Background Lymphocyte-activation gene 3 (LAG-3), a checkpoint molecule contributing to immune suppressive microenvironment, is regarded as a promising target in cancer treatment. SHR-1802 is a novel anti-LAG-3 monoclonal antibody. Objectives To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of SHR-1802. Design A phase I dose-escalation and expansion trial of SHR-1802 in patients with advanced solid tumors. Methods Patients with confirmed advanced solid tumors who failed previous standard-of-care or for whom no effective therapy was available were enrolled to receive SHR-1802 once every 21-day cycle. Dose escalation was performed in an accelerated titration design followed by a 3 + 3 scheme at escalating doses from 0.3 to 10 mg/kg. On the basis of results from dose-escalation phase, one or two dose levels were expanded to establish the recommended phase II dose (RP2D). The primary end points were dose-limiting toxicity (DLT) and RP2D. Results Between 01 July 2020, and 07 September 2021, 28 patients were enrolled. No DLTs were observed, and all doses investigated were well tolerated. Treatment-related adverse events occurred in 20 patients (71.4%), all grade 1 or 2, with the most common ones being anemia (14.3%), asthenia (14.3%), electrocardiogram QT prolonged (14.3%), followed by increased blood fibrinogen (10.7%), infusion-related reaction (10.7%), and hypoalbuminemia (10.7%). No adverse event-related discontinuation occurred. Three patients died from adverse events, but none of the deaths were deemed related to study treatment. SHR-1802 exposure enhanced with the increasing doses in a greater than dose-proportional manner over the investigated dose range. The disease control rate was 32.0% (95% CI 14.9%-53.5%). The median progression-free survival was 2.0 months (95% CI 1.2-6.1). Conclusions SHR-1802 demonstrated a tolerable safety profile and preliminary antitumor activity in patients with advanced solid tumors. Further studies with larger sample size and in combination forms are warranted for future clinical application. Registration ClinicalTrialsgov NCT04414150.

中文翻译：

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抗 LAG-3 抗体 SHR-1802 在晚期实体瘤患者中的安全性、耐受性和药代动力学：I 期剂量递增和剂量扩展研究。

背景淋巴细胞激活基因3（LAG-3）是一种有助于免疫抑制微环境的检查点分子，被认为是癌症治疗中一个有前途的靶点。SHR-1802 是一种新型抗 LAG-3 单克隆抗体。目的 评估 SHR-1802 的安全性、耐受性、药代动力学和抗肿瘤活性。设计 SHR-1802 在晚期实体瘤患者中的 I 期剂量递增和扩展试验。方法 确诊为晚期实体瘤但未达到既往标准治疗或无有效治疗的患者被纳入每 21 天周期接受一次 SHR-1802 治疗。剂量递增采用加速滴定设计，随后采用 3 + 3 方案，剂量从 0.3 mg/kg 递增至 10 mg/kg。根据剂量递增阶段的结果，扩大一或两个剂量水平以确定推荐的 II 期剂量 (RP2D)。主要终点是剂量限制毒性 (DLT) 和 RP2D。结果 2020年7月1日至2021年9月7日期间，共有28名患者入组。没有观察到 DLT，并且所有研究的剂量都具有良好的耐受性。20例患者（71.4%）发生治疗相关不良事件，均为1级或2级，最常见的是贫血（14.3%）、乏力（14.3%）、心电图QT间期延长（14.3%），其次是血流量增加纤维蛋白原（10.7%）、输注相关反应（10.7%）和低白蛋白血症（10.7%）。没有发生与不良事件相关的停药。三名患者死于不良事件，但没有一例死亡被认为与研究治疗有关。在研究的剂量范围内，SHR-1802 暴露随着剂量的增加以大于剂量比例的方式增强。疾病控制率为32.0%（95% CI 14.9%-53.5%）。中位无进展生存期为 2.0 个月（95% CI 1.2-6.1）。结论 SHR-1802 在晚期实体瘤患者中表现出良好的安全性和初步的抗肿瘤活性。为了未来的临床应用，需要进行更大样本量和组合形式的进一步研究。注册 ClinicalTrialsgov NCT04414150。