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<p>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<sup>−1</sup> 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, <i>P</i> = 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 (<i>n</i> = 305) or placebo (<i>n</i> = 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; <i>P</i> &lt; 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: <a href="https://clinicaltrials.gov/study/NCT05008783?term=NCT05008783&amp;rank=1">NCT05008783</a>.</p>

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First-line cadonilimab plus chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: a randomized, double-blind, phase 3 trial

  • 期刊论文

  • 发表日期：

    2025年1月22日

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  • Lin Shen,
  • Yanqiao Zhang,
  • Ziyu Li,
  • Xiaotian Zhang,
  • Xiangyu Gao,
  • Bo Liu,
  • Yusheng Wang,
  • Yi Ba,
  • Ning Li,
  • Ruixing Zhang,
  • Jingdong Zhang,
  • Ye Chen,
  • Jian Chen,
  • Mingzhu Huang,
  • Yang Fu,
  • Mulin Liu,
  • Zheng Liu,
  • Jun Zhao,
  • Wei Li,
  • Jia Wei,
  • Changzheng Li,
  • Nong Xu,
  • Zengqing Guo,
  • Bangwei Cao,
  • Lian Liu,
  • Peng Nie,
  • Lixin Wan,
  • Lili Sheng,
  • Zhenyang Liu,
  • Yifu He,
  • Kangsheng Gu,
  • Guowu Wu,
  • Weibo Wang,
  • Futong Zhang,
  • Wensheng Qiu,
  • Jun Guo,
  • Jieer Ying,
  • Hongming Pan,
  • Huiting Xu,
  • Yuan Yuan,
  • Yuansong Bai,
  • Zhenghua Wang,
  • Jiye Xu,
  • Xuehong Zhao,
  • Hao Liu,
  • Xizhi Zhang,
  • Wenxiang Dai,
  • Hongyan Xu,
  • Ming Liu,
  • Lin Xie,
  • Yong Tang,
  • Jianying Jin,
  • Xiujuan Qu,
  • Xuefeng Fang,
  • Mingwei Huang,
  • Hao Chen,
  • Zhendong Zheng,
  • Ying Wang,
  • Daqing Wang,
  • Xiaoqin Li,
  • Guohua Yu,
  • Haiyan Liu,
  • Yongjian Zhou,
  • Diansheng Zhong,
  • Shan Zeng,
  • Mafei Kang,
  • Meiqing Wang,
  • Yong Gao,
  • Wenxin Li,
  • Zejun Wang,
  • Minghui Zhang,
  • Jinghua Zhang,
  • Qingshan Li,
  • Shujuan Sun,
  • Aimin Zang,
  • Lizhu Lin,
  • Ming Xie,
  • Zhixiang Zhuang,
  • Tao Zhang,
  • Zhifang Yao,
  • Dongmei Lu,
  • Wei Liu,
  • Mingxiu Hu,
  • Zhongmin Maxwell Wang,
  • Baiyong Li,
  • Michelle Xia,
  • Jiajia Zhang,
  • Xiangji Ying,
  • Drew M. Pardoll,
  • Jiafu Ji

摘要

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−1 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.