Ruan Dan-Yun, Liu Fu-Rong, Wei Xiao-Li, Luo Su-Xia, Zhuang Zhi-Xiang, Wang Zhen-Ning, Liu Fu-Nan, Zhang Yan-Qiao, Yang Jian-Wei, Chen Zhen-Dong, Wang Yong-Sheng, Wang Jun-Ye, Liang Xiao-Hua, Wu Xiao-Jie, Zheng Yu-Long, Liu Jian, Shi Xi, Kumar Rakesh, Liu Wei, Chen Bo, Zhang Dong-Sheng, Xu Rui-Hua
Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.
Lancet Oncol. 2025 Feb;26(2):227-238. doi: 10.1016/S1470-2045(24)00636-3. Epub 2025 Jan 6.
CMG901 is a novel first-in-class antibody-drug conjugate with a humanised anticlaudin 18.2 antibody linked to microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the antitumour activity and safety of CMG901 in patients with advanced gastric or gastro-oesophageal junction cancer and other solid tumours.
KYM901 is a multicentre, open-label, single-arm, phase 1 trial consisting of dose-escalation and dose-expansion stages. Patients with advanced solid tumours, including gastric or gastro-oesophageal junction and pancreatic cancers, were recruited from 31 hospital sites in China. Eligible patients were aged 18 years or older, were refractory to standard therapy or had no available standard-of-care regimen, and had an Eastern Cooperative Oncology Group performance status score of 0-1, a life expectancy of at least 3 months, and at least one measurable lesion. Patients received intravenous CMG901 every 3 weeks (0·3-3·4 mg/kg in dose escalation and 2·2-3·0 mg/kg in dose expansion) until disease progression, unacceptable toxic effects, initiation of new antitumour therapy, study withdrawal, or death. Primary endpoints were adverse events and dose-limiting toxic effects in the dose-escalation phase, and objective response rate and recommended phase 2 dose in the dose-expansion phase. Confirmed objective response was defined as a partial or complete response that was verified by follow-up imaging at least 4 weeks after the initial assessment. Safety was assessed in all patients who received at least one dose of CMG901 with at least one post-dose safety evaluation. Antitumour activity was assessed in all patients who received at least one dose of CMG901 (full analysis set) and in all CMG901-treated patients with at least one post-dose imaging evaluation and no major protocol deviations (efficacy analysis set). Dose-expansion data for patients with pancreatic cancer will be published separately. Due to small sample sizes, results in patients with other solid tumours (n=2) are not planned for publication. This ongoing trial is registered with ClinicalTrials.gov, NCT04805307.
Between Dec 24, 2020, and Feb 23, 2023, 27 patients were enrolled in the dose-escalation phase (median age 57·0 years [IQR 48·0-63·0]; 14 [52%] male, 13 [48%] female) and 107 patients with gastric or gastro-oesophageal junction cancer in the dose-expansion phase (median age 56·0 years [44·0-64·0]; 57 [53%] male, 50 [47%] female). As of Feb 24, 2024, one dose-limiting toxic effect (grade 3 pancreatitis) occurred at 2·2 mg/kg, and the maximum tolerated dose was not reached in the dose-escalation phase. All 27 patients reported at least one treatment-emergent adverse event, most frequently vomiting (19 [70%]), decreased appetite (16 [59%]), proteinuria (16 [59%]), and anaemia (15 [56%]), and five (19%) had drug-related grade 3 or worse treatment-emergent adverse events. In 107 patients, grade 3 or worse treatment-emergent adverse events occurred in 73 (68%) patients and serious adverse events occurred in 54 (50%) patients in dose expansion. The most common grade 3-4 adverse events were neutrophil count decreased (22 [21%]), anaemia (15 [14%]), and vomiting (11 [10%]). One treatment-related death was reported. At median follow-up of 9·0 months (IQR 4·4-12·9), among 113 patients with gastric or gastro-oesophageal junction cancer in the 2·2-3·0 mg/kg cohort full analysis set across both the dose-escalation and dose-expansion phases, the confirmed objective response rate was 28% (95% CI 20-38; 32 of 113 patients). In the 109 patients included in the efficacy analysis set, the confirmed objective response rate was 29% (95% CI 21-39; 32 of 109 patients). Based on overall safety, activity, and pharmacokinetics of CMG901, 2·2 mg/kg was the proposed recommended phase 2 dose.
