• Xue Zhang, Xin Dai, Aina Liu, Meili Sun, Lei Cong, Jing Liang, Zimin Liu, Zhen Li, Jinling Zhang, Jing Lv, Fangli Cao, Linli Qu, Haiyan Liu, Lu Yue, Yi Zhai, Fujun Yang, Jiahui Chu, Shuang Wang, Qian Xu, Jianyuan Zhou, Shulun Nie, Miao Huang, Ruitao Xu, Qiushi Wang, Xinyu Song, Di Zhang, Zhaodi Nan, Song Li, and Lian Liu.
• Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
• Bmc Med. 2024 Dec 18; 22 (1): 585585.

BackgroundRecent phase III randomized controlled trials have demonstrated that first-line immune checkpoint inhibitors (ICIs) improve prognosis in advanced HER-2-negative gastric cancer patients with programmed death ligand 1 (PD-L1) combined positive score (CPS) higher than 5. However, these findings are not confirmed in real-world settings, and the benefits in PD-L1 CPS < 5 patients remain controversial.MethodsIn this multicenter, retrospective cohort study, data from across thirteen medical centers were analyzed by inverse probability of treatment weighting for matching, alongside univariate and multivariate COX proportional hazard regression models. Genomic and transcriptomic analyses were conducted to identify efficacy prognostic models and resistance mechanisms.ResultsThis study included 573 patients with advanced gastric cancer, 265 treated with chemotherapy and 308 with ICIs plus chemotherapy. In the overall cohort and HER-2-negative patients, the combination therapy significantly improved progression-free survival and overall survival, without marked increases in severe adverse events. Notably, patients with PD-L1 CPS 1-4 showed significant overall survival prolongation and a trend towards improved progression-free survival with combination therapy. Patients with unknown PD-L1 status also benefitted from ICIs. SMARCA4 and BRCA2 mutations were more frequent in patients with responses, while CCNE1 and ZFHX3 alternation, alongside high "ABC transporters" signatures, were more common in non-responsive patients. A novel risk model, PGFIC, outperformed traditional biomarkers in predicting treatment outcomes.ConclusionsAdding ICIs to first-line treatment significantly prolongs survival in overall patients and in those with PD-L1 CPS 1-4 or unknown. This study also provides valuable insights into prognostic markers and resistance mechanisms, potentially guiding immunotherapy strategies.© 2024. The Author(s).

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