eprenetapopt（APR-246）联合 pembrolizumab 治疗晚期或转移性实体瘤的 Ib 期研究。
Phase Ib study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with advanced or metastatic solid tumors.
机构信息
Division of Oncology, Alvin J Siteman Cancer Center, Washington University, St. Louis, USA.
Dana Farber Cancer Institute, Department of Medical Oncology, Boston, USA.
出版信息
ESMO Open. 2022 Oct;7(5):100573. doi: 10.1016/j.esmoop.2022.100573. Epub 2022 Sep 7.
BACKGROUND
We conducted a phase I, multicenter, open-label, dose-finding, and expansion study to determine the safety and preliminary efficacy of eprenetapopt (APR-246) combined with pembrolizumab in patients with advanced/metastatic solid tumors (ClinicalTrials.gov NCT04383938).
PATIENTS AND METHODS
For dose-finding, requirements were non-central nervous system primary solid tumor, intolerant to/progressed after ≥1 line of treatment, and eligible for pembrolizumab; for expansion: (i) gastric/gastroesophageal junction tumor, intolerant to/progressed after first-line treatment, and no prior anti-programmed cell death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy; (ii) bladder/urothelial tumor, intolerant to/progressed after first-line cisplatin-based chemotherapy, and no prior anti-PD-1/PD-L1 therapy; (iii) non-small-cell lung cancer (NSCLC) with previous anti-PD-1/PD-L1 therapy. Patients received eprenetapopt 4.5 g/day intravenously (IV) on days 1-4 with pembrolizumab 200 mg IV on day 3 in each 21-day cycle. Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and recommended phase II dose (RP2D) of eprenetapopt.
RESULTS
Forty patients were enrolled (median age 66 years; range 27-85) and 37 received eprenetapopt plus pembrolizumab. No DLTs were reported and the RP2D for eprenetapopt in combination was 4.5 g/day IV on days 1-4. The most common eprenetapopt-related AEs were dizziness (35.1%), nausea (32.4%), and vomiting (29.7%). AEs leading to eprenetapopt discontinuation occurred in 2/37 patients (5.4%). In efficacy-assessable patients (n = 29), one achieved complete response (urothelial cancer), two achieved partial responses (NSCLC, urothelial cancer), and six patients had stable disease.
CONCLUSIONS
The eprenetapopt plus pembrolizumab combination was well tolerated with an acceptable safety profile and showed clinical activity in patients with solid tumors.
背景
我们开展了一项 I 期、多中心、开放标签、剂量探索和扩展研究，以确定 eprenetapopt（APR-246）联合 pembrolizumab 用于晚期/转移性实体瘤患者的安全性和初步疗效（ClinicalTrials.gov NCT04383938）。
患者和方法
剂量探索要求为非中枢神经系统原发性实体瘤、对≥1 线治疗不耐受/进展、有资格接受 pembrolizumab；扩展要求为：（i）胃/胃食管交界处肿瘤，对一线治疗不耐受/进展，且无先前抗程序性细胞死亡受体-1（PD-1）/程序性死亡配体 1（PD-L1）治疗；（ii）膀胱/尿路上皮肿瘤，对一线顺铂为基础的化疗不耐受/进展，且无先前抗 PD-1/PD-L1 治疗；（iii）非小细胞肺癌（NSCLC），先前接受过抗 PD-1/PD-L1 治疗。患者接受 eprenetapopt 4.5 g/天静脉输注（IV），于第 1-4 天，每 21 天周期的第 3 天给予 pembrolizumab 200 mg IV。主要终点为剂量限制性毒性（DLT）、不良事件（AE）和 eprenetapopt 的推荐 II 期剂量（RP2D）。
结果
共纳入 40 例患者（中位年龄 66 岁；范围 27-85 岁），37 例患者接受了 eprenetapopt 联合 pembrolizumab 治疗。未报告剂量限制性毒性，e prenetapopt 的 RP2D 为 4.5 g/天 IV，于第 1-4 天。最常见的与 eprenetapopt 相关的 AE 为头晕（35.1%）、恶心（32.4%）和呕吐（29.7%）。有 2/37 例（5.4%）患者因 AE 而停用 eprenetapopt。在可评估疗效的患者（n=29）中，1 例患者达到完全缓解（尿路上皮癌），2 例患者达到部分缓解（NSCLC、尿路上皮癌），6 例患者疾病稳定。
结论
eprenetapopt 联合 pembrolizumab 具有良好的耐受性，安全性可接受，在实体瘤患者中显示出临床活性。
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