Department of Medicine, Section of Hematology & Oncology, University of Chicago, Chicago, IL 60637, USA.
Clinical Research, MacroGenics, Inc., Rockville, MD 20850, USA.
Future Oncol. 2021 Apr;17(10):1155-1164. doi: 10.2217/fon-2020-1007. Epub 2020 Dec 2.
Standard-of-care, first-line therapy for patients with advanced HER2+ gastric/gastroesophageal junction adenocarcinoma is chemotherapy plus trastuzumab, a monoclonal antibody (mAb) targeting HER2. Margetuximab is an Fc-optimized mAb that binds HER2. Retifanlimab, a humanized IgG4 mAb, binds to PD-1 and blocks its interaction with PD-L1/2. Tebotelimab, an IgG4κ bispecific DART molecule, binds PD-1 and lymphocyte activation gene 3 concomitantly, disrupting these nonredundant inhibitory pathways to further restore exhausted T-cell function. Here, we describe the design and rationale of the randomized, open-label, Phase II/III MAHOGANY trial evaluating margetuximab plus retifanlimab with/without chemotherapy and margetuximab plus tebotelimab with chemotherapy in first-line unresectable metastatic/locally advanced gastroesophageal junction adenocarcinoma. Primary end points include objective response rate, overall survival and safety/tolerability. NCT04082364 (ClinicalTrials.gov).
标准护理，即曲妥珠单抗联合化疗，是治疗晚期 HER2+胃/胃食管交界腺癌患者的一线治疗方法。Margetuximab 是一种靶向 HER2 的 Fc 优化单克隆抗体。Retifanlimab 是人源化 IgG4 mAb，与 PD-1 结合并阻断其与 PD-L1/2 的相互作用。Tebotelimab 是一种 IgG4κ 双特异性 DART 分子，同时与 PD-1 和淋巴细胞激活基因 3 结合，破坏这些非冗余抑制途径，进一步恢复耗竭 T 细胞功能。在这里，我们描述了一项随机、开放标签、II/III 期 MAHOGANY 试验的设计和原理，该试验评估了 margetuximab 联合 retifanlimab 加/不加化疗，以及 margetuximab 联合 tebotelimab 加化疗在不可切除的转移性/局部晚期胃食管交界腺癌一线治疗中的疗效。主要终点包括客观缓解率、总生存期和安全性/耐受性。NCT04082364（ClinicalTrials.gov）。
