D3S-001 in advanced solid tumors with KRASG12C mutations: a phase 1 trial

doi:10.1038/s41591-025-03688-6

. 2025 Aug;31(8):2768-2777.

doi: 10.1038/s41591-025-03688-6. Epub 2025 Apr 29.

D3S-001 in advanced solid tumors with KRAS^G12C mutations: a phase 1 trial

Byoung Chul Cho^#¹, Shun Lu^#², Myung Ah Lee³, Zhengbo Song⁴, John J Park⁵, Sun Min Lim⁶, Ziming Li², Jun Zhao⁷, Gary Richardson⁸, Yanqiao Zhang⁹, Jun Zhang¹⁰, Anwen Liu¹¹, Herbert H Loong^{12

13}, Cheng Chen¹⁴, Jia Wang¹⁴, Yandong Shen¹⁴, Zifei Fan¹⁴, Qian Chen¹⁴, Hui Wang¹⁴, Jing Zhang¹⁴, Zhi Jian Chen^#¹⁴, Melissa L Johnson¹⁵, Tony Mok^{12

13}

Affiliations

¹ Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. CBC1971@yuhs.ac.
² Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
³ Division of Medical Oncology, Cancer Research Institute, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
⁴ Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, China.
⁵ Macquarie Medical School, Macquarie University, Sydney, New South Wales, Australia.
⁶ Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
⁷ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
⁸ Cabrini Hospital-Malvern, Melbourne, Victoria, Australia.
⁹ Cancer Hospital Affiliated to Harbin Medical University, Harbin, China.
¹⁰ Ruijin Hospital Affiliated to The Shanghai Jiao Tong University Medical School, Shanghai, China.
¹¹ 2nd Affiliated Hospital of Nanchang University, Nanchang, China.
¹² The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China.
¹³ Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Hong Kong, China.
¹⁴ D3 Bio Inc., Shanghai, China.
¹⁵ Sarah Cannon Research Institute, Nashville, TN, USA.

^# Contributed equally.

PMID: 40301557
DOI: 10.1038/s41591-025-03688-6

D3S-001 in advanced solid tumors with KRAS^G12C mutations: a phase 1 trial

Byoung Chul Cho et al. Nat Med. 2025 Aug.

. 2025 Aug;31(8):2768-2777.

doi: 10.1038/s41591-025-03688-6. Epub 2025 Apr 29.

Authors

Affiliations

¹ Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. CBC1971@yuhs.ac.
² Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
³ Division of Medical Oncology, Cancer Research Institute, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
⁴ Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, China.
⁵ Macquarie Medical School, Macquarie University, Sydney, New South Wales, Australia.
⁶ Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
⁷ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
⁸ Cabrini Hospital-Malvern, Melbourne, Victoria, Australia.
⁹ Cancer Hospital Affiliated to Harbin Medical University, Harbin, China.
¹⁰ Ruijin Hospital Affiliated to The Shanghai Jiao Tong University Medical School, Shanghai, China.
¹¹ 2nd Affiliated Hospital of Nanchang University, Nanchang, China.
¹² The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China.
¹³ Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Hong Kong, China.
¹⁴ D3 Bio Inc., Shanghai, China.
¹⁵ Sarah Cannon Research Institute, Nashville, TN, USA.

^# Contributed equally.

PMID: 40301557
DOI: 10.1038/s41591-025-03688-6

Abstract

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^G12C 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 .

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Conflict of interest statement

