背景:CheckMate 649 是基于晚期胃癌/胃食管交界癌/食管腺癌(GC/GEJC/EAC) 一线用药中程序性死亡(PD)-1 抑制剂治疗最大的随机性、全球性 3 期研究。在联合阳性评分(CPS)为≥5 和≥1的肿瘤表达 pd 配体(L)1 的患者和所有随机患者中，一线用药尼鲁单抗联合化疗（1L NIVO +化疗）显示的总生存期(OS)，无进展生存期(PFS)受益和可接受的安全性均优于单纯化疗组 (Moehler et al. Ann Oncol 2020)。本文展示了所有随机患者的额外数据。

Background: CheckMate 649 is the largest randomized, global phase 3 study of 1L programmed death (PD)-1 inhibitor–based therapy in GC/GEJC/EAC. 1L NIVO + chemo demonstrated superior overall survival (OS) vs chemo, with progression-free survival (PFS) benefit and an acceptable safety profile in pts whose tumors expressed PD-ligand (L)1 at combined positive score (CPS) ≥ 5 and ≥ 1, and in all randomized pts (Moehler et al. Ann Oncol 2020). We report additional data for all randomized pts.

方法:符合条件的患者为先前未经治疗、不可切除的晚期或转移性 GC/GEJC/EAC 患者。而已知的 her2 阳性患者被排除在外。患者随机接受尼鲁单抗 NIVO (360 mg Q3W 或 240 mg Q2W) +化疗(XELOX Q3W 或 FOLFOX Q2W)、NIVO 联合易普利姆玛化疗或单纯化疗。在满足 PD-L1 CPS≥ 5 患者中，NIVO +化疗与单纯化疗的评判指标分别为 OS 和 PFS。分级检测的次要指标是 PD-L1 CPS ≥1 和所有随机患者的总生存期(OS)。

Methods: Eligible pts had previously untreated, unresectable advanced or metastatic GC/GEJC/EAC. Known HER2-positive pts were excluded. Pts were randomized to receive NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded central review in PD-L1 CPS ≥ 5 pts. Hierarchically tested secondary endpoints were OS in PD-L1 CPS ≥ 1 and all randomized pts.

结果:对 1581 名随机患者最少 12 个月的随访结果显示：与单纯化疗相比，NIVO +化疗的总生存期(OS)获益有统计学意义(HR 0.80 [99.3% CI 0.68-0.94;P = 0.0002]); 无进展生存期(PFS)也有改善(HR 0.77 [95% CI 0.68-0.87])。在多个预先确定的亚组中观察到 OS 获益与主要人群一致。59% (NIVO +化疗)和 44%(单纯化疗)的患者报告了 3-4 级治疗相关不良事件(TRAEs)。具有潜在免疫病原学的 TRAEs(选择 TRAEs;表中显示了 sTRAEs)。与单纯化疗组相比，NIVO + 化疗组患者接受治疗后症状恶化的风险有降低(HR 0.77 [95% CI 0.63-0.95;P = 0.0129)。通过FACT-Ga GP5 项目测量的耐受性在两组治疗中是相似的。

Results: At 12-month minimum follow-up for 1581 randomized pts, NIVO + chemo had a statistically significant OS benefit vs chemo (HR 0.80 [99.3% CI 0.68–0.94; P = 0.0002]) in all randomized pts; PFS benefit was also seen (HR 0.77 [95% CI 0.68–0.87]). OS benefit was observed in multiple prespecified subgroups, consistent with the primary population. Grade 3–4 treatment-related adverse events (TRAEs) were reported in 59% (NIVO + chemo) and 44% (chemo) of pts. TRAEs with potential immunologic etiology (select TRAEs; sTRAEs) are shown in the table. Pts in the NIVO + chemo arm had decreased risk of symptom deterioration on treatment vs those in the chemo arm (HR 0.77 [95% CI 0.63–0.95; P = 0.0129]). Tolerability as measured by the FACT-Ga GP5 item was similar in both treatment groups.

a：There were no grade 5 events; bEvents without a stop date or where stop date was death date were considered unresolved. Events without worsening from baseline were excluded.

结论:在化疗中加入尼鲁单抗可改善所有随机患者的总生存期(OS)和无进展 存期(PFS)，并具有可接受的安全性，维持耐受性和生活质量，进一步支持尼鲁单抗联合化疗（NIVO +）作为晚期 GC/GEJC/EAC 的标准一线用药治疗方案。

Conclusions: The addition of NIVO to chemo demonstrated improved OS and PFS benefit in all randomized pts, along with an acceptable safety profile and maintained tolerability as well as QoL, providing further support for NIVO + chemo as a standard 1L treatment for advanced GC/GEJC/EAC.