Zhang Xue, Dai Xin, Liu Aina, Sun Meili, Cong Lei, Liang Jing, Liu Zimin, Li Zhen, Zhang Jinling, Lv Jing, Cao Fangli, Qu Linli, Liu Haiyan, Yue Lu, Zhai Yi, Yang Fujun, Chu Jiahui, Wang Shuang, Xu Qian, Zhou Jianyuan, Nie Shulun, Huang Miao, Xu Ruitao, Wang Qiushi, Song Xinyu, Zhang Di, Nan Zhaodi, Li Song, Liu Lian
Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
Institute of Marine Science and Technology, Shandong University, Qingdao, China.
BMC Med. 2024 Dec 18;22(1):585. doi: 10.1186/s12916-024-03801-5.
Recent 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.
In 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.
This 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.
Adding 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.
近期的III期随机对照试验表明，一线免疫检查点抑制剂（ICI）可改善程序性死亡配体1（PD-L1）联合阳性评分（CPS）高于5的晚期HER-2阴性胃癌患者的预后。然而，这些发现尚未在真实世界中得到证实，且PD-L1 CPS < 5的患者的获益仍存在争议。
在这项多中心回顾性队列研究中，通过倾向评分匹配的逆概率加权法以及单变量和多变量COX比例风险回归模型，分析了来自13个医疗中心的数据。进行了基因组和转录组分析，以确定疗效预后模型和耐药机制。
本研究纳入了573例晚期胃癌患者，其中265例接受化疗，308例接受ICI联合化疗。在整个队列和HER-2阴性患者中，联合治疗显著改善了无进展生存期和总生存期，且严重不良事件没有明显增加。值得注意的是，PD-L1 CPS为1-4的患者联合治疗后总生存期显著延长，无进展生存期有改善趋势。PD-L1状态未知的患者也从ICI中获益。SMARCA4和BRCA2突变在有反应的患者中更常见，而CCNE1和ZFHX3改变以及高“ABC转运蛋白”特征在无反应的患者中更常见。一种新的风险模型PGFIC在预测治疗结果方面优于传统生物标志物。
一线治疗中添加ICI可显著延长总体患者以及PD-L1 CPS为1-4或状态未知患者的生存期。本研究还为预后标志物和耐药机制提供了有价值的见解，可能指导免疫治疗策略。
