卡度尼利单抗（一种抗 PD-1/CTLA-4 双特异性抗体）治疗晚期实体瘤患者的安全性和抗肿瘤活性（COMPASSION-03）：一项多中心、开放标签、Ib/II 期试验。

Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial.

机构信息

State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China.

The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

出版信息

Lancet Oncol. 2023 Oct;24(10):1134-1146. doi: 10.1016/S1470-2045(23)00411-4.

DOI:10.1016/S1470-2045(23)00411-4

PMID:37797632

Abstract

BACKGROUND

Immune 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.

METHODS

This 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.

FINDINGS

Between 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).

INTERPRETATION

Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours.

FUNDING

Akeso Biopharma.

TRANSLATION

For the Chinese translation of the abstract see Supplementary Materials section.

摘要

背景

针对 PD-1 或 CTLA-4 的免疫检查点抑制剂在恶性肿瘤的治疗中显示出了显著的临床获益。我们旨在评估 cadonilimab 单药治疗晚期实体瘤患者的安全性和抗肿瘤活性，cadonilimab 是一种双特异性 PD-1/CTLA-4 抗体。

方法

这是一项在中国 30 家医院进行的多中心、开放标签、1b/2 期试验。年龄在 18 岁或以上、组织学或细胞学证实的不可切除的晚期实体瘤、至少一种先前系统治疗失败、东部肿瘤协作组体力状态 0 或 1 的患者有资格入组。先前接受过抗 PD-1、抗 PD-L1 或抗 CTLA-4 治疗的患者不符合入组条件。在 1b 期的剂量递增阶段，患者每 2 周静脉注射 6 mg/kg 和 10 mg/kg 的 cadonilimab。在 1b 期的剂量扩展阶段，每 2 周静脉注射 cadonilimab 6 mg/kg 和固定剂量 450 mg。在 2 期，3 个队列中每 2 周静脉注射 cadonilimab 6 mg/kg：宫颈癌队列、食管鳞状细胞癌队列和肝细胞癌队列。主要终点是 1b 期 cadonilimab 的安全性和 2 期的客观缓解率，根据实体瘤反应评估标准（RECIST），版本 1.1。安全性分析在所有至少接受一剂 cadonilimab 的患者中进行。在宫颈癌队列的全分析集和食管鳞状细胞癌和肝细胞癌队列中所有基线时可测量疾病且至少接受一剂 cadonilimab 的患者中评估抗肿瘤活性。该研究在 ClinicalTrial.gov 上注册，NCT03852251，现已关闭新参与者；随访已完成。

结果

在 2019 年 1 月 18 日至 2021 年 1 月 8 日期间，共有 240 名患者（1b 期 83 名[43 名男性和 40 名女性]，2 期 157 名）入组。2 期入组了 111 名女性宫颈癌患者、22 名食管鳞状细胞癌患者（15 名男性和 7 名女性）和 24 名肝细胞癌患者（17 名男性和 7 名女性）。在剂量递增期间，没有发生剂量限制毒性。240 名患者中有 67 名（28%）发生 3-4 级治疗相关不良事件；最常见的 3 级或更高级别的治疗相关不良事件是贫血（7 例[3%]）、脂肪酶升高（4 例[2%]）、体重下降（3 例[1%]）、食欲下降（4 例[2%]）、中性粒细胞计数下降（3 例[1%]）和输注相关反应（2 例[1%]）。17 名（7%）患者因治疗相关不良事件而停止治疗。240 名患者中有 54 名（23%）报告了严重的治疗相关不良事件，包括 5 名死亡患者（1 例死于心肌梗死；4 例死因不明）。在 2 期宫颈癌队列中，中位随访时间为 14.6 个月（IQR 13.1-17.5），客观缓解率为 32.3%（99 例中的 32 例；95%CI 23.3-42.5）。在食管鳞状细胞癌队列中，中位随访时间为 17.9 个月（IQR 4.0-15.1），客观缓解率为 18.2%（22 例中的 4 例；95%CI 5.2-40.3）。在肝细胞癌队列中，中位随访时间为 19.6 个月（IQR 8.7-19.8），客观缓解率为 16.7%（24 例中的 4 例；95%CI 4.7-37.4）。