抗表皮生长因子受体抗体药物偶联物塞鲁他单抗他利林的I期研究：晚期胶质母细胞瘤的安全性、药代动力学及抗肿瘤活性
Phase I study of anti-epidermal growth factor receptor antibody-drug conjugate serclutamab talirine: Safety, pharmacokinetics, and antitumor activity in advanced glioblastoma.
作者信息
Carneiro Benedito A, Papadopoulos Kyriakos P, Strickler John H, Lassman Andrew B, Waqar Saiama N, Chae Young Kwang, Patel Jyoti D, Shacham-Shmueli Einat, Kelly Karen, Khasraw Mustafa, Bestvina Christine M, Merrell Ryan, Huang Kevin, Atluri Harisha, Ansell Peter, Li Rachel, Jin Janet, Anderson Mark G, Reilly Edward B, Morrison-Thiele Gladys, Patel Kalpesh, Robinson Randy R, Aristide Martha R Neagu, Gan Hui K
机构信息
Legorreta Cancer Center at Brown University, Providence, Rhode Island, USA.
Lifespan Cancer Institute, Providence, Rhode Island, USA.
出版信息
Neurooncol Adv. 2022 Dec 21;5(1):vdac183. doi: 10.1093/noajnl/vdac183. eCollection 2023 Jan-Dec.
BACKGROUND
Serclutamab talirine (Ser-T, formerly ABBV-321) is an antibody-drug conjugate consisting of an antibody (AM-1-ABT-806) directed against activated epidermal growth factor receptor (EGFR) and a pyrrolobenzodiazepine dimer. We investigated Ser-T monotherapy in a phase I, first-in-human, dose-escalation, and dose-expansion study in patients with advanced solid tumors associated with EGFR overexpression.
METHODS
Eligible patients (≥18 years) had advanced, histologically confirmed solid tumors associated with EGFR overexpression (centralized testing). Patients received Ser-T intravenously once every 4 weeks (Q4W; 5-50 μg/kg) in the dose-escalation phase. Herein, preliminary antitumor activity at the recommended phase II dose (RP2D) is reported only for patients with glioblastoma ( = 24); additional assessments included all treated patients.
RESULTS
Sixty-two patients (median age: 58 years) were enrolled within the dose-escalation ( = 43) and dose-expansion ( = 19) phases. One dose-limiting toxicity, grade 3 aspartate aminotransferase and alanine aminotransferase elevation, occurred at 20 μg/kg during dose escalation. The Ser-T RP2D regimen of 50 μg/kg × 1 (loading dose) followed by 25 μg/kg Q4W (maintenance dose) was administered during dose expansion. Fatigue (37%) was the only treatment-emergent adverse event (AE) occurring in >25% of patients. Two patients (3%) reported mild treatment-related ocular AEs (eye pruritus). Responses in patients with glioblastoma included 1 partial response (~33 months), 6 stable disease, and 14 progressive disease (not evaluable: = 3).
CONCLUSIONS
Ser-T monotherapy at doses up to 50 μg/kg initial dose, followed by 25 μg/kg Q4W demonstrated a tolerable safety profile with minimal antitumor activity observed in patients with glioblastoma. The glioblastoma dose-expansion cohort was closed due to a lack of efficacy (NCT03234712).
背景
Serclutamab talirine（Ser-T，原名ABBV-321）是一种抗体药物偶联物，由一种针对活化表皮生长因子受体（EGFR）的抗体（AM-1-ABT-806）和一个吡咯并苯二氮䓬二聚体组成。我们在一项针对EGFR过表达相关晚期实体瘤患者的I期、首次人体、剂量递增和剂量扩展研究中，对Ser-T单药治疗进行了研究。
方法
符合条件的患者（≥18岁）患有经组织学确诊的与EGFR过表达相关的晚期实体瘤（集中检测）。在剂量递增阶段，患者每4周静脉注射一次Ser-T（Q4W；5-50μg/kg）。在此，仅报告了胶质母细胞瘤患者（n = 24）在推荐的II期剂量（RP2D）下的初步抗肿瘤活性；其他评估包括所有接受治疗的患者。
结果
62例患者（中位年龄：58岁）纳入了剂量递增（n = 43）和剂量扩展（n = 19）阶段。在剂量递增期间，20μg/kg时发生了1例剂量限制性毒性，即3级天冬氨酸转氨酶和丙氨酸转氨酶升高。在剂量扩展期间，采用了Ser-T的RP2D方案，即50μg/kg×1（负荷剂量），随后25μg/kg Q4W（维持剂量）。疲劳（37%）是唯一在超过25%的患者中出现的治疗中出现的不良事件（AE）。两名患者（3%）报告了轻度的与治疗相关的眼部AE（眼部瘙痒）。胶质母细胞瘤患者的反应包括1例部分缓解（约33个月）、6例病情稳定和14例病情进展（不可评估：n = 3）。
结论
初始剂量高达50μg/kg，随后25μg/kg Q4W的Ser-T单药治疗显示出可耐受的安全性，在胶质母细胞瘤患者中观察到的抗肿瘤活性极小。由于缺乏疗效，胶质母细胞瘤剂量扩展队列已关闭（NCT03234712）。
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