Efficacy and safety of PD-1/PD-L1 inhibitors as first-line treatment for esophageal squamous cell carcinoma: a systematic review and meta-analysis
Wei Ren, Hanyu Zhang, Yixin Li, Wu Sun, Hexiang Peng, Huangda Guo, Tianjiao Hou, Mengying Wang, Zhendong Hu, Tao Wu, Baorui Liu
Abstract
Purpose This study aims to investigate the efficacy and safety of PD-1/PD-L1 inhibitors in the first-line treatment of esophageal squamous cell carcinoma (ESCC) and identify factors influencing efficacy through a meta-analysis of multiple phase 3 randomized controlled trials (RCTs). Methods A systematic literature search was conducted in Cochrane, PubMed, and Embase databases. Two researchers independently extracted trial data, including efficacy-related outcomes such as overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR), along with their subgroup data and safety-related indicators. The overall hazard ratio (HR) and 95% confidence interval (CI) were calculated for OS and PFS, while the overall odds ratio (OR) and 95% CI were computed for ORR to compare the classification and predictive abilities of combined positive score (CPS) and tumor proportion score (TPS) for PD-L1 status. Additionally, survival outcomes across different subgroups were evaluated to explore the potential influencing factors for the efficacy of PD-1/PD-L1 inhibitors in ESCC. Results This meta-analysis included eight phase 3 RCTs encompassing 4,479 participants. PD-1/PD-L1 inhibitors combined with chemotherapy significantly improved OS ( HR : 0.68, 95% CI : 0.63-0.74) and PFS ( HR : 0.62, 95% CI : 0.58-0.67) in ESCC patients compared to non-combination therapy. Patients with higher PD-L1 expression (CPS>1 or TPS>1) demonstrated superior responses to PD-1/PD-L1 inhibitions, with CPS identified as a stronger predictor of therapeutic benefit, particularly at a threshold of CPS =10. Subgroup analysis revealed that male, Asian, smoking, and liver metastasis patients exhibited a greater trend toward improved disease control with PD-1/PD-L1 inhibitors. However, there was no significant difference in treatment efficacy between immune therapy combined with TP (taxol [paclitaxel] + cisplatin) and FP (5-fluorouracil [5-FU] + cisplatin) regimens ( P OS =0.51, P PFS =0.11). Finally, PD-1/PD-L1 inhibition was associated with a higher incidence of grade ≥3 adverse events compared to chemotherapy alone ( HR : 1.21, 95% CI : 1.07-1.37). Conclusions This study confirms that the combination of PD-1/PD-L1 inhibitors and chemotherapy provides significant clinical benefits in ESCC. CPS =10 serves as a key threshold for predicting treatment response. There is a trend suggesting that male, Asian, smoking, and liver metastasis patients may experience better survival benefits, while no significant difference was observed between TP- and FP-based regimens. Systematic Review Registration https://www.crd.york.ac.uk/prospero , identifier CRD42024536221