Naing Aung, Papadopoulos Kyriakos P, Pishvaian Michael J, Rahma Osama, Hanna Glenn J, Garralda Elena, Saavedra Omar, Gogov Sven, Kallender Howard, Cheng LuLu, Smith Michael, Chen Xuejun, Kuriakose Emil, Bauer Todd
MD Anderson Cancer Center, Houston, Texas, USA.
START San Antonio, San Antonio, Texas, USA.
BMJ Oncol. 2024 May 9;3(1):e000249. doi: 10.1136/bmjonc-2023-000249. eCollection 2024.
The arginase inhibitor INCB001158 was evaluated for safety (primary endpoint) in locally advanced or metastatic solid tumours; pharmacokinetics, pharmacodynamics and efficacy were also assessed.
In this non-randomised, open-label, three-part phase 1 study, INCB001158 was orally administered two times per day as monotherapy or in combination with intravenous pembrolizumab 200 mg every 3 weeks. Dose expansion was conducted in tumour-type cohorts (with or without prior anti-PD-1/PD-L1 (programmed death protein 1/programmed death ligand 1) therapy).
A total of 107 patients received INCB001158 50-150 mg two times per day as monotherapy, and 153 patients, including 6 with moderate renal impairment, received INCB001158 50-100 mg two times per day combined with pembrolizumab. INCB001158 exposure was similar between groups (median, 56 days (monotherapy); 84 days (combination)). 49 patients (45.8%) on monotherapy and 76 (51.7%) on combination therapy experienced grade ≥3 treatment-emergent adverse events (AEs). The most common INCB001158-related AEs were fatigue (n=10/107 (9.3%)) and nausea (n=10/107 (9.3%)) with monotherapy and diarrhoea (n=24/147 (16.3%)) and fatigue (n=22/147 (15.0%)) with combination therapy. The highest response rate was seen in the anti-PD-1/PD-L1-naive combination therapy group with head/neck squamous cell carcinoma (overall response rate, 19.2%; 4/26 partial responses, 1/26 complete response). Consistent with arginase inhibition activity, plasma arginine dose-dependently increased. Arginase 1 expression in the tumour microenvironment did not correlate with response.
INCB001158 was generally well tolerated. Response rates did not exceed background for given tumour types despite demonstrable pharmacodynamic activity. Overall, the limited antitumour activity of arginase inhibition observed suggests that the role of arginine depletion in cancer is multifaceted.
NCT02903914.
评估精氨酸酶抑制剂INCB001158在局部晚期或转移性实体瘤中的安全性（主要终点）；同时评估其药代动力学、药效学和疗效。
在这项非随机、开放标签的三部分1期研究中，INCB001158作为单药治疗或与静脉注射派姆单抗（每3周200mg）联合使用，每日口服2次。在肿瘤类型队列中进行剂量扩展（有或无既往抗PD-1/PD-L1（程序性死亡蛋白1/程序性死亡配体1）治疗）。
共有107例患者接受INCB001158每日2次、每次50 - 150mg的单药治疗，153例患者（包括6例中度肾功能损害患者）接受INCB001158每日2次、每次50 - 100mg联合派姆单抗治疗。两组间INCB001158的暴露情况相似（中位数，单药治疗组为56天；联合治疗组为84天）。单药治疗组49例患者（45.8%）和联合治疗组76例患者（51.7%）发生≥3级治疗中出现的不良事件（AE）。单药治疗中最常见的与INCB001158相关的AE为疲劳（n = 10/107（9.3%））和恶心（n = 10/107（9.3%）），联合治疗中为腹泻（n = 24/147（16.3%））和疲劳（n = 22/147（15.0%））。在未接受过抗PD-1/PD-L1治疗的头颈部鳞状细胞癌联合治疗组中观察到最高缓解率（总体缓解率，19.2%；4/26例部分缓解，1/26例完全缓解）。与精氨酸酶抑制活性一致，血浆精氨酸剂量依赖性增加。肿瘤微环境中的精氨酸酶1表达与缓解无关。
INCB001158总体耐受性良好。尽管有明显的药效学活性，但对于特定肿瘤类型，缓解率未超过基线水平。总体而言，观察到的精氨酸酶抑制的抗肿瘤活性有限，提示精氨酸消耗在癌症中的作用是多方面的。
NCT02903914。
