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Authors
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Shen L, Zhang Y, Li Z, Zhang X, Gao X, Liu B, Wang Y, Ba Y, Li N, Zhang R, Zhang J, Chen Y, Chen J, Huang M, Fu Y, Liu M, Liu Z, Zhao J, Li W, Wei J, Li C, Xu N, Guo Z, Cao B, Liu L, Nie P, Wan L, Sheng L, Liu Z, He Y, Gu K, Wu G, Wang W, Zhang F, Qiu W, Guo J, Ying J, Pan H, Xu H, Yuan Y, Bai Y, Wang Z, Xu J, Zhao X, Liu H, Zhang X, Dai W, Xu H, Liu M, Xie L, Tang Y, Jin J, Qu X, Fang X, Huang M, Chen H, Zheng Z, Wang Y, Wang D, Li X, Yu G, Liu H, Zhou Y, Zhong D, Zeng S, Kang M, Wang M, Gao Y, Li W, Wang Z, Zhang M, Zhang J, Li Q, Sun S, Zang A, Lin L, Xie M, Zhuang Z, Zhang T, Yao Z, Lu D, Liu W, Hu M, Wang ZM, Li B, Xia M, Zhang J, Ying X, Pardoll DM, Ji J
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Abstract Text
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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 .
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