Abstract 640P
Background
D3S-001 is a 2nd-generation GDP-bound KRAS G12C inhibitor (G12Ci) that overcomes GDP to GTP cycling. Aligning with high covalent efficiency and rapid target engagement (TE), D3S-001 showed promising clinical efficacy and favorable safety profile in a multi-national phase I dose-escalation trial. Herein, we correlated ctDNA dynamics with clinical efficacy.
Methods
As of July 8, 2024, 42 patients (pts) (25 NSCLC, 13 CRC and 4 PDAC) were enrolled by local testing of p.G12C positivity. Dose ranges 50-900mg QD. Mutant allele frequencies (MAF) were analyzed by NGS (Guardant360 or BNR OncoCompass) on liquid biopsy at baseline, C1D8, C4D1 and end-of-treatment (EOT). Prior G12Ci naïve pts (n=36) were analyzed.
Results
34/36 pts received post-dose tumor assessment (evaluable). D3S-001 achieved a confirmed PR (cPR) of 71% (n=34 95%CI 53%, 85%) and a 6-month PFS (6mPFS) rate of 68% (n=36 95%CI 50%, 81%). KRAS G12C mutation was detected in 26/36 pts (72%) at baseline (bG12Cpos). 25/26 bG12Cpos pts were evaluable, and 22 achieved PR (20 confirmed, cPR=80%). 9/10 bG12Cneg pts were evaluable, 4/9 achieved cPR (44%). bG12Cpos pts were more likely to achieve PR than bG12Cneg pts (Odds ratio=9.2 P=0.02). The 6mPFS rate of bG12Cpos pts was similar to that of the bG12Cneg pts (68% vs 68% HR 1.3 P=0.7) despite a higher cPR. All bG12Cpos pts showed decline of G12C MAF as early as C1D8; 20 achieved 100% G12C MAF clearance and 5 pts <100% clearance by C4D1. 20 pts with 100% clearance achieved 90% cPR (18/20) and 6mPFS rate of 79%, while 5 pts with <100% clearance achieved 40% cPR (2/5) and 6mPFS rate of 40%. 100% clearance of G12C was associated with lower risk of progression (HR 0.2 P=0.005). Baseline STK11 co-mutation was detected in 6/25 bG12Cpos pts. All 6 achieved 100% clearance of both G12C and STK11 MAF by C4D1 (cPR 100%). Newly acquired mutations at EOT (8 pts) included KRAS (Q61H, G12D), MAP2K1, CDKN2A, etc., suggesting RAS bypass mechanisms via MAPK/ERK or cell cycle control.
Conclusions
Rapid and sustained molecular response correlated with clinical efficacy and highlighted the importance of TE kinetics of D3S-001. Our data shows that bG12Cpos and 100% G12C clearance were associated with better treatment outcome.
Clinical trial identification
NCT05410145.
Editorial acknowledgement
Legal entity responsible for the study
D3 Bio (Wuxi) Co., Ltd.
Funding
D3 Bio (Wuxi) Co., Ltd.
Disclosure
B.C. Cho: Financial Interests, Personal, Other, Consulting role: Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, Medpacto, Blueprint medicines, RandBio, Hanmi; Financial Interests, Personal, Advisory Board: KANAPH Therapeutic Inc, Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc, J INTS Bio, Therapex Co., Ltd, Gilead, Amgen; Financial Interests, Personal, Member of Board of Directors: J INTS BIO; Financial Interests, Personal, Full or part-time Employment: Yonsei University Health System; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc, Gencurix Inc, Bridgebio therapeutics, KANAPH Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Personal, Royalties, PDX, PDO, PDC Licensing Contract – not patent: Champions Oncology, Crown Bioscience, Imagen, PearlRiver Bio GmbH; Financial Interests, Institutional, Research Grant: CHA Bundang Medical Center, MOGAM Institute, LG Chem, Oscotec, GIInnovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Onoclogy, CJ bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridgebio therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph therapeutics, JINTSbio, Hanmi, Vertical Bio AG, National Research Foundation of Korea, KHIDI, Therapex; Other, Personal, Other, Founder: DAAN Biotherapeutics; Other, Personal, Other, Invited speaker: ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, Pfizer, Liangyihui Network Technology Co., Ltd. Y. Shen: Financial Interests, Institutional, Full or part-time Employment: D3 Bio (Wuxi) Co., Ltd. S.M. Lim: Financial Interests, Institutional, Local PI: AstraZeneca, Boehringer Ingelheim, Roche, GSK, Jiansu Hengrui, Amgen, Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: BridgeBio Therapeutics, Oscotec. G. Richardson: Financial Interests, Institutional, Coordinating PI: Bristol Myers Squibb, Roche, Genentech, Shanghai Fosun Pharmaceutical Development Company; Financial Interests, Institutional, Local PI: AstraZenica, Merck, Takeda, BeiGene, Pfizer, CBT Pharmaceuticals, Corvus Pharmaceuticals, Novotech, Shanghai Henlius Biotech Inc, Five Prime Therapeutics Inc, Suzhou Alphamab Co, Boehringer Ingelheim, Adagene Inc, Bio-Thera Solutions, ChemoCentryx, Curon Biopharmaceutical, D3io Co Ltd, Inventis Bio, Senz Oncology Pty