615MO - Phase I/II study of D3S-001, a second generation KRAS G12C inhibitor in advanced/metastatic solid tumors with KRAS G12C mutations

Background

D3S-001 is a 2nd generation KRAS G12C inhibitor (G12Ci) with faster target engagement kinetics, depletes cellular active G12C at nanomolar levels, a MoA relevant to stronger anti-tumor activity (Cancer Discov. 2024 in press). Preliminary results of FIH dose escalation cohorts were reported at AACR 2024. Here we report the updated analyses.

Methods

In the ongoing Phase 1/2 study (NCT05410145), pts were administered D3S-001 (50-900 mg po daily) until intolerable toxicity or disease progression. Endpoints included safety and preliminary efficacy by investigators per RECIST v1.1.

Results

As of 07 May 2024, a total of 42 pts (25 NSCLC, 13 CRC and 4 PDAC) were treated. Median follow-up was 6.8 months (m, range 0.2-18.3m) and 21 pts (50.0%) remain on-study treatment. No treatment-related DLTs or deaths during assessment period. TRAE of any grade occurred in 32 pts (76.2%). Of which, 7 (16.7%) were Grade 3 (no ≥ Grade 4) TRAEs. D3S-001 dose was modified in 12 pts (28.6%) due to TRAE, and none had dose discontinuation. In all 42 dosed pts, 38 had post-baseline tumor assessments, of which 34 were naïve to G12Ci and 4 were G12Ci pre-treated. In 34 G12Ci naïve pts (21 NSCLC, 9 CRC and 4 PDAC), PRs were achieved in 26/34 overall population (76.5%, 95% CI 58.8, 89.3%), with a confirmed ORR (cORR) of 70.6% (95% CI: 52.5%, 84.9%) and DCR of 97.1%. The 6m DoR rate was 70.5% (95% CI: 45.9%, 93.0%). The 6m PFS rate was 65.3% (95 CI%: 45.7%, 79.3%). Among 21 NSCLC pts, 15/21 (71.4%, 95% CI: 47.8, 88.7%) achieved PR, with a cORR of 66.7% (95% CI: 43.0%, 85.4%) and DCR of 100%. The 6m DoR rate was 70.0% (95% CI: 32.9%, 89.2%). The 6m PFS rate was 64.1% (95 CI%: 38.7%, 81.2%). Tumor shrinkage was observed in 2/6 NSCLC pts with stable brain metastases. Among 9 CRC pts, 7/9 (77.8%, 95% CI: 40.0%, 97.2%) achieved PR (all confirmed), with DCR of 88.9% and 6m DoR of 100%. Among 4 PDAC pts, 4/4 (100%) achieved PRs (3/4 confirmed). DCR of 100% achieved in 4 G12Ci pre-treated pts (2 NSCLC and 2 CRC). Over 90% plasma ctDNA clearance as early as at C1D8 was detected in 18 of 31 (58.1%) baseline ctDNA G12C positive pts.

Conclusions

D3S-001, a 2G G12Ci, demonstrated favorable tolerability and consistent promising efficacy across KRAS G12C-mutated NSCLC, CRC, and PDAC.

Clinical trial identification

NCT05410145.

Editorial acknowledgement

Legal entity responsible for the study

D3 Bio.

Funding

D3 Bio.

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, GC Cell, Gilead, Ridgeline Discovery GmbH; Financial Interests, Personal, Advisory Board: Kanaph Therapeutic Inc, Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc, J INTS Bio, Therapex Co., Ltd, Gilead, Amgen, AstraZeneca, Regeneron, Seagen, Samsung Bioepis; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., 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: Champions Oncology, Crown Bioscience, Imagen, PearlRiver Bio GmbH, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: CHA Bundang Medical Center, Mogam Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, Gradiant Bioconvergence, Therapex, 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, Daewoong Pharmaceutical Co., Ltd., Vertical Bio AG, Korea Institute of Oriental Medicine, National Research Foundation of Korea, KHIDI; Other, Founder: DAAN Biotherapeutics; 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. S. Lu: Financial Interests, Institutional, Invited Speaker: Hansoh, AstraZeneca, Roche, Hengrui; Financial Interests, Institutional, Advisory Board: AstraZeneca, Pfizer, Boehringer lngelheim, Hutchison MediPharma, ZaiLab, GenomiCare, Yuhan Corporation, Menarini, InventisBio Co.Ltd, Roche, Simcere Zaiming Pharmaceutical Co., Ltd.; Financial Interests, Research Grant: AstraZeneca, Hutchison, BMS, Heng Rui, Roche, Hansoh, BeiGene, Lilly Suzhou Pharmaceutical Co.Ltd; Financial Interests, Coordinating PI: FibroGen. 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: AstraZeneca, 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, J. Wang, J. Chen, A. Wang, J. Zhang, Z.G. Chen: Financial Interests, Institutional, Full or part-time Employment: D3 Bio. 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; 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, Advisory Role: geneDecode; Non-Financial Interests, Other, Invited Speaker: AstraZeneca, Aurora Tele-Oncology, Lunit USA, Inc.; Non-Financial Interests, Leadership Role, Term ended: Chinese Society of Clinical Oncology (CSCO); Non-Financial Interests, Leadership Role, Term ended on 30 June 2022: American Society of Clinical Oncology (ASCO); Non-Financial Interests, 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, Leadership Role, Term ended on 30 April 2019: International Association for the Study of Lung Cancer (IASLC); Non-Financial Interests, Leadership Role, Honorary Secretary, from Dec 2022 - Present: Hong Kong Academy of Sciences. M.L. Johnson: Financial Interests, Institutional, Other, Consulting: AbbVie, Amgen, Arcus Biosciences, Arrivent, AstraZeneca, Daiichi Sankyo, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Immunocore, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Pyramid Biosciences, Alentis Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, D3 Bio Limitied, Fate Therapeutics, Gilead Sciences, Hookipa Biotech, Lilly, Normunity, Novocure, Pfizer, Revolution Medicines, Sanofi-Aventis, SeaGen, Synthekine, Takeda Pharmaceuticals, VBL Therapeutics; Financial Interests, Institutional, Research Grant: AbbVie, Adaptimmune, Amgen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, Ideaya Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Kartos Therapeutics, Loxo Oncology, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, 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 BioPharmaceuticals, Shattuck Labs, Silicon Therapeutics, Syndax Pharmaceuticals, Takeda Pharmaceuticals, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, Tmunity Therapeutics, Turning Point Therapeutics, Vyriad, Y-mAbs Therapeutics, ArriVent BioPharma, Bayer, LockBody Therapeutics, Taiho Oncology, Conjupro, Immuneering Corporation, Impact Therapeutics, NextPoint Therapeutics, OncoC4, Summit Therapeutics, Systimmune, TheRas, Vividion. All other authors have declared no conflicts of interest.