背景:CheckMate 649 是基於晚期胃癌/胃食管交界癌/食管腺癌(GC/GEJC/EAC) 一線用藥中程序性死亡(PD)-1 抑製劑治療最大的隨機性、全球性 3 期研究。在聯合陽性評分(CPS)為≥5 和≥1的腫瘤表達 pd 配體(L)1 的患者和所有隨機患者中，一線用藥尼魯單抗聯合化療（1L NIVO +化療）顯示的總生存期(OS)，無進展生存期(PFS)受益和可接受的安全性均優於單純化療組 (Moehler et al. Ann Oncol 2020)。本文展示了所有隨機患者的額外數據。

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:符合條件的患者為先前未經治療、不可切除的晚期或轉移性 GC/GEJC/EAC 患者。而已知的 her2 陽性患者被排除在外。患者隨機接受尼魯單抗 NIVO (360 mg Q3W 或 240 mg Q2W) +化療(XELOX Q3W 或 FOLFOX Q2W)、NIVO 聯合易普利姆瑪化療或單純化療。在滿足 PD-L1 CPS≥ 5 患者中，NIVO +化療與單純化療的評判指標分別為 OS 和 PFS。分級檢測的次要指標是 PD-L1 CPS ≥1 和所有隨機患者的總生存期(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.

結果:對 1581 名隨機患者最少 12 個月的隨訪結果顯示：與單純化療相比，NIVO +化療的總生存期(OS)獲益有統計學意義(HR 0.80 [99.3% CI 0.68-0.94;P = 0.0002]); 無進展生存期(PFS)也有改善(HR 0.77 [95% CI 0.68-0.87])。在多個預先確定的亞組中觀察到 OS 獲益與主要人群一致。59% (NIVO +化療)和 44%(單純化療)的患者報告了 3-4 級治療相關不良事件(TRAEs)。具有潛在免疫病原學的 TRAEs(選擇 TRAEs;表中顯示了 sTRAEs)。與單純化療組相比，NIVO + 化療組患者接受治療後症狀惡化的風險有降低(HR 0.77 [95% CI 0.63-0.95;P = 0.0129)。通過FACT-Ga GP5 項目測量的耐受性在兩組治療中是相似的。

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.

結論:在化療中加入尼魯單抗可改善所有隨機患者的總生存期(OS)和無進展 存期(PFS)，並具有可接受的安全性，維持耐受性和生活質量，進一步支持尼魯單抗聯合化療（NIVO +）作為晚期 GC/GEJC/EAC 的標準一線用藥治療方案。

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.