Fei Shengqi, Lu Yu, Chen Jing, Qi Jia, Wu Wenxuan, Wang Beidi, Han Yaxuan, Wang Kefan, Han Xiaying, Zhou Haiyan, Wang Jun, Chen Jian
Department of Gastroenterology Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Gastrointestinal Surgery, Changxing People's Hospital, Huzhou, China.
Chemotherapy. 2023;68(4):197-209. doi: 10.1159/000531457. Epub 2023 Jun 16.
PD-1 inhibitors have been approved for the first-line treatment of patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. However, the results of several clinical trials are not entirely consistent, and the dominant population of first-line immunotherapy for advanced gastric/gastroesophageal junction cancer still needs to be precisely determined.
This objective of this study is to evaluate the efficacy of anti-PD-1/PD-L1 therapy in advanced gastric/gastroesophageal junction adenocarcinoma patients through a systematic review and meta-analysis of relevant clinical trials.
The PubMed, Embase, and Cochrane Library electronic databases were searched up to August 1, 2022, for clinical trials of anti-PD-1/PD-L1 immunotherapy for the first-line treatment of advanced gastroesophageal cancer. Hazard ratios and 95% confidence intervals for overall survival, progression-free survival, and objective response rates were extracted and pooled for meta-analysis. Prespecified subgroups included the following: agent type, PD-L1 expression, and high microsatellite instability.
This study analyzed 5 RCTs involving 3,355 patients. Compared with the chemotherapy group, the combined immunotherapy group had a significantly higher objective response rate (OR = 0.63, 95% CI: 0.55-0.72, p < 0.00001) and prolonged overall survival (HR = 0.82, 95% CI: 0.76-0.88, p < 0.00001) and progression-free survival (HR = 0.75, 95% CI: 0.69-0.82, p < 0.00001). The combination of immunotherapy and chemotherapy prolonged OS in both MSI-H (HR = 0.38, p = 0.002) and MSS (HR = 0.78, p < 0.00001) populations, but there was a significant difference between groups (p = 0.02). However, in improving ORR, the benefit of ICI combined with chemotherapy in the MSS group and MSI-H group was not significantly different between groups (p = 0.52). Combination therapy with ICIs was more effective than chemotherapy alone in prolonging OS in the subgroup with a high CPS, regardless of the CPS cutoff for PD-L1. However, when the cutoff of CPS was 1, the difference between subgroups did not reach statistical significance (p = 0.12), while the benefit ratio of the MSI-H group was higher when the cutoff was 10 (p = 0.004) than when the cutoff value was 5 (p = 0.002).
For first-line treatment of advanced gastroesophageal cancer, an ICI combination strategy is more effective than chemotherapy. The subgroup of patients with a CPS ≥10 has a more significant benefit, and CPS ≥10 has the potential to be used as an accurate marker of the dominant population of immuno-combined therapy.
PD-1抑制剂已被批准用于晚期胃癌、胃食管交界癌或食管腺癌患者的一线治疗。然而，多项临床试验的结果并不完全一致，晚期胃癌/胃食管交界癌一线免疫治疗的优势人群仍需精确确定。
本研究旨在通过对相关临床试验进行系统评价和荟萃分析，评估抗PD-1/PD-L1疗法在晚期胃癌/胃食管交界腺癌患者中的疗效。
检索截至2022年8月1日的PubMed、Embase和Cochrane图书馆电子数据库，查找抗PD-1/PD-L1免疫疗法一线治疗晚期胃食管癌的临床试验。提取总生存期、无进展生存期和客观缓解率的风险比及95%置信区间，并进行汇总以进行荟萃分析。预设亚组包括：药物类型、PD-L1表达和高微卫星不稳定性。
本研究分析了5项随机对照试验，共3355例患者。与化疗组相比，免疫治疗联合组的客观缓解率显著更高（OR = 0.63，95%CI：0.55 - 0.72，p < 0.00001），总生存期延长（HR = 0.82，95%CI：0.76 - 0.88，p < 0.00001），无进展生存期延长（HR = 0.75，95%CI：0.69 - 0.82，p < 0.00001）。免疫治疗与化疗联合在微卫星高度不稳定（MSI-H）人群（HR = 0.38，p = 0.002）和微卫星稳定（MSS）人群（HR = 0.78，p < 0.00001）中均延长了总生存期，但两组之间存在显著差异（p = 0.02）。然而，在提高客观缓解率方面，免疫检查点抑制剂（ICI）联合化疗在MSS组和MSI-H组之间的获益无显著差异（p = 0.52）。无论PD-L1的综合阳性评分（CPS）临界值如何，ICI联合治疗在高CPS亚组中比单纯化疗更有效地延长了总生存期。然而，当CPS临界值为1时，亚组间差异未达到统计学意义（p = 0.12），而当临界值为10时，MSI-H组的获益率高于临界值为5时（p = 0.004，p = 0.002）。
对于晚期胃食管癌的一线治疗，ICI联合策略比化疗更有效。CPS≥10的患者亚组获益更显著，CPS≥10有潜力作为免疫联合治疗优势人群的精确标志物。
