Tusamitamab ravtansine是一种靶向癌胚抗原相关细胞黏附分子5 (CEACAM5) 、输送细胞毒性maytansinoid药荷构建物的抗体药物结合物。在一项I期剂量递增研究中，最大耐受剂量(MTD)为每2周100 mg/m2 (Q2W)。在本文中，我们报告了两种替代方案的结果。接受静脉注射tusamitamab ravtansine的成年人≥18岁 (范围，34-73岁) ，局部晚期/转移性实体肿瘤患者 (N = 43 ;结肠/直肠, 29 ;胃, 7 ;胰腺, 4 ;其他, 3) ，表达/可能表达CEACAM5，接受tusamitamab ravtansine 120-170 mg/m2【负荷剂量 (LD)】，然后是100 mg/m2 Q2W (Q2W-LD, n = 28) ，或者是120-190 mg/m2固定剂量【每3周 (Q3W) ，n = 15]。主要终点是在第1-2周期 (Q2W-LD) 和第1周期 (Q3W) 中的剂量限制性毒性 (DLTs) 。可逆的DLTs在Q2W-LD的9名患者中发现了2例 (2级角膜病变; 2级角膜炎) ，在Q3W的3名患者中发现了2例 (2级角膜病变; 3级转氨酶升高) 。 Q2W-LD组中的19名 (67.9%)患者和Q3W组中的13名 (86.7%)患者出现了与治疗相关的不良事件 (AE) 。43名患者中有3名因AE而中止治疗。最常见的不良事件包括虚弱、胃肠症状、角膜病变、角膜炎和周围感觉神经病变。在这个小型、经过大量预处理的人群中，未观察到确切的疗效反应；然而，在Q2W-LD组中的35.7%的患者和Q3W组中的40.0%的患者中出现了稳定疾病。Tusamitamab ravtansine在这两种替代给药方案中具有良好的安全性；MTD分别为170 mg/m2 (LD) ，然后是100 mg/m2 Q2W，和170 mg/m2 Q3W的固定剂量。(NCT02187848)。本I期剂量递增研究的综合结果将为进一步研究具有CEACAM5表达的实体瘤及非小细胞肺癌患者中的tusamitamab ravtansine提供参考。© 2023 The Authors; 由美国癌症研究协会出版。

Tusamitamab ravtansine is an antibody-drug conjugate that targets carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivers a cytotoxic maytansinoid payload. In a phase I dose-escalation study, the maximum tolerated dose (MTD) was 100 mg/m2 every 2 weeks (Q2W). Here we report results for two alternative schedules.Adults ages ≥18 years (range, 34-73) with locally advanced/metastatic solid tumors (N = 43; colon/rectum, 29; stomach, 7; pancreas, 4; other, 3) expressing/likely to express CEACAM5 received intravenous tusamitamab ravtansine 120-170 mg/m2 [loading dose (LD)], then 100 mg/m2 Q2W (Q2W-LD, n = 28), or 120-190 mg/m2 fixed dose [every 3 weeks (Q3W), n = 15]. The primary endpoint was dose-limiting toxicities (DLTs) during cycles 1-2 (Q2W-LD) and cycle 1 (Q3W).Reversible DLTs were observed in 2 of 9 patients (grade 2 keratopathy; grade 2 keratitis) with 170 mg/m2 in Q2W-LD and in 2 of 3 patients (grade 2 keratopathy; grade 3 transaminase elevation) with 190 mg/m2 in Q3W. Nineteen (67.9%) patients in Q2W-LD and 13 (86.7%) patients in Q3W experienced treatment-related adverse events (AE); 3 of 43 patients discontinued treatment because of AEs. The most common AEs were asthenia, gastrointestinal complaints, keratopathy, keratitis, and peripheral sensory neuropathy. In this small, heavily pretreated population, no confirmed responses were observed; however, stable disease occurred in 35.7% of patients in Q2W-LD and 40.0% of patients in Q3W.Tusamitamab ravtansine had a favorable safety profile with both alternative administration schedules; MTDs were 170 mg/m2 (LD) followed by 100 mg/m2 Q2W, and 170 mg/m2 Q3W as a fixed dose. (NCT02187848).The collective results of this phase I dose-escalation study will inform further studies of tusamitamab ravtansine in patients with solid tumors with CEACAM5 expression, including patients with non-small cell lung cancer.© 2023 The Authors; Published by the American Association for Cancer Research.