PO.CT01.02 · 临床试验
D3S-002（一种专门设计的ERK1/2抑制剂）在伴MAPK通路突变的晚期实体瘤中的首次人体1期研究
First in human phase 1 study of D3S-002, a purposely designed ERK1/2 inhibitor, in advanced solid tumors with MAPK pathway mutations
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：D3S-002是一种强效、选择性口服ERK1/2抑制剂，专门设计为KRAS G12X抑制剂的联合搭档，以克服这些药物诱导的反馈性MAPK激活。在KRAS G12Ci耐药模型中，D3S-002与新一代KRAS G12Ci D3S-001联用，与D3S-001或D3S-002单药相比显示出显著改善的疗效，支持对该联合方案进行临床评估。
方法：这项正在进行的1/2期、开放标签、剂量递增和剂量扩展研究（NCT05886920）旨在评估D3S-002单药或联合治疗在携带MAPK通路突变的晚期实体瘤成人患者中的安全性、耐受性、药代动力学（PK）和推荐的2期剂量。D3S-002单药治疗的剂量递增部分已完成。在BOIN设计下，评估了D3S-002 QD从10mg到240mg共8个剂量水平的PK和安全性特征。
结果：32名患者入组D3S-002单药治疗的剂量递增部分，分布于美国（n=2）、澳大利亚（n=15）和中国（n=15）的10个中心。接受10mg、20mg、40mg、60mg、90mg、135mg、180mg或240mg D3S-002 QD的患者数分别为3、3、3、3、5、3、6、6。中位暴露持续时间为1.3个月（0.2-5.6）。D3S-002表现出剂量比例的PK特征，从10 mg到240 mg QD暴露量呈剂量依赖性增加，重复给药后蓄积极小。Tmax为1-3小时，终末半衰期约3-5小时，在各剂量水平间一致。这种PK行为与D3S-002有意设计的临床前药理学相符，支持脉冲式ERK抑制，从而在正常组织中允许无药间期，同时在ERK活性升高的肿瘤中维持有效的MAPK通路抑制。D3S-002耐受性良好，18.8%（6/32）的患者观察到≥3级TRAE。未报告5级TRAE。发生于≥10%患者的TRAE包括AST/ALT升高和恶心。PK与肝酶变化之间未观察到显著相关性。与其他ERKi不同，皮肤毒性（痤疮样皮炎：6.5%，皮疹：3.1%）和眼部毒性（6.5%）不常见。最大耐受剂量在240 mg QD达到。在27名疗效可评估患者中，DCR为25.9%。3名患者观察到肿瘤缩小，包括1例未确认的部分缓解（PR）。在PK/安全性特征的指导下，D3S-002与D3S-001的联合将从40 mg QD开始。
结论：D3S-002表现出可预测的、剂量比例的PK，与其临床前设计的脉冲式暴露特征一致，支持其作为最佳ERKi搭档与其他MAPK通路靶向疗法进行协同联合的开发。一项评估D3S-002联合D3S-001治疗KRAS G12C突变NSCLC患者的临床研究目前正在进行中。
查看英文原文 English abstract
Background: D3S-002 is a potent, selective oral ERK1/2 inhibitor, purposefully designed as a combination partner for KRAS G12X inhibitors to overcome feedback MAPK activation induced by these agents. In KRAS G12Ci resistant models, D3S-002 combined with D3S-001, a next-generation KRAS G12Ci, demonstrated significantly improved efficacy compared with either D3S-001 or D3S-002 alone, supporting clinical evaluation of this combination.
Methods: This ongoing phase 1/2, open-label, dose-escalation and dose expansion study (NCT05886920) was designed to evaluate safety, tolerability, pharmacokinetics (PK) and recommended phase 2 dose of D3S-002 monotherapy or combination therapy in adult patients with advanced solid tumors harboring MAPK pathway mutations. The dose escalation part of D3S-002 monotherapy has been completed. The PK and safety profiles were evaluated with D3S-002 QD at 8 dose levels from 10mg to 240mg under BOIN design.
Results: Thirty-two patients were enrolled in the dose escalation part of D3S-002 monotherapy across 10 sites in the US (n=2), Australia (n=15), and China (n=15). The No. of patients receiving 10mg, 20mg, 40mg, 60mg, 90mg, 135mg, 180mg or 240mg D3S-002 QD were 3, 3, 3, 3, 5, 3, 6, 6 respectively. The median duration of exposure was 1.3m (0.2-5.6). D3S-002 exhibits a dose-proportional PK profile with dose-dependent exposure increases from 10 mg to 240 mg QD and minimal accumulation after repeated dosing. T max was 1-3 hours, and terminal half-life of ~3-5 hours was consistent across dose levels. This PK behavior aligns with D3S-002's intentionally designed preclinical pharmacology, supporting pulsatile ERK inhibition that allows drug-free intervals in normal tissues while maintaining effective MAPK pathway suppression in tumors with elevated ERK activity. D3S-002 was well tolerated, with ≥Grade 3 TRAEs observed in 18.8% (6/32) of patients. No Grade 5 TRAEs were reported. TRAEs occurred in ≥10% of patients including AST/ALT increase and nausea. No significant correlation was observed between PK and changes in liver enzymes. Unlike other ERKi(s), skin toxicities (dermatitis acneiform: 6.5%, rash: 3.1%) and ocular toxicities (6.5%) are uncommon. The maximum tolerated dose was reached at 240 mg QD. Among 27 efficacy evaluable patients, the DCR was 25.9%. Tumor shrinkage was observed in 3 patients, including 1 unconfirmed partial response (PR). Guided by PK/safety profile, D3S-002 combination with D3S-001 will be initiated at 40 mg QD.
