PO.CL09.02 · 临床研究
PD-L1表达依赖的一线免疫检查点抑制剂联合化疗在晚期胃癌及胃食管结合部腺癌中的疗效：III期临床试验的系统评价与荟萃分析
PD-L1 expression-dependent efficacy of first-line immune checkpoint inhibitor plus chemotherapy in advanced gastric and gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis of phase III trials
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：免疫检查点抑制剂（ICI）已改变了晚期胃癌及胃食管结合部腺癌的一线治疗格局。多项III期试验评估了在化疗基础上加用ICI，但结果存在异质性。本研究旨在通过对随机III期试验的系统评价与荟萃分析，确定一线ICI联合化疗相比单纯化疗的疗效与安全性，并界定具有临床意义的PD-L1表达阈值。
方法：系统检索PubMed、Embase及Cochrane临床对照试验注册库，截至2025年9月。纳入分析的研究为比较免疫检查点抑制剂（ICI）联合化疗与单纯化疗治疗晚期或转移性胃癌或GEJ腺癌患者的III期随机对照试验。采用随机效应模型计算总生存期（OS）和无进展生存期（PFS）的合并风险比（HR）及95%置信区间（CI）。基于PD-L1联合阳性评分（CPS）、年龄、性别、ECOG体能状态评分（ECOG）、地理区域、肝转移和肿瘤部位进行亚组分析。通过≥3级不良事件（AE）和严重不良事件（SAE）的合并风险比（RR）评估安全性。
结果：共纳入8项III期试验，涉及7,127例既往未经治疗、HER2阴性的晚期或转移性胃癌或GEJ腺癌患者。合并分析显示，ICI联合化疗相比单纯化疗显著改善OS（HR = 0.79，95% CI 0.75-0.83）和PFS（HR = 0.71，95% CI 0.65-0.79）。治疗获益随PD-L1 CPS升高而增加：OS的HR分别为0.90（CPS < 1）、0.76（CPS ≥ 1）、0.75（CPS ≥ 5）和0.65（CPS ≥ 10）；PFS呈现相似趋势（分别为0.87、0.73、0.65、0.63）。各主要亚组疗效一致（所有交互作用p > 0.05）。联合治疗相比单纯化疗轻度增加≥3级AE（RR = 1.16，95% CI 1.09-1.23）和SAE（RR = 1.54，95% CI 1.35-1.77）。
结论：一线ICI联合化疗可显著延长晚期胃癌及GEJ腺癌的OS和PFS，且毒性可控。获益幅度主要由PD-L1表达驱动，支持将CPS作为治疗选择中具有临床意义的生物标志物。基于ICI的联合方案应被视为跨临床相关亚组的新标准治疗。
查看英文原文 English abstract
Background: Immune checkpoint inhibitors (ICIs) have transformed the first-line management of advanced gastric and gastroesophageal junction adenocarcinoma. Several phase III trials have evaluated adding an ICI to chemotherapy, yet results have been heterogeneous. This study aimed to determine the efficacy and safety of first-line ICI plus chemotherapy versus chemotherapy alone and to define a clinically meaningful PD-L1 expression threshold through a systematic review and meta-analysis of randomized phase III trials.
Methods: PubMed, Embase, and the Cochrane Registry of Clinical Controlled Trials were systematically searched up to September 2025. The studies included in this analysis were Phase III randomized controlled trials that compared immune checkpoint inhibitors (ICI) combined with chemotherapy to chemotherapy alone in the treatment of patients with advanced or metastatic gastric cancer or GEJ adenocarcinoma. The combined hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) were calculated using a random-effects model. Subgroup analyses were conducted based on the PD-L1 combined positive score (CPS), age, gender, ECOG performance status score (ECOG), geographical region, liver metastasis and tumor location. Safety was assessed through the combined hazard ratio (RR) of grade ≥3 adverse events (AEs) and serious adverse events (SAEs).
Results: Eight phase III trials involving 7,127 patients with previously untreated, HER2-negative, advanced or metastatic gastric or GEJ adenocarcinoma were included. The pooled analysis showed significant improvement in OS (HR = 0.79, 95% CI 0.75-0.83) and PFS (HR = 0.71, 95% CI 0.65-0.79) with ICI plus chemotherapy versus chemotherapy alone. Treatment benefit increased with higher PD-L1 CPS: OS HRs were 0.90 (CPS < 1), 0.76 (CPS ≥ 1), 0.75 (CPS ≥ 5), and 0.65 (CPS ≥ 10); similar trends were seen for PFS (0.87, 0.73, 0.65, 0.63, respectively). Efficacy was consistent across major subgroups (all interaction p > 0.05). Combination therapy modestly increased grade ≥3 AEs (RR = 1.16, 95% CI 1.09-1.23) and SAEs (RR = 1.54, 95% CI 1.35-1.77) compared with chemotherapy alone.
Conclusions: First-line ICI plus chemotherapy significantly prolongs OS and PFS in advanced gastric and GEJ adenocarcinoma, with manageable toxicity. The magnitude of benefit is mainly driven by PD-L1 expression, supporting CPS as a clinically meaningful biomarker for treatment selection. ICI-based combinations should be considered a new standard of care across clinically relevant subgroups.
利益披露 Disclosure
J. Lyu, None..
Z. Zhang, None..
K. Thangaretnam, None..
M. Islam, None..
J. Tang, None..
S. Denize, None..
N. Bhat, None..
D. Peng, None..
W. El Rifai, None.