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Claudin 18.2-targeting antibody–drug conjugate CMG901 in patients with advanced gastric or gastro-oesophageal junction cancer (KYM901): a multicentre, open-label, single-arm, phase 1 trial - 07/01/25

Doi : 10.1016/S1470-2045(24)00636-3 
Dan-Yun Ruan, MD a, , Fu-Rong Liu, MD a, , Xiao-Li Wei, MD b, , Su-Xia Luo, ProfMD c, Zhi-Xiang Zhuang, ProfMD d, Zhen-Ning Wang, ProfMD e, Fu-Nan Liu, ProfMD e, Yan-Qiao Zhang, ProfMD f, Jian-Wei Yang, BS g, Zhen-Dong Chen, ProfMD h, Yong-Sheng Wang, ProfMD i, Jun-Ye Wang, ProfBS j, Xiao-Hua Liang, ProfMD k, Xiao-Jie Wu, ProfMD l, Yu-Long Zheng, ProfMD m, Jian Liu, ProfMS n, Xi Shi, ProfMD o, Rakesh Kumar, PhD p, Wei Liu, PhD q, Bo Chen, PhD q, Dong-Sheng Zhang, ProfMD b, , Rui-Hua Xu, ProfMD b,
a 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 
b 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 
c Department of Medical Oncology, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China 
d Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China 
e Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China 
f Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China 
g Department of Abdominal Oncology, Fujian Cancer Hospital, Fuzhou, China 
h Department of Oncology, The Second Hospital of Anhui Medical University, Hefei, China 
i Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China 
j Department of Digestive Oncology, The Affiliated Hospital of Jining Medical College, Jining, China 
k Department of Oncology, Huashan Hospital, Fudan University, Shanghai, China 
l Clinical Pharmacology Research Center, Huashan Hospital, Fudan University, Shanghai, China 
m Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China 
n Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine & Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Hangzhou, China 
o Department of Medical Oncology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China 
p Oncology R&D, AstraZeneca, Gaithersburg, MD, USA 
q KYM Biosciences, Chengdu, China 

* Correspondence to: Prof Rui-Hua Xu, 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 510060, 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 510060 China ** Prof Dong-Sheng Zhang, 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 510060, 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 510060 China
Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Tuesday 07 January 2025

Summary

Background

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.

Methods

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.

Findings

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.

Interpretation

CMG901 showed a manageable safety profile and had promising antitumour activity in patients with advanced gastric or gastro-oesophageal junction cancer.

Funding

KYM Biosciences.

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