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Abstract：
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.
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.
摘要：
■Tusamitamabravtansine是一种抗体-药物缀合物，靶向癌胚抗原相关细胞粘附分子5（CEACAM5）并递送细胞毒性类美登素有效载荷。在I期剂量递增研究中，最大耐受剂量(MTD)为每2周100mg/m2(Q2W).在这里，我们报告两个替代时间表的结果。
■成年人年龄≥18岁（范围，34-73）伴有局部晚期/转移性实体瘤（N=43；结肠/直肠，29;胃，7；胰腺，4；其他，3）表达/可能表达CEACAM5接受静脉内Tusamitamabravtansine120-170mg/m2[负荷剂量（LD）]，然后100毫克/平方米Q2W(Q2W-LD，n=28),或120-190mg/m2固定剂量[每3周（Q3W），n=15]。主要终点是第1-2周期（Q2W-LD）和第1周期（Q3W）的剂量限制性毒性（DLTs）。
■在9例患者中的2例（2级角膜病变；2级角膜炎）在Q2W-LD中观察到170mg/m2的可逆性DLT，在3例患者中的2例（2级角膜病变；3级转氨酶升高）在Q3W中观察到190mg/m2的可逆性DLT。Q2W-LD中的19例（67.9％）患者和Q3W中的13例（86.7％）患者经历了治疗相关的不良事件（AE）；43例患者中有3例因AE而停止治疗。最常见的不良事件是虚弱，肠胃不适,角膜病变,角膜炎,和周围感觉神经病变。在这个小小的,大量预处理的人群，没有观察到确认的反应；然而，在Q2W-LD中有35.7％的患者病情稳定，在Q3W中有40.0％的患者病情稳定。
■Tusamitamabravtansine在两种替代给药方案下都具有良好的安全性；MTD为170mg/m2（LD），随后为100mg/m2Q2W，和170mg/m2Q3W作为固定剂量。（NCT02187848）。
■这项I期剂量递增研究的集体结果将为进一步研究具有CEACAM5表达的实体瘤患者的tusamitamabravtansine提供信息，包括非小细胞肺癌患者。
■成年人年龄≥18岁（范围，34-73）伴有局部晚期/转移性实体瘤（N=43；结肠/直肠，29;胃，7；胰腺，4；其他，3）表达/可能表达CEACAM5接受静脉内Tusamitamabravtansine120-170mg/m2[负荷剂量（LD）]，然后100毫克/平方米Q2W(Q2W-LD，n=28),或120-190mg/m2固定剂量[每3周（Q3W），n=15]。主要终点是第1-2周期（Q2W-LD）和第1周期（Q3W）的剂量限制性毒性（DLTs）。
■在9例患者中的2例（2级角膜病变；2级角膜炎）在Q2W-LD中观察到170mg/m2的可逆性DLT，在3例患者中的2例（2级角膜病变；3级转氨酶升高）在Q3W中观察到190mg/m2的可逆性DLT。Q2W-LD中的19例（67.9％）患者和Q3W中的13例（86.7％）患者经历了治疗相关的不良事件（AE）；43例患者中有3例因AE而停止治疗。最常见的不良事件是虚弱，肠胃不适,角膜病变,角膜炎,和周围感觉神经病变。在这个小小的,大量预处理的人群，没有观察到确认的反应；然而，在Q2W-LD中有35.7％的患者病情稳定，在Q3W中有40.0％的患者病情稳定。
■Tusamitamabravtansine在两种替代给药方案下都具有良好的安全性；MTD为170mg/m2（LD），随后为100mg/m2Q2W，和170mg/m2Q3W作为固定剂量。（NCT02187848）。
■这项I期剂量递增研究的集体结果将为进一步研究具有CEACAM5表达的实体瘤患者的tusamitamabravtansine提供信息，包括非小细胞肺癌患者。
