PD-L1 expression predicts the efficacy of PD-1 blockade plus chemotherapy versus chemotherapy alone in treatment-naïve advanced or metastatic gastric cancer: a pooled analysis of reconstructed individual patient-level data from two randomized trials
BackgroundChemotherapy 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)...
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Frontiers Media S.A.
2025-07-01
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| author | Wei Zhou Zeng-Zhi Cai Zhuolin Fan Xu Zheng Yu-Tong Chen |
| author_facet | Wei Zhou Zeng-Zhi Cai Zhuolin Fan Xu Zheng Yu-Tong Chen |
| author_sort | Wei Zhou |
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| description | BackgroundChemotherapy 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.MethodsElectronic 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.ResultsNine 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).ConclusionThe 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. |
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| spelling | doaj-art-54a2ee68cf2f4b128445d316ee99a8a02025-07-03T05:26:43ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2025-07-011310.3389/fcell.2025.16362881636288PD-L1 expression predicts the efficacy of PD-1 blockade plus chemotherapy versus chemotherapy alone in treatment-naïve advanced or metastatic gastric cancer: a pooled analysis of reconstructed individual patient-level data from two randomized trialsWei Zhou0Zeng-Zhi Cai1Zhuolin Fan2Xu Zheng3Yu-Tong Chen4State 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, ChinaState 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, ChinaDepartment of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, ChinaShenyang Kingmed Diagnostics Co., Ltd., Shenyang, ChinaFaculty of Medical Science, Jinan University, Guangzhou, ChinaBackgroundChemotherapy 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.MethodsElectronic 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.ResultsNine 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).ConclusionThe 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.https://www.frontiersin.org/articles/10.3389/fcell.2025.1636288/fulladvanced gastric cancerprogrammed cell death Protein-1 blockadechemotherapyprogrammed cell death-ligand 1 expressioncombined positive scorerandomized controlled trials |
| spellingShingle | Wei Zhou Zeng-Zhi Cai Zhuolin Fan Xu Zheng Yu-Tong Chen PD-L1 expression predicts the efficacy of PD-1 blockade plus chemotherapy versus chemotherapy alone in treatment-naïve advanced or metastatic gastric cancer: a pooled analysis of reconstructed individual patient-level data from two randomized trials Frontiers in Cell and Developmental Biology advanced gastric cancer programmed cell death Protein-1 blockade chemotherapy programmed cell death-ligand 1 expression combined positive score randomized controlled trials |
| title | PD-L1 expression predicts the efficacy of PD-1 blockade plus chemotherapy versus chemotherapy alone in treatment-naïve advanced or metastatic gastric cancer: a pooled analysis of reconstructed individual patient-level data from two randomized trials |
| title_full | PD-L1 expression predicts the efficacy of PD-1 blockade plus chemotherapy versus chemotherapy alone in treatment-naïve advanced or metastatic gastric cancer: a pooled analysis of reconstructed individual patient-level data from two randomized trials |
| title_fullStr | PD-L1 expression predicts the efficacy of PD-1 blockade plus chemotherapy versus chemotherapy alone in treatment-naïve advanced or metastatic gastric cancer: a pooled analysis of reconstructed individual patient-level data from two randomized trials |
| title_full_unstemmed | PD-L1 expression predicts the efficacy of PD-1 blockade plus chemotherapy versus chemotherapy alone in treatment-naïve advanced or metastatic gastric cancer: a pooled analysis of reconstructed individual patient-level data from two randomized trials |
| title_short | PD-L1 expression predicts the efficacy of PD-1 blockade plus chemotherapy versus chemotherapy alone in treatment-naïve advanced or metastatic gastric cancer: a pooled analysis of reconstructed individual patient-level data from two randomized trials |
| title_sort | pd l1 expression predicts the efficacy of pd 1 blockade plus chemotherapy versus chemotherapy alone in treatment naive advanced or metastatic gastric cancer a pooled analysis of reconstructed individual patient level data from two randomized trials |
| topic | advanced gastric cancer programmed cell death Protein-1 blockade chemotherapy programmed cell death-ligand 1 expression combined positive score randomized controlled trials |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2025.1636288/full |
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