PO.CT01.02 · 临床试验

First in human phase 1 study of D3S-002, a purposely designed ERK1/2 inhibitor, in advanced solid tumors with MAPK pathway mutations

编号 CT060 展板 20 时间 4/20 09:00–12:00 区域 Section 50 主讲 Shaonan Wang, B Eng;MBA;MS;PhD

分会场 First-in-Human Phase I Clinical Trials

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作者与单位

Yi-Long Wu¹, Michael Millward², Yanqiao Zhang³, Matteo S. Carlino⁴, Xian Wang⁵, Amitesh Roy⁶, Jun Zhang⁷, Jun Zhao⁸, Zhen Wang¹, Amy Weise⁹, Debora Doroshow¹⁰, Shaonan Wang¹¹, Zifei Fan¹¹, Rong Su¹¹, Jing Zhang¹¹, Jia Wang¹¹, Wenqian Wang¹¹, Cheng Chen¹¹, Qian Chen¹¹, Hui Wang¹¹, Zhijian Chen¹¹

¹Guangdong Provincial People's Hospital, Guangzhou, China,²Linear Clinical Research Ltd, Nedlands, Australia,³Harbin Medical University Cancer Hospital, Harbin, China,⁴Blacktown and Westmead Hospitals, The University of Sydney and the Melanoma Institute, Sydney, Australia,⁵Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China,⁶Southern Oncology Clinical Research Unit (SOCRU), Bedford Park, Australia,⁷Ruijin Hospital Affiliated to The Shanghai Jiao Tong University, Shanghai, China,⁸Beijing Cancer Hospital, Beijing, China,⁹Henry Ford Health System, Detroit, MI,¹⁰Icahn School of Medicine at Mt.Sinai, New York, NY,¹¹D3 Bio Inc., Shanghai, China

摘要 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.

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