Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3⁺ non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2⁺ tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268.

Tebotelimab 是一种双特异性 PD-1×LAG-3 DART 分子，可同时阻断 PD-1 和 LAG-3，在一项针对实体瘤或实体瘤患者的 1 期剂量递增和队列扩展临床试验中研究了其临床安全性和活性。血液系统恶性肿瘤和先前治疗的疾病进展。主要终点是 tebotelimab 作为单一药物 ( n  = 269) 或与抗 HER2 抗体 margetuximab 联合用药 ( n  = 84) 时的安全性和最大耐受剂量。次要终点包括抗肿瘤活性。在接受替博替利单抗单药治疗的晚期癌症患者中，68% (184/269) 经历了治疗相关不良事件 (TRAE；22% ≥ 3 级)。没有规定最大耐受剂量；推荐的 2 期剂量 (RP2D) 为每 2 周一次 600 mg。在剂量递增队列中，34% (59/172) 的可评估疗效患者的肿瘤有所减少，多种实体瘤类型（包括 PD-1 难治性疾病）和 LAG-3 ⁺非霍奇金淋巴瘤均出现客观缓解淋巴瘤，包括 CAR-T 难治性疾病。为了增强潜在的抗肿瘤反应，我们测试了 margetuximab 加 tebotelimab。^{在接受 tebotelimab 加 margetuximab 治疗的 HER2 +}肿瘤患者中，74% (62/84) 出现 TRAE（17% ≥ 3 级）。RP2D 为 600 mg，每 3 周一次。这些患者的客观缓解率为 19% (14/72)，其中包括通常对抗 HER2/抗 PD-1 联合治疗无反应的患者。ClinicalTrials.gov 标识符：NCT03219268。