联合ipilimumab一线治疗高肿瘤突变负荷的NSCLC的无进展生存期显著长于化疗。该结果验证了nivolumab联合ipilimumab在NSCLC中的益处以及肿瘤突变负荷作为患者选择的生物标志物的作用。 (由Bristol-Myers Squibb和Ono Pharmaceutical资助; CheckMate 227 ClinicalTrials.gov编号,NCT02477826)。
北京市朝阳区桓兴肿瘤医院 桓兴医讯编译组 吴永勇
2018年4月18日 星期三
Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden
BACKGROUND
Nivolumab plus ipilimumab showed promising efficacy for the treatment of non–small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase).
METHODS
We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay.
RESULTS
Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD-L1 expression level of at least 1% and those with a level of less than 1%. The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy.
CONCLUSIONS
Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.)

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