Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden.
Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden.
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DOI：
10.1056/nejmoa1801946
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发表时间：
2018-05-31
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影响因子：
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通讯作者：
Paz-Ares L
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作者：
Hellmann MD;Ciuleanu TE;Pluzanski A;Lee JS;Otterson GA;Audigier-Valette C;Minenza E;Linardou H;Burgers S;Salman P;Borghaei H;Ramalingam SS;Brahmer J;Reck M;O'Byrne KJ;Geese WJ;Green G;Chang H;Szustakowski J;Bhagavatheeswaran P;Healey D;Fu Y;Nathan F;Paz-Ares L
在1期试验中，纳武利尤单抗联合伊匹木单抗在非小细胞肺癌（NSCLC）治疗中显示出有前景的疗效，并且肿瘤突变负荷已成为一种潜在的获益生物标志物。在这项开放标签、多部分的3期试验的这一部分中，我们检测了肿瘤突变负荷高（每兆碱基≥10个突变）的患者使用纳武利尤单抗联合伊匹木单抗对比化疗的无进展生存期。
我们纳入了既往未接受过化疗的IV期或复发性NSCLC患者。肿瘤程序性死亡配体1（PD - L1）表达水平至少为1%的患者按1∶1∶1的比例随机分配接受纳武利尤单抗联合伊匹木单抗、纳武利尤单抗单药治疗或化疗；肿瘤PD - L1表达水平低于1%的患者按1∶1∶1的比例随机分配接受纳武利尤单抗联合伊匹木单抗、纳武利尤单抗联合化疗或化疗。肿瘤突变负荷通过FoundationOne CDx检测确定。
在肿瘤突变负荷高的患者中，纳武利尤单抗联合伊匹木单抗的无进展生存期显著长于化疗。纳武利尤单抗联合伊匹木单抗组1年无进展生存率为42.6%，化疗组为13.2%；中位无进展生存期分别为7.2个月（95%置信区间[CI]，5.5 - 13.2）和5.5个月（95%CI，4.4 - 5.8）（疾病进展或死亡的风险比为0.58；97.5%CI，0.41 - 0.81；P < 0.001）。客观缓解率在纳武利尤单抗联合伊匹木单抗组为45.3%，化疗组为26.9%。纳武利尤单抗联合伊匹木单抗相对于化疗的优势在各亚组中基本一致，包括PD - L1表达水平至少为1%的患者和低于1%的患者。纳武利尤单抗联合伊匹木单抗组3级或4级治疗相关不良事件发生率为31.2%，化疗组为36.1%。
在非小细胞肺癌且肿瘤突变负荷高的患者中，无论PD - L1表达水平如何，一线使用纳武利尤单抗联合伊匹木单抗的无进展生存期显著长于化疗。这些结果验证了纳武利尤单抗联合伊匹木单抗在非小细胞肺癌中的益处以及肿瘤突变负荷作为患者选择生物标志物的作用。（由百时美施贵宝和小野制药资助；CheckMate 227，Clinicaltrials.gov编号，NCT02477826）
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). 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. 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. 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.)