Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Department of Medical Oncology, The Christie Hospital NHS Foundation Trust and University of Manchester, Manchester, UK.
J Immunother Cancer. 2021 Jul;9(7). doi: 10.1136/jitc-2021-002447.
Probody therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing 'off-tumor' toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1).
In the dose-escalation phase of this multicenter, open-label study (NCT03013491), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1).
An MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, >50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1).
Pacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression.
NCT03013491.
前药疗法是一种抗体前药，可在肿瘤相关蛋白酶的作用下在肿瘤微环境中被激活，从而将活性限制在肿瘤微环境中，并最大程度地减少“肿瘤外”毒性。我们报告了首例人体研究中 CX-072（pacmilimab）的剂量递增和单药扩展阶段数据，CX-072 是一种针对程序性死亡配体 1（PD-L1）的 Probody 检查点抑制剂。
在这项多中心、开放标签研究（NCT03013491）的剂量递增阶段，接受过程序性死亡-1/PD-L1 或细胞毒性 T 淋巴细胞相关抗原 4 抑制剂治疗的晚期实体瘤成人患者（naive to programmed-death-1/PD-L1 或 cytotoxic T-lymphocyte-associated antigen 4 inhibitors）被纳入七个剂量递增队列之一，每 14 天静脉注射 pacmilimab。主要终点是安全性和最大耐受剂量（MTD）的确定。在扩展阶段，具有六个预定恶性肿瘤之一的患者（三阴性乳腺癌[TNBC]；肛门鳞状细胞癌[aSCC]；皮肤鳞状细胞癌[cSCC]；未分化多形性肉瘤[UPS]；小肠腺癌[SBA]；和胸腺癌[TET]）或高肿瘤突变负担（hTMB）肿瘤被纳入。主要终点是客观缓解（实体瘤反应评估标准 v.1.1）。
最高剂量 30mg/kg 仍未达到最大耐受剂量。根据扩展阶段的药代动力学和药效学发现，选择了 10mg/kg 的推荐 2 期剂量（RP2D）。98 名患者入组扩展阶段：TNBC（n=14）、aSCC（n=14）、cSCC（n=14）、UPS（n=20）、SBA（n=14）、TET（n=8）和 hTMB 肿瘤（n=14）。在接受 RP2D pacmilimab 的 114 名患者中，10 名患者（9%）出现≥3 级治疗相关不良事件（TRAEs），6 名患者（5%）出现严重 TRAEs，2 名患者（2%）因 TRAEs 停药。两名患者（皮疹，心肌炎）出现≥3 级免疫相关 AEs。22/144（19%）患者观察到高 PD-L1 表达（即>50%肿瘤比例评分）。在 cSCC（n=5，包括 1 例完全缓解）、hTMB（n=4，包括 1 例完全缓解）、aSCC（n=2）、TNBC（n=1）、UPS（n=1）和间变性甲状腺癌（n=1）患者中观察到确认的客观缓解。
Pacmilimab 以 10mg/kg 的推荐 2 期剂量（RP2D）每 14 天安全给药。在该剂量下，pacmilimab 免疫介导的毒性发生率低，并在未选择高 PD-L1 表达的患者中显示出抗肿瘤活性的迹象。
NCT03013491。