Conclusions: D3S-002 demonstrates predictable, dose-proportional PK consistent with its preclinically designed pulsatile exposure profile, supporting its development as an optimal ERKi partner for synergistic combination with other MAPK pathway-targeted therapies. A clinical study evaluating D3S-002 in combination with D3S-001 for the treatment of patients with KRAS G12C-mutant NSCLC is currently underway.
利益披露 Disclosure
Y. Wu,
Guangdong Provincial People's Hospital Employment.
BMS Other, Honoraria, Research Funding.
Boehringer Ingelheim Other, Honoraria, Research Funding, Consulting or Advisory Role.
Pfizer Other, Honoraria, Research Funding.
Roche Other, Honoraria, Research Funding，Consulting or Advisory Role.
AstraZeneca Other, Honoraria, Consulting or Advisory Role.
Takeda Other, Consulting or Advisory Role.
BeiGene Beijing Other, Honoraria.
Hengrui Pharmaceutical Other, Honoraria.
MSD Oncology Other, Honoraria.
M. Millward,
Linear Clinical Research Ltd Employment.
AstraZeneca Other, Consulting or Advisory Role.
BeiGene Other, Consulting or Advisory Role.
IQvia Other, Consulting or Advisory Role.
Lilly Other, Consulting or Advisory Role.
The Limbic Other, Consulting or Advisory Role.
Abbvie (Inst); Akeso Biopharma (Inst); Albion Laboratories (Inst); Alpine Immune Sciences (Inst); Amgen (Inst); Apollomics (Inst); AstraZeneca (Inst); AtriCure (Inst); ).
Bristol-Myers Squibb (Inst); CStone Pharmaceuticals (Inst); Cullinan Oncology (Inst); Dizal Pharma (Inst); Eucure Biopharma (Inst); Five Prime Therapeutics (Inst); Genentech/Roche (Inst); ).
Genfleet Therapeutics (Inst); GlaxoSmithKline (Inst); IMPAC Medical Systems (Inst); InventisBio (Inst); InxMed (Inst); Kinnate Biopharma (Inst); ).
Lilly (Inst); Maxinovel (Inst);Relay Therapeutics (Inst); Turning Point Therapeutics (Inst); Tyra Biosciences (Inst); Vivace Therapeutics (Inst);Axelia Oncology (Inst); BeiGene ).
Y. Zhang,
Harbin Medical University Cancer Hospital Employment.
M. S. Carlino,
Blacktown and Westmead Hospitals, The University of Sydney and the Melanoma Institute Employment.
Bristol-Myers Squibb; MSD; Novartis Other, Honoraria.
Amgen; Bristol-Myers Squibb; Eisai; IDEAYA Biosciences; Innovent Biologics; Medison; Medison; Merck Serono; Moderna Therapeutics; MSD; Nektar; Novartis; OncoSec; Pierre Fabre; QBiotics; Regeneron; Other, Consulting or Advisory Role.
Roche; Sanofi Other, Consulting or Advisory Role.
X. Wang,
Sir Run Run Shaw Hospital, Zhejiang University School of Medicine Employment.
A. Roy,
Southern Oncology Clinical Research Unit (SOCRU) Employment.
BeiGene; Bristol-Myers Squibb; Ipsen; Merck Sharp & Dohme; Roche; SERVIER Other, Honoraria.
MSD Oncology; Roche Other, Consulting or Advisory Role.
Merck Serono (Inst) ).
Bristol-Myers Squibb; Ipsen Travel.
J. Zhang,
Ruijin Hospital Affiliated to The Shanghai Jiao Tong University Employment.
J. Zhao,
Beijing Cancer Hospital Employment.
Z. Wang,
Guangdong Provincial People's Hospital Employment.
A. Weise,
Henry Ford Health System Employment.
D. Doroshow,
Icahn School of Medicine at Mt.Sinai Employment.
MJH Life Sciences Other, Honoraria.
AstraZeneca; Atheneum; Boehringer Ingelheim; Dedham Group; G1 Therapeutics; MJH Life Sciences; Sanofi; Sonata Therapeutics; Summit Therapeutics; Takeda Other, Consulting or Advisory Role.
Boehringer Ingelheim; MJH Life Sciences Travel.
Bristol Myers Squibb Foundation; Conquer Cancer Foundation Other, Other Relationship.
S. Wang,
D3 Bio Inc. Employment.
Z. Fan,
D3 Bio Inc. Employment.
R. Su,
D3 Bio Inc. Employment.
J. Zhang,
D3 Bio Inc. Employment.
J. Wang,
D3 Bio Inc. Employment.
W. Wang,
D3 Bio Inc. Employment.
C. Chen,
D3 Bio Inc. Employment.
Q. Chen,
D3 Bio Inc. Employment.
H. Wang,
D3 Bio Inc. Employment.
Z. Chen,
D3 Bio Inc. Employment.