Abstract：
BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA.
METHODS: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR).
RESULTS: As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA.
CONCLUSIONS: The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.
METHODS: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR).
RESULTS: As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA.
CONCLUSIONS: The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.
摘要：
背景：人类表皮生长因子受体2（HER2）阳性的转移性胃和胃食管腺癌（GEA）在全球范围内接受化疗加曲妥珠单抗治疗。新的治疗策略不仅致力于优化疗效，但也限制毒性。在MAHOGANY队列A中，margetuximab,Fc工程，抗HER2单克隆抗体（mAb）与Retifanlimab联合使用，一种抗程序性细胞死亡蛋白1mAb，在一线HER2阳性/程序性死亡配体1（PD-L1）阳性GEA中。
方法：MAHOGANY队列第1部分是一项单臂试验，用于评估患有HER2免疫组织化学3+的患者的margetuximab联合retifanlimab，PD-L1阳性（合并阳性评分≥1%），和非微卫星不稳定性高肿瘤。队列A的主要目标是安全性/耐受性和确认的客观缓解率(ORR)。
结果：截至2021年8月3日，纳入43例患者并接受margetuximab/retifanlimab治疗。8例（18.6%）患者报告了9例3级治疗相关不良事件（TRAEs），7例（16.3%）患者报告了8例严重TRAEs。没有4/5级TRAE。由于免疫相关的不良事件，三名患者停止了margetuximab/retifanlimab。独立评估的ORR为53%[21/40(95%置信区间(CI)36.1-68.5)]，中位缓解持续时间为10.3个月(95%CI4.6-不可评估);疾病控制率为73%[29/40(95%CI56.1-85.4)].由于GEA治疗的最新进展，研究设计显然不再符合药物批准的要求，因此研究赞助者在计划入组之前终止了研究。
结论：在双重生物标志物选择的患者中，margetuximab/retifanlimab联合无化疗方案作为一线治疗，与使用化疗加曲妥珠单抗的历史结果相比，显示出良好的毒性特征。在这项研究中观察到的ORR与其他无化疗方法观察到的ORR相比具有优势。
方法：MAHOGANY队列第1部分是一项单臂试验，用于评估患有HER2免疫组织化学3+的患者的margetuximab联合retifanlimab，PD-L1阳性（合并阳性评分≥1%），和非微卫星不稳定性高肿瘤。队列A的主要目标是安全性/耐受性和确认的客观缓解率(ORR)。
结果：截至2021年8月3日，纳入43例患者并接受margetuximab/retifanlimab治疗。8例（18.6%）患者报告了9例3级治疗相关不良事件（TRAEs），7例（16.3%）患者报告了8例严重TRAEs。没有4/5级TRAE。由于免疫相关的不良事件，三名患者停止了margetuximab/retifanlimab。独立评估的ORR为53%[21/40(95%置信区间(CI)36.1-68.5)]，中位缓解持续时间为10.3个月(95%CI4.6-不可评估);疾病控制率为73%[29/40(95%CI56.1-85.4)].由于GEA治疗的最新进展，研究设计显然不再符合药物批准的要求，因此研究赞助者在计划入组之前终止了研究。
结论：在双重生物标志物选择的患者中，margetuximab/retifanlimab联合无化疗方案作为一线治疗，与使用化疗加曲妥珠单抗的历史结果相比，显示出良好的毒性特征。在这项研究中观察到的ORR与其他无化疗方法观察到的ORR相比具有优势。
