Shen Lin, Zhang Yanqiao, Li Ziyu, Zhang Xiaotian, Gao Xiangyu, Liu Bo, Wang Yusheng, Ba Yi, Li Ning, Zhang Ruixing, Zhang Jingdong, Chen Ye, Chen Jian, Huang Mingzhu, Fu Yang, Liu Mulin, Liu Zheng, Zhao Jun, Li Wei, Wei Jia, Li Changzheng, Xu Nong, Guo Zengqing, Cao Bangwei, Liu Lian, Nie Peng, Wan Lixin, Sheng Lili, Liu Zhenyang, He Yifu, Gu Kangsheng, Wu Guowu, Wang Weibo, Zhang Futong, Qiu Wensheng, Guo Jun, Ying Jieer, Pan Hongming, Xu Huiting, Yuan Yuan, Bai Yuansong, Wang Zhenghua, Xu Jiye, Zhao Xuehong, Liu Hao, Zhang Xizhi, Dai Wenxiang, Xu Hongyan, Liu Ming, Xie Lin, Tang Yong, Jin Jianying, Qu Xiujuan, Fang Xuefeng, Huang Mingwei, Chen Hao, Zheng Zhendong, Wang Ying, Wang Daqing, Li Xiaoqin, Yu Guohua, Liu Haiyan, Zhou Yongjian, Zhong Diansheng, Zeng Shan, Kang Mafei, Wang Meiqing, Gao Yong, Li Wenxin, Wang Zejun, Zhang Minghui, Zhang Jinghua, Li Qingshan, Sun Shujuan, Zang Aimin, Lin Lizhu, Xie Ming, Zhuang Zhixiang, Zhang Tao, Yao Zhifang, Lu Dongmei, Liu Wei, Hu Mingxiu, Wang Zhongmin Maxwell, Li Baiyong, Xia Michelle, Zhang Jiajia, Ying Xiangji, Pardoll Drew M, Ji Jiafu
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China.
Harbin Medical University Cancer Hospital, Harbin, China.
Nat Med. 2025 Apr;31(4):1163-1170. doi: 10.1038/s41591-024-03450-4. Epub 2025 Jan 22.
Programmed cell death protein-1 (PD-1) inhibitors plus chemotherapy have been the standard of care in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma; however, the survival benefits are modest in patients with low programmed death ligand 1 (PD-L1) expression. Here we investigated the efficacy and safety of cadonilimab (PD-1/cytotoxic T lymphocyte antigen-4 (CTLA-4) bispecific antibody) plus chemotherapy as first-line treatment in G/GEJ adenocarcinoma. The prespecified interim analysis is reported here. This was a randomized, double-blind, placebo-controlled phase 3 study. Eligible patients were adults with untreated, unresectable, locally advanced or metastatic G/GEJ adenocarcinoma. Patients were randomized 1:1 to receive cadonilimab (10 mg kg every 3 weeks) or placebo plus chemotherapy (every 3 weeks). The primary endpoint was overall survival (OS) in the intention-to-treat population (one-sided significance level, P = 0.025). Secondary endpoints included OS in patients with a PD-L1 combined positive score ≥5, progression-free survival, objective response rate, duration of response and safety. As of 18 August 2023, 610 patients from 75 study centers were randomized to cadonilimab (n = 305) or placebo (n = 305). With a median follow-up of 18.7 months, the cadonilimab group had a significantly longer median OS (14.1 versus 11.1 months; hazard ratio (HR) 0.66; 95% confidence interval (CI) 0.54-0.81; P < 0.001) than the placebo group. The primary endpoint was met. The median progression-free survival was 7.0 months versus 5.3 months (HR 0.53, 95% CI 0.44-0.65). The median OS in patients with a PD-L1 combined positive score ≥5 was 15.3 months versus 10.9 months (HR 0.58, 95% CI 0.41-0.82). The objective response rate was 65.2% versus 48.9% with a median duration of response of 8.8 months versus 4.4 months. Grade ≥3 treatment-related adverse events occurred in 65.9% of the cadonilimab group and 53.6% of the placebo group, and the most common were decreased platelet count, decreased neutrophil count and anemia. Most of the immune-related adverse events were grade 1 or 2. No new safety signals were observed. Cadonilimab plus chemotherapy significantly improved OS with a manageable safety profile in patients with advanced G/GEJ adenocarcinoma. ClinicalTrials.gov registration: NCT05008783 .
程序性细胞死亡蛋白1（PD-1）抑制剂联合化疗一直是晚期胃癌或胃食管交界（G/GEJ）腺癌一线治疗的标准方案；然而，对于程序性死亡配体1（PD-L1）低表达的患者，生存获益并不显著。在此，我们研究了卡度尼利单抗（一种PD-1/细胞毒性T淋巴细胞相关抗原4（CTLA-4）双特异性抗体）联合化疗作为G/GEJ腺癌一线治疗的疗效和安全性。本文报告了预先设定的中期分析结果。这是一项随机、双盲、安慰剂对照的3期研究。符合条件的患者为未接受过治疗、无法切除、局部晚期或转移性G/GEJ腺癌的成年人。患者按1:1随机分组，分别接受卡度尼利单抗（每3周10mg/kg）或安慰剂联合化疗（每3周一次）。主要终点是意向性治疗人群的总生存期（OS）（单侧显著性水平，P = 0.025）。次要终点包括PD-L1联合阳性评分≥5的患者的OS、无进展生存期、客观缓解率、缓解持续时间和安全性。截至2023年8月18日，来自75个研究中心的610例患者被随机分配至卡度尼利单抗组（n = 305）或安慰剂组（n = 305）。中位随访18.7个月，卡度尼利单抗组的中位OS显著长于安慰剂组（14.1个月对11.1个月；风险比（HR）0.66；95%置信区间（CI）0.54 - 0.81；P < 0.001）。达到了主要终点。中位无进展生存期为7.0个月对5.3个月（HR 0.53，95% CI 0.44 - 0.65）。PD-L1联合阳性评分≥5的患者的中位OS为15.3个月对10.9个月（HR 0.58，95% CI 0.41 - 0.82）。客观缓解率分别为65.2%和48.9%，中位缓解持续时间分别为8.8个月和4.4个月。卡度尼利单抗组65.9%的患者和安慰剂组53.6%的患者发生了≥≥3级治疗相关不良事件，最常见的是血小板计数减少、中性粒细胞计数减少和贫血。大多数免疫相关不良事件为1级或2级。未观察到新的安全信号。卡度尼利单抗联合化疗显著改善了晚期G/GEJ腺癌患者的OS，且安全性可控。ClinicalTrials.gov注册号：NCT05008783 。
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