Competing interests: B.C.C. reports research funding from GIInovation, AstraZeneca, Champions Oncology, CJ Bioscience, Cyrus, Janssen, Merck Sharp & Dohme, Dong-A ST, Yuhan, ImmuneOncia, Therapex, JINTSbio and Vertical Bio AG; royalties from Champions Oncology, Crown Bioscience, Imagen and PearlRiver Bio GmbH; consulting fees from BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, CJ, Cyrus Therapeutics, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, Merck Sharp & Dohme, Gilead, Amgen, Daiichi Sankyo, Regeneron, Sanofi, AnHeart Therapeutics, Seagen, Harpoon Therapeutics, GlaxoSmithKline and ArriVent; honoraria as an invited speaker from ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, Merck Sharp & Dohme, the Chinese Thoracic Oncology Society, Pfizer and ZaiLab; participation on scientific advisory boards for KANAPH Therapeutic Inc., Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, J INTS Bio and Therapex Co. Ltd; stock ownership with TheraCanVac Inc., Gencurix Inc., Bridgebio Therapeutics, KANPH Therapeutic Inc., Cyrus Therapeutics, Interpark Bio Convergence Corp. and J INTS Bio; and other financial or nonfinancial interests with Yonsei University Health System (employment), DAAN Biotherapeutics (founder) and J INTS BIO (member of the board of directors). S.L. reports research funding from AstraZeneca, Hutchison, Bristol Myers Squibb, Hengrui Therapeutics, BeiGene, Roche and Hansoh; consulting fees from AstraZeneca, Hutchison, Simcere, ZaiLab and Yuhan Corporation; honoraria from AstraZeneca, Roche, Hansoh and Hengrui Therapeutics; participation on advisory boards for AstraZeneca, Yuhan Corporation, Inventis Bio, Merck Sharp & Dohme, Simcere Zaiming Pharmaceutical, Shanghai Fosun Pharmaceutical and Phase Therapeutics; and a leadership role with Innovent Biologics. Z.L. reports honoraria from AstraZeneca, Roche, Hansoh and Pfizer. G.R. reports research funding from Bristol Myers Squibb, Roche/Genentech, AstraZeneca, Merck, Takeda, BeiGene, Pfizer, CBT Pharmaceuticals, Corvus Pharmaceuticals, Novotech, Shanghai Fosun Pharmaceutical Development, Shanghai Henlius Biotech, Five Prime Therapeutics, Suzhou Alphamab, Boehringer Ingelheim, Adagene Inc., Bio-Thera Solutions, ChemoCentryx, Curon Biopharmaceutical, D3 Bio, Inventis Bio, Senz Oncology, Genfleet Therapeutics, GeneQuantum Healthcare, Keythera Pharmaceuticals, LaNova Australia, Medicenna Therapeutics, Minghui Pharmaceutical, Neoleukin Therapeutics, PharmAbcine Australia, RemeGen, Seagen, Surface Oncology, Eucure Biopharma, Janssen Oncology, ImmuGen, Imugene, Therapim, Zentalis and Agenus. Jun Zhang reports participation on advisory boards for Astellas and Shanghai HengRui. H.H.L. reports research funding from MSD, MundiPharma and Novartis; consulting fees from Boehringer Ingelheim, Celgene, Eli Lilly, Illumina, Novartis, Merck Serono, Takeda and George Clinical; honoraria from AbbVie, Bayer, Eisai, Eli Lilly, Guardant Health and Novartis; and support for meeting attendance and/or travel from Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis and Pfizer. C.C., J.W., Y.S., Z.F., Q.C., H.W., Jing Zhang and Z.J.C. report employment and stock or stock options with D3 Bio. M.L.J. reports funding to the institution from D3 Bio for the current work; grants to the institution from AbbVie, Adaptimmune, Amgen, Arcus Biosciences, Array BioPharma, ArriVent BioPharma, Artios Pharma, AstraZeneca, Bayer, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, City of Hope National Medical Center, Conjupro Biotherapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Immuneering Corporation, Immunitas Therapeutics, Immunocore, Impact Therapeutics, Incyte, Janssen, Kartos Therapeutics, LockBody Therapeutics, Loxo Oncology, Memorial Sloan Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, NextPoint Therapeutics, Novartis, Numab Therapeutics, Nuvalent, OncoC4, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Pharmaceuticals, Shattuck Laboratories, Silicon Therapeutics, Systimmune, Taiho Oncology, Takeda Pharmaceuticals, TCR2 Therapeutics, Tempest Therapeutics, TheRas, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, Vividion, Vyriad and Y-mAbs Therapeutics; consulting fees from AbbVie, Alentis Therapeutics, Amgen, Arcus Biosciences, AstraZeneca, Biohaven Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, D3 Bio Limited, Daiichi Sankyo, Fate Therapeutics, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Gritstone Oncology, Hookipa Biotech, Immunocore, Janssen Pharmaceuticals, Lilly, Merck, Mirati Therapeutics, ModeX Therapeutics, Normunity, Novartis, Novocure, Pfizer, Regneron Pharmaceuticals, Revolution Medicines, Sanofi-Aventis, SeaGen, Synthekine, Takeda Pharmaceuticals and Zai Laboratory. T.M. reports research funding from AstraZeneca, Bristol Myers Squibb, G1 Therapeutics, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda and XCovery; consulting fees from AbbVie, ACEA Pharma, Adagen, Alentis Therapeutics, Alpha Biopharma, Amgen, Amoy Diagnostics Co, AnHeart Therapeutics, AVEO Pharmaceuticals, Bayer Healthcare Pharmaceuticals, BeiGene, BerGenBio ASA, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines Corporation, BridgeBio, Bristol Myers Squibb, Bowtie Life Insurance Company Limited, Bridge Biotherapeutics Inc., Covidien LP, C4 Therapeutics Inc., Cirina, CStone Pharmaceuticals, Curio Science, D3 Bio, Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, Erasca, F. Hoffmann–La Roche/Genentech, Fishawack Facilitate, G1 Therapeutics, geneDecode, Gilead Sciences, GLG’s Healthcare, Gritstone Oncology, Guardant Health, HengRui Therapeutics, HiberCell, HutchMed, Ignyta, Illumina, Imagene AI, Incyte Corporation, Inivata, InxMed, IQVIA, Janssen, Lakeshore Biotech, Lilly, Lunit USA, Loxo Oncology, Lucence Health, Medscape/WebMD, Medtronic, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics, MiRXES, MoreHealth, Novartis, Novocure GmbH, Ningbo NewBay Technology Development, Omega Therapeutics, OrigiMed, OSE Immunotherapeutics, PeerVoice, Phanes Therapeutics, Pfizer, PrIME Oncology, Prenetics Global, Puma Biotechnology, Qiming Development (HK), Regen Medtech Holdings, Regeneron Pharmaceuticals, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Schrödinger, Seagen International GmbH, SFJ Pharmaceutical, Simcere of America, Synergy Research, Summit Therapeutics, Takeda Pharmaceuticals HK, Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, Xencor and Yuhan Corporation; honoraria from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Daz Group, Fishawack Facilitate, InMed Medical Communication, Janssen Pharmaceutica NV, Jiahui Holdings, LiangYiHui Healthcare, Lilly, Lucence Health, MD Health Brazil, Medscape, Merck Pharmaceuticals HK, Merck Sharp & Dohme, MiRXES, Novartis, OrigiMed, P. Permanyer SL, PeerVoice, Physicians’ Education Resource, Pfizer, PrIME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting, Taiho Pharmaceutical, Takeda Oncology, and Touch Independent Medical Education; support for meeting attendance and/or travel from Novartis, Roche, Pfizer, AstraZeneca, Daiichi Sankyo, Boehringer Ingelheim, MiRXES, Bristol Myers Squibb, Merck Sharp & Dohme, AbbVie, ZaiLab and Liangyihui; participation in advisory boards for AbbVie, ACEA Pharma, Amgen, AstraZeneca, Alentis Therapeutics AG, BerGenBio ASA, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim, Bowtie Life Insurance, Bristol Myers Squibb, C4 Therapeutics, Covidien LP, CStone Pharmaceuticals, Curio Science, D3 Bio, Daiichi Sankyo, Eisai, Erasca, Fishawack Facilitate, G1 Therapeutics, Gilead Sciences, Gritstone Oncology, Guardant Health, geneDecode (uncompensated), Hengrui Therapeutics, HutchMed, Ignyta, Incyte Corporation, Imagene AI, Inivata, IQVIA, Janssen, Lakeshore Biotech, Lilly, Loxo Oncology, Lunit, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics, MiRXES Group, Novartis, OrigiMed, Phanes Therapeutics, Pfizer, Prenetics Global, Puma Biotechnology, Roche/Genentech, Regeneron Pharmaceuticals, Sanofi-Aventis R&D, SFJ Pharmaceutical, Simcere of America, Simcere Zaiming, Takeda, Vertex Pharmaceuticals, Virtus Medical Group, Xencor and Yuhan Corporation; leadership role for AstraZeneca, HutchMed, Aurora, Epoch Biosciences and Insighta; stock or stock options with AstraZeneca, Aurora Tele-Oncology, Biolidics, HutchMed, Prenetics Global, D3 Bio, Lunit, Bowtie Life Insurance, Lakeshore Biotech, Loxo Oncology, Virtus Medical Group, Yinson Capital, Phanes Therapeutics, Insighta and Alentis Therapeutics AG. The other authors declare no competing interests.

