• Xiangyu Gao, Nong Xu, Ziyu Li, Lin Shen, Ke Ji, Zhong Zheng, Dan Liu, Hanmei Lou, Li Bai, Tianshu Liu, Yunxia Li, Yuzhi Li, Qingxia Fan, Mei Feng, Haijun Zhong, Yi Huang, Ge Lou, Jing Wang, Xiaoyan Lin, Ye Chen, Ruifang An, Changzheng Li, Qi Zhou, Xin Huang, Zengqing Guo, Shubin Wang, Guiling Li, Junwei Fei, Lijing Zhu, Hong Zhu, Xiumin Li, Fenghu Li, Sihai Liao, Qinghua Min, Lei Tang, Fei Shan, Jifang Gong, Yunong Gao, Jun Zhou, Zhihao Lu, Xiaofan Li, Jianjie Li, Hui Ren, Xiaohong Liu, Hongxia Yang, Wenting Li, Weifeng Song, Zhongmin Maxwell Wang, Baiyong Li, Michelle Xia, Xiaohua Wu, and Jiafu Ji.
• State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China.
• Lancet Oncol. 2023 Oct 1; 24 (10): 113411461134-1146.

BackgroundImmune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours.MethodsThis multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed.FindingsBetween Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4).InterpretationCadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours.FundingAkeso Biopharma.TranslationFor the Chinese translation of the abstract see Supplementary Materials section.Copyright © 2023 Elsevier Ltd. All rights reserved.

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