The University of Chicago Medical Center, Chicago, IL, USA.
Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Lancet Oncol. 2020 Aug;21(8):1066-1076. doi: 10.1016/S1470-2045(20)30326-0. Epub 2020 Jul 9.
Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma.
CP-MGAH22-05 was a single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing.
Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7-23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15-27·93) of 92 evaluable patients.
These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab).
MacroGenics.
Margetuximab 是一种新型、研究性、Fc 工程化的抗 HER2 单克隆抗体，旨在比曲妥珠单抗更有效地增强先天免疫。我们旨在评估先前接受过曲妥珠单抗联合化疗治疗的局部晚期不可切除或转移性 HER2 阳性胃食管腺癌患者中，马吉妥昔单抗联合帕博利珠单抗（一种抗 PD-1 单克隆抗体）的安全性、耐受性和抗肿瘤活性。
CP-MGAH22-05 是一项在美国和加拿大的 11 个学术中心以及东南亚的 15 个中心（韩国、中国台湾和新加坡）进行的单臂、开放标签、1b-2 期剂量递增和队列扩展研究，招募了年龄在 18 岁或以上的男性和女性，组织学证实、不可切除的局部晚期或转移性、HER2 阳性、未经选择的 PD-L1 的胃食管腺癌，东部合作肿瘤学组的体能状态为 0 或 1，在局部晚期不可切除或转移性环境中接受过至少一线曲妥珠单抗联合化疗治疗后进展。在剂量递增阶段，9 名患者接受治疗：3 名患者接受马吉妥昔单抗 10mg/kg 静脉注射加帕博利珠单抗 200mg 静脉注射每 3 周一次，6 名患者接受马吉妥昔单抗推荐的 2 期剂量 15mg/kg 静脉注射加帕博利珠单抗 200mg 静脉注射每 3 周一次。另外 86 名患者入组了 2 期队列扩展，并接受了推荐的 2 期剂量。主要终点是安全性和耐受性，在安全性人群（至少接受过一次马吉妥昔单抗或帕博利珠单抗治疗的患者）和根据实体瘤反应评估标准（RECIST），版本 1.1，在反应可评估人群（基线有可测量疾病且接受推荐的马吉妥昔单抗和帕博利珠单抗 2 期剂量的患者）中评估客观缓解率。该试验在 ClinicalTrials.gov 注册，NCT02689284。该试验的招募工作已经完成，随访工作正在进行中。
2016 年 2 月 11 日至 2018 年 10 月 2 日期间，共纳入 95 例患者。中位随访时间为 19.9 个月（IQR 10.7-23.1）。联合治疗显示出可接受的安全性和耐受性；在剂量递增阶段没有剂量限制毒性。最常见的 3-4 级治疗相关不良事件为贫血（4[4%]）和输液相关反应（3[3%]）。9（9%）例患者报告严重的治疗相关不良事件。没有报告与治疗相关的死亡。在 92 例可评估患者中，17 例（18.48%；95%CI 11.15-27.93）观察到客观缓解。
这些发现证明了与 Fc 优化的抗 HER2 药物（马吉妥昔单抗）联合抗 PD-1 检查点阻断（帕博利珠单抗）具有协同抗肿瘤活性。
MacroGenics。
