Zhou Wei, Cai Zeng-Zhi, Fan Zhuolin, Zheng Xu, Chen Yu-Tong
State Key Laboratory of Oncology in South China, Department of Medical Oncology, Collaborative Innovation Center for Cancer Medicine, Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Sun Yat-sen University Cancer Center, Chinese Academy of Medical Sciences, Guangzhou, China.
Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
Front Cell Dev Biol. 2025 Jul 3;13:1636288. doi: 10.3389/fcell.2025.1636288. eCollection 2025.
Chemotherapy alone exhibits suboptimal efficacy in patients with treatment-naïve advanced gastric cancer (GC). Randomized controlled trials (RCTs) have demonstrated that combining Programmed Cell Death Protein-1 (PD-1) blockade with chemotherapy significantly improves overall survival (OS) compared to chemotherapy alone. However, the efficacy of PD-1 inhibitors in patients with low Programmed Cell Death-Ligand 1 (PD-L1) expression remains unclear.
Electronic databases were searched for RCTs comparing PD-1/PD-L1 inhibitors plus chemotherapy to placebo plus chemotherapy or chemotherapy alone in treatment-naïve advanced gastric or gastroesophageal junction adenocarcinoma patients. Individual patient-level data (IPD) for overall survival (OS) and progression-free survival (PFS) were reconstructed. The KMSubtraction algorithm was employed to derive IPD for the PD-L1-low subgroup. Treatment effects in PD-L1-high and PD-L1-low subgroups were evaluated using Cox proportional hazards models with shared frailty to account for between-study heterogeneity. Interaction tests were performed to assess differences in treatment effects between these subgroups.
Nine RCTs were included in the qualitative analysis. A combined positive score (CPS) of 5 was selected as the cutoff for analysis, with CheckMate 649 and ORIENT-16 trials included. In the CPS<5 subgroup, OS (CheckMate 649: HR = 0.97, 95% CI 0.81-1.17, P = 0.758; ORIENT-16: HR = 0.94, 95% CI 0.68-1.31, P = 0.725) and PFS (CheckMate 649: HR = 0.95, 95% CI 0.79-1.14, P = 0.580; ORIENT-16: HR = 0.73, 95% CI 0.52-1.01, P = 0.055) did not significantly differ between patients receiving PD-1 blockade plus chemotherapy and those receiving chemotherapy alone. Pooled analysis of reconstructed OS IPD from CheckMate 649 and ORIENT-16 (N = 2,231) revealed that PD-1 blockade significantly improved OS in the CPS≥5 subgroup (HR = 0.69, 95% CI 0.60-0.79, P < 0.001), but not in the CPS<5 subgroup (HR = 0.96, 95% CI 0.82-1.13, P = 0.643). Interaction tests showed a significantly attenuated treatment effect on OS in the CPS<5 subgroup compared to the CPS≥5 subgroup (Pinteraction = 0.002). Similar findings were observed in the pooled analysis of PFS data (Pinteraction = 0.011).
The addition of PD-1 inhibitors to first-line chemotherapy provides minimal benefit in patients with CPS<5. Therefore, PD-1 inhibitors should be individualized for this patient subset.
单纯化疗对初治晚期胃癌（GC）患者的疗效欠佳。随机对照试验（RCT）表明，与单纯化疗相比，程序性细胞死亡蛋白1（PD-1）阻断联合化疗可显著提高总生存期（OS）。然而，PD-1抑制剂在程序性细胞死亡配体1（PD-L1）低表达患者中的疗效仍不明确。
检索电子数据库，查找比较PD-1/PD-L1抑制剂联合化疗与安慰剂联合化疗或单纯化疗用于初治晚期胃癌或胃食管交界腺癌患者的RCT。重建总生存期（OS）和无进展生存期（PFS）的个体患者水平数据（IPD）。采用KMSubtraction算法推导PD-L1低亚组的IPD。使用具有共享脆弱性的Cox比例风险模型评估PD-L1高和PD-L1低亚组的治疗效果，以考虑研究间的异质性。进行交互检验以评估这些亚组之间治疗效果的差异。
9项RCT纳入定性分析。选择联合阳性评分（CPS）为5作为分析的临界值，纳入CheckMate 649和ORIENT-16试验。在CPS<5亚组中，接受PD-1阻断联合化疗的患者与接受单纯化疗的患者相比，OS（CheckMate 649：HR = 0.97，95%CI 0.81-1.17，P = 0.758；ORIENT-16：HR = 0.94，95%CI 0.68-1.31，P = 0.725）和PFS（CheckMate 649：HR = 0.95，95%CI 0.79-1.14，P = 0.580；ORIENT-16：HR = 0.73，95%CI 0.52-1.01，P = 0.055）无显著差异。对CheckMate 649和ORIENT-16（N = 2,231）重建的OS IPD进行汇总分析显示，PD-1阻断在CPS≥5亚组中显著改善了OS（HR = 0.69，95%CI 0.60-0.79，P < 0.001），但在CPS<5亚组中未改善（HR = 0.96，95%CI 0.82-1.13，P = 0.643）。交互检验显示，与CPS≥5亚组相比，CPS<5亚组对OS的治疗效果显著减弱（P交互作用 = 0.002）。在PFS数据的汇总分析中也观察到类似结果（P交互作用 = 0.011）。
对于CPS<5的患者，一线化疗加用PD-1抑制剂获益极小。因此对于该患者亚组，PD-1抑制剂应个体化使用。