CMG901 showed a manageable safety profile and had promising antitumour activity in patients with advanced gastric or gastro-oesophageal junction cancer.
KYM Biosciences.
CMG901是一种新型的一流抗体药物偶联物，其将人源化抗Claudin 18.2抗体与微管破坏剂单甲基奥瑞他汀E连接。我们旨在评估CMG901在晚期胃癌或胃食管交界癌及其他实体瘤患者中的抗肿瘤活性和安全性。
KYM901是一项多中心、开放标签、单臂1期试验，包括剂量爬坡和剂量扩展阶段。晚期实体瘤患者，包括胃癌或胃食管交界癌及胰腺癌患者，从中国31个医院招募。符合条件的患者年龄在18岁及以上，对标准治疗难治或没有可用的标准治疗方案，东部肿瘤协作组体能状态评分为0 - 1，预期寿命至少3个月，且至少有一个可测量病变。患者每3周接受一次静脉注射CMG901（剂量爬坡阶段为0·3 - 3·4 mg/kg，剂量扩展阶段为2·2 - 3·0 mg/kg），直至疾病进展、出现不可接受的毒性作用、开始新的抗肿瘤治疗、研究退出或死亡。主要终点在剂量爬坡阶段为不良事件和剂量限制毒性，在剂量扩展阶段为客观缓解率和推荐的2期剂量。确认的客观缓解定义为部分或完全缓解，在初始评估后至少4周通过随访影像学检查证实。在所有接受至少一剂CMG901并至少进行一次给药后安全性评估的患者中评估安全性。在所有接受至少一剂CMG901的患者（全分析集）以及所有接受CMG901治疗且至少进行一次给药后影像学评估且无重大方案偏离的患者（疗效分析集）中评估抗肿瘤活性。胰腺癌患者的剂量扩展数据将单独发表。由于样本量小，其他实体瘤患者（n = 2）的结果不计划发表。这项正在进行的试验已在ClinicalTrials.gov注册，NCT04805307。
在2020年12月24日至2023年2月23日期间，27名患者进入剂量爬坡阶段（中位年龄57·0岁[四分位间距48·0 - 63·0]；男性14名[52%]，女性13名[48%]），107名胃癌或胃食管交界癌患者进入剂量扩展阶段（中位年龄56·0岁[44·0 - 64·0]；男性57名[53%]，女性50名[47%]）。截至2024年2月24日，在2·2 mg/kg剂量时出现1例剂量限制毒性（3级胰腺炎），剂量爬坡阶段未达到最大耐受剂量。所有27名患者均报告了至少1次治疗中出现的不良事件，最常见的是呕吐（19例[70%]）、食欲下降（16例[59%]）、蛋白尿（16例[59%]）和贫血（15例[56%]），5例（19%）出现与药物相关的3级或更严重的治疗中出现的不良事件。在107名患者中，剂量扩展阶段73例（68%）患者出现3级或更严重的治疗中出现的不良事件，54例（50%）患者出现严重不良事件。最常见的3 - 4级不良事件是中性粒细胞计数减少（22例[21%]）、贫血（15例[14%]）和呕吐（11例[10%]）。报告了1例与治疗相关的死亡。在剂量爬坡和剂量扩展阶段的2·2 - 3·0 mg/kg队列全分析集中，113例胃癌或胃食管交界癌患者的中位随访时间为9·0个月（四分位间距4·4 - 12·9）时，确认的客观缓解率为28%（95%CI 20 - 38；113例患者中的32例）。在疗效分析集中纳入的109例患者中，确认的客观缓解率为29%（95%CI 21 - 39；109例患者中的32例）。基于CMG901的总体安全性、活性和药代动力学，2·2 mg/kg被提议作为推荐的2期剂量。
CMG901在晚期胃癌或胃食管交界癌患者中显示出可管理的安全性，具有有前景的抗肿瘤活性。
康诺亚生物科技。
