608O - Preliminary safety and clinical activity of ASP3082, a first-in-class, KRAS G12D selective protein degrader in adults with advanced pancreatic (PC), colorectal (CRC), and non-small cell lung cancer (NSCLC)

Background

ASP3082 is a novel protein degrader selectively targeting KRAS G12D. Here, we describe the preliminary safety and antitumor activity of ASP3082 monotherapy in patients (pts) with previously treated advanced solid tumors.

Methods

In this phase 1, dose-escalation, first-in-human study, adults with unresectable or metastatic KRAS G12D-positive solid tumors were included. Pts received escalating doses of ASP3082 monotherapy (10–600 mg) intravenously once weekly over a 21-day cycle. Primary endpoints were incidence of dose-limiting toxicities (DLTs) and adverse events (AEs).

Results

Data cutoff was 1 April 2024, with 98 pts enrolled (median age: 64 years; 56% male; median [range] prior lines of systemic therapy: 2 [1–7]) who had PC (n=67), CRC (n=16), NSCLC (n=13), or other cancers (n=2). Treatment-related AEs (TRAEs) occurred in 68/98 (69.4%) pts, including 5 pts with grade (Gr) 3 and 0 pts with Gr 4 or 5 events. TRAEs occurring in ≥5% of pts were fatigue (15.3%), infusion-related reactions (14.3%), pruritus (9.2%), nausea (7.1%), urticaria (7.1%), aspartate aminotransferase (AST) increased (7.1%), alanine aminotransferase (ALT) increased (6.1%), and vomiting (5.1%). DLTs were observed in 2 pts at 450 mg (Gr 3 ALT increased; Gr 3 ALT/AST increased) and 1 pt at 600 mg (Gr 3 ALT increased). The maximum tolerated dose has not been reached. Based on a preclinical modeling simulation, the predicted lowest dose for clinical efficacy was >100 mg. Efficacy evaluation included 65 pts receiving 10–300 mg. A total of 35 pts received ≤90 mg; objective response rate (ORR) was 0% and disease control rate (DCR) was 25.7%. At 140 mg (n=9), ORR was 11.1% (1 partial response [PR]/5 PC) and DCR was 33.3% (2/5 PC, 1/4 CRC). At 200 mg (n=9), ORR was 0% and DCR was 55.6% (3/7 PC, 1/1 NSCLC, 1/1 CRC). At 300 mg (n=12), ORR was 33.3% (3 PR/7 PC, 1 PR/4 NSCLC, 0 PR/1 CRC) and DCR was 75.0% (5/7 PC, 4/4 NSCLC, 0/1 CRC).

Conclusions

The ongoing study suggests that ASP3082, a novel KRAS G12D degrader, has an acceptable safety profile and promising antitumor activity, especially in pts with heavily pretreated PC. Based on these results, further studies are needed.

Clinical trial identification

NCT05382559.

Editorial acknowledgement

Medical writing support was provided by Steven F. Merkel, PhD, of Oxford PharmaGenesis Inc.

Legal entity responsible for the study

Astellas Pharma Inc.

Funding

Astellas Pharma Inc.