Ltd, Genfleet Therapeutics, GeneQuantum Healthcare Co Ltd, Keythera Pharmaceuticals Pty Ltd, LaNova Australia Pty Ltd, Medicenna Therapeutics Inc, Minghui Pharmaceutical, Neoleukin Therapeutics, PharmAbcine Australia Pty Ltd, Remegen, Seattle Genetics, Surface Oncology, Eucure Biopharma, Janssen Oncology, ImmunGen Inc, Imugene Ltd, Therapim, Agenus. J. Zhang: Financial Interests, Personal, Invited Speaker: Roche, HengRui Pharmacy, MSD; Financial Interests, Personal, Advisory Board: AstraZeneca. C. Chen, Y. Liu, H. Rui, J.Q. Chen, A.H. Wang, J. Zhang: Financial Interests, Institutional, Full or part-time Employment: D3 Bio (Wuxi) Co., Ltd. T.S.K. Mok: Financial Interests, Personal, Invited Speaker: ACEA Pharma, AbbVie, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Daz Group, Eli Lilly, Fishawack Facilitate, InMed Medical Communication, Janssen Pharmaceutical NV, Jiahui Holdings Co., LiangYiHui Healthcare, Lucence Health Inc., Lunit USA, Inc., MD Health, MSD, Medscape/WebMD, Merck Pharmaceuticals HK Ltd, Merck Serono, MiRXES, Novartis, OrigiMed Co. Ltd., PER, PeerVoice, Permanyer SL, Pfizer, Prime Oncology, Research to Practice, Roche, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co., Ltd., Shanghai Promedican Pharmaceuticals Co., Ltd, Taiho Pharmaceutical Co., Ltd, Takeda, Touch Medical Media; Financial Interests, Personal, Advisory Board: ACEA Pharma, AbbVie, Alpha Biopharma, Amgen, Amoy Diagnostics, Bayer Healthcare Pharmaceuticals Ltd., BeiGene, BerGenBio ASA, Berry Oncology, Berry Oncology, Blueprint Medicines, Boehringer Ingelheim, Bowtie Life Insurance Co Ltd, Bristol Myers Squibb, C4 Therapeutics, CStone Pharma, Cirina Ltd., Covidien LP, Curio Science, D3 Bio Ltd., Da Volterrra, Daiichi Sankyo, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd / Genentech, Fishawack Facilitate, G1 Therapeutics, Gilead Sciences, Gritstone Oncology, Guardant Health, Hengrui, IQVIA, Ignyta, Imagene AI Ltd, Incyte Corporation, Inivata, Janssen, Lakeshore Biotech, Loxo Oncology, Lucence Health Inc., Lunit USA, Inc., MSD, Medscape LLC / WebMD, Merck Serono, MiRXES, Mirati Therapeutics, MoreHealth, Novartis, OSE Immunotherapeutics, OrigiMed, Pfizer, Prenetics Global Limited, Puma Tech., Qiming Dev., Regeneron Pharmaceuticals Inc., Roche, SFJ Pharmaceutical Ltd., Sanofi-Aventis, Simcere Zaiming, Inc, Simcere of America Inc, Synergy Research, Takeda, Tigermed, Vertex Pharmaceuticals, Virtus Medical, Yuhan Corporation; Financial Interests, Personal, Other, consultation services: AVEO Pharmaceuticals, Inc, Alentis Therapeutics AG, BerGenBio ASA, Bridge Biotherapeutics Inc, Elevation Oncology, GLG’s Healthcare, Genentech, Illumina, Inc., Novocure GmbH, Phanes Therapeutics, geneDecode Co., Ltd; Financial Interests, Personal, Other, Consultation services: Adagene, XENCOR, Inc; Financial Interests, Personal, Other, Consultation Services: HiberCell, Inc., Seagen International GmbH, AnHeart Therapeutics Inc, Ningbo NewBay Technology Development Co., Ltd., InxMed (Hong Kong) Limited; Financial Interests, Personal, Other, Consultant Services: Schrödinger, Inc; Financial Interests, Personal, Member of Board of Directors: AstraZeneca, Aurora, Insighta; Financial Interests, Personal, Member of Board of Directors, Former known as Hutchison Chi-Med: HutchMed; Financial Interests, Personal, Stocks/Shares, Former known as Hutchison Chi-Med: HutchMed; Financial Interests, Personal, Stocks/Shares: Biolidics Ltd., Aurora Tele-Oncology, AstraZeneca, D3 Bio, Lunit Inc., Precentics, Alentis Therapeutics AG; Financial Interests, Institutional, Funding, For clinical trials performed at CUHK: AstraZeneca, BMS, Merck Serono, MSD, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, XCovery, Takeda, G1 Therapeutics, Clovis Oncology; Non-Financial Interests, Personal, Advisory Role: geneDecode; Non-Financial Interests, Personal, Other, Invited Speaker: AstraZeneca, Aurora Tele-Oncology, Lunit USA, Inc.; Non-Financial Interests, Personal, Leadership Role, Term ended: Chinese Society of Clinical Oncology (CSCO); Non-Financial Interests, Personal, Leadership Role, Term ended on 30 June 2022: American Society of Clinical Oncology (ASCO); Non-Financial Interests, Personal, Leadership Role: Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Society (HKCTS), St. Stephen’s College & Prep. School (Hong Kong); Non-Financial Interests, Personal, Leadership Role, Term ended on 30 April 2019: International Association for the Study of Lung Cancer (IASLC); Non-Financial Interests, Personal, Leadership Role, Honorary Secretary, from Dec 2022 - Present: Hong Kong Academy of Sciences. All other authors have declared no conflicts of interest.