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[1] Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017). - PubMed - PMC

[2] Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017). - PubMed - PMC

[3] Prior, I. A., Lewis, P. D. & Mattos, C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 72, 2457–2467 (2012). - PubMed - PMC

[4] Prior, I. A., Lewis, P. D. & Mattos, C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 72, 2457–2467 (2012). - PubMed - PMC

[5] Nassar, A. H., Adib, E. & Kwiatkowski, D. J. Distribution of KRAS (G12C) somatic mutations across race, sex, and cancer type. N. Engl. J. Med. 384, 185–187 (2021). - PubMed

[6] Nassar, A. H., Adib, E. & Kwiatkowski, D. J. Distribution of KRAS (G12C) somatic mutations across race, sex, and cancer type. N. Engl. J. Med. 384, 185–187 (2021). - PubMed

[7] Frost, M. G. et al. KRAS G12C mutated advanced non-small cell lung cancer (NSCLC): characteristics, treatment patterns and overall survival from a Danish nationwide observational register study. Lung Cancer 178, 172–182 (2023). - PubMed

[8] Frost, M. G. et al. KRAS G12C mutated advanced non-small cell lung cancer (NSCLC): characteristics, treatment patterns and overall survival from a Danish nationwide observational register study. Lung Cancer 178, 172–182 (2023). - PubMed

[9] Sebastian, M. et al. KRAS G12C-mutated advanced non-small cell lung cancer: a real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315). Lung Cancer 154, 51–61 (2021). - PubMed

[10] Sebastian, M. et al. KRAS G12C-mutated advanced non-small cell lung cancer: a real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315). Lung Cancer 154, 51–61 (2021). - PubMed

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D3S-001 in advanced solid tumors with KRAS^G12C mutations: a phase 1 trial

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D3S-001 in advanced solid tumors with KRAS^G12C mutations: a phase 1 trial

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