Cho Byoung Chul, Lu Shun, Lee Myung Ah, Song Zhengbo, Park John J, Lim Sun Min, Li Ziming, Zhao Jun, Richardson Gary, Zhang Yanqiao, Zhang Jun, Liu Anwen, Loong Herbert H, Chen Cheng, Wang Jia, Shen Yandong, Fan Zifei, Chen Qian, Wang Hui, Zhang Jing, Chen Zhi Jian, Johnson Melissa L, Mok Tony
Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Nat Med. 2025 Apr 29. doi: 10.1038/s41591-025-03688-6.
D3S-001 is a next-generation KRAS-G12C inhibitor (G12Ci) designed to enhance target engagement efficiency and overcome growth factor-induced nucleotide exchange. D3S-001 was evaluated in a phase 1a dose-escalation study in patients with advanced solid tumors harboring KRAS mutation (N = 42) and a phase 1b expansion cohort of patients with non-small-cell lung cancer (NSCLC) whose disease progressed after prior G12Ci therapy (N = 20). The primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints included pharmacokinetics, confirmed objective response rate (ORR) and disease control rate. D3S-001 demonstrated dose-dependent pharmacokinetics and no dose-limiting toxicities, and the maximum tolerated dose was not reached. Grade 3 treatment-related adverse events were reported in seven patients (16.7%) in the G12Ci-naive dose-escalation cohort and two patients (10.0%) in the G12Ci-pretreated NSCLC expansion cohort. There were no grade 4 or 5 treatment-related adverse events. D3S-001 600 mg was selected as the dose for further investigation based on pharmacokinetics. Confirmed ORR in the G12Ci-naive population was 73.5% overall (25 of 34), and 66.7% (14 of 21), 88.9% (8 of 9) and 75.0% (3 of 4) in patients with NSCLC, colorectal cancer and pancreatic ductal adenocarcinoma, respectively. Among patients with G12Ci-pretreated NSCLC, ORR was 30.0% (6 of 20) and disease control rate was 80.0% (16 of 20). This study demonstrates the safety and tolerability of D3S-001 monotherapy with promising antitumor activity. The phase 1b expansion phase is ongoing. ClinicalTrials.gov identifier: NCT05410145 .
D3S-001是一种新一代KRAS-G12C抑制剂（G12Ci），旨在提高靶点结合效率并克服生长因子诱导的核苷酸交换。在一项1a期剂量递增研究中，对携带KRAS突变的晚期实体瘤患者（N = 42）进行了D3S-001评估，并在一组1b期扩展队列中，对先前接受G12Ci治疗后疾病进展的非小细胞肺癌（NSCLC）患者（N = 20）进行了评估。主要终点是安全性和最大耐受剂量的确定。次要终点包括药代动力学、确认的客观缓解率（ORR）和疾病控制率。D3S-001表现出剂量依赖性药代动力学，且无剂量限制性毒性，未达到最大耐受剂量。在未接受过G12Ci治疗的剂量递增队列中，7名患者（16.7%）报告了3级治疗相关不良事件，在接受过G12Ci预处理的NSCLC扩展队列中，2名患者（10.0%）报告了此类事件。没有4级或5级治疗相关不良事件。基于药代动力学，选择600 mg的D3S-001作为进一步研究的剂量。在未接受过G12Ci治疗的人群中，确认的总体ORR为73.5%（34例中的25例），在NSCLC、结直肠癌和胰腺导管腺癌患者中分别为66.7%（21例中的14例）、88.9%（9例中的8例）和75.0%（4例中的3例）。在接受过G12Ci预处理的NSCLC患者中，ORR为30.0%（20例中的6例），疾病控制率为80.0%（20例中的16例）。本研究证明了D3S-001单药治疗的安全性和耐受性，并具有有前景的抗肿瘤活性。1b期扩展阶段正在进行中。ClinicalTrials.gov标识符：NCT05410145 。