Disclosure

W. Park: Financial Interests, Personal, Other, Consultancy: Astellas; Financial Interests, Personal, Advisory Board: EXACT Therapeutics; Financial Interests, Personal, Invited Speaker, Continuing Medical Education: American Physician Institute, Integrity; Financial Interests, Institutional, Research Grant: Merck, Break Through Cancer, Parker Institute for Cancer Immunotherapy, The Society of MSK, National Institute of Health - National Cancer Institute; Financial Interests, Institutional, Local PI: Astellas, Miracogen, Amgen, Revolution Medicines. A. Kasi: Financial Interests, Personal, Advisory Board: Ipsen, Cardinal Health; Financial Interests, Institutional, Research Funding: Tesaro, Astellas Pharma, Rafael Pharmaceuticals, Geistlich Pharma, Cardiff Oncology, FibroGen, Bavarian Nordic, Novocure, Cend Therapeutics, Ability Pharma. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med, Regeneron, Loxo, Alkermes, Medikine, Black Diamond Therapeutics, Nalo Therapeutics, Scorpion Therapeutics, Arrivent Biopharma. J.D. Berlin: Financial Interests, Personal, Advisory Board: Merck KGA, mirati, merus, Bristol Myers, bexion, Ipsen, Merck, Sharp, Dohme, Biosapien, Insmed, Oxford Biotherapeutics; Financial Interests, Institutional, Local PI: Astellas, Atreca, Bayer, BMS, Dragonfly, I-MAB, Transient Therapeutic, Totus, Tyra, Sumitomo Dainippon Pharma Oncology, 23 and Me, Strata, Eli Lilly, Hibercell; Other, DSMB member: AstraZeneca, Novocure, I-SPY. J.S. Wang: Financial Interests, Personal, Advisory Role: Janssen Research & Development; Financial Interests, Personal, Advisory Board: Stemline Therapeutics, Kanaph Therapeutics, Fusion Pharmaceuticals; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Eisai; Financial Interests, Institutional, Research Funding: AstraZeneca, Bicycle Therapeutics, BioNTech, Boehringer Ingelheim, Celgene, Cyteir, Daiichi Sankyo, Genentech/Roche, GSK, H3 Biomedicine, Jacobio, Janssen Research & Development, Klus Pharma, Kymab, Loxo, LSK BioPharma, Macrogenics, Merck, Moderna Therapeutics, Phoenix Pharmaceuticals, Prelude Therapeutics, QiLu Pharmaceutical, Revolution Medicines, Ribon Therapeutics, Syndax, Taiho Pharmaceutical, Tesaro, TopAlliance BioSciences Inc, Xencor, Artios, Erasca, Inc, Immunogen, Cullinan Oncology, Immune-Onc Therapeutics, Bayer Health, Biosplice, Zymeworks, BioTheryX, TeneoBio, Nurix, IgM Biosciences, Forty Seven, Treadwell Therapeutics, MabSpace Biosciences, Novartis, Olema Oncology, Seven and Eight BioPharmaceuticals, ORIC Pharmaceuticals, Relay Therapeutics, Jazz Pharmaceuticals, Adagene, NGM BioPharmaceuticals, Agenus, Metabomed, BeiGene, Astellas Pharma, Blueprint Medicines, Hotspot Therapeutics; Financial Interests, Institutional, Sponsor/Funding: Hutchison MediPharma; Financial Interests, Institutional, Advisory Board: PureTech. B. Herzberg: Financial Interests, Personal, Other, consulting fees/honoraria: Amgen; Financial Interests, Personal, Other, consulting: Eisai, Astellas, Boxer Capital; Financial Interests, Institutional, Research Funding: Amgen, Astellas, Ideaya, Repare Therapeutics, Monte Rosa Therapeutics, Revolution Medicines, Roche/Genentech. Y. Kuboki: Financial Interests, Personal, Advisory Board: Takeda, Amgen, Abbie, Incyte, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Taiho, Lilly; Financial Interests, Institutional, Local PI: Taiho, Astellas, Lilly, Takeda, AstraZeneca, Boehringer Ingelheim, Chugai, Genmab, Incyte, Abbie, Merck, Novartis, Hengrui; Financial Interests, Institutional, Coordinating PI: Amgen; Non-Financial Interests, Member: JSMO, ASCO, JSCO, JCA. S. Kitano: Financial Interests, Personal, Advisory Board, Scientific Advisor: ImmuniT Research, United Immunity, Sumitomo Pharma; Financial Interests, Personal, Advisory Board, Scientific advisor: Rakuten Medical; Financial Interests, Personal, Other, lecture fee: AstraZeneca; Financial Interests, Personal, Other, Lecture fee: Pfizer, Taiho, Novartis, MSD, Eisai, Bristol Myers Squibb, GSK, Chugai, Takeda, Janssen, Merck KGaA; Financial Interests, Personal, Other, Scientific adviser, Lecture fee: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: PMDA(Pharmaceuticals and Medical Devices Agency); Financial Interests, Personal and Institutional, Local PI, Clinical Trial, Resarch Grant: Daiichi Sankyo; Financial Interests, Personal and Institutional, Local PI, Clinical Trial: AstraZeneca, Pfizer, MSD, Eisai, Incyte, Takeda, Eli Lilly Japan K.K., Loxo Oncology, AbbVie; Financial Interests, Personal and Institutional, Local PI, Clinical trial, Research Grant: Nippon Boehringer Ingelheim; Financial Interests, Personal and Institutional, Local PI, Cliincal trial: Astellas; Financial Interests, Personal and Institutional, Coordinating PI, Clinical trial, Research Grant: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal and Institutional, Local PI, Clinical trial: GSK; Financial Interests, Personal and Institutional, Local PI, Clinical Trial, Research Grant: Chugai; Financial Interests, Personal and Institutional, Research Grant, Research Grant: Takara Bio Inc. M. Pelster: Financial Interests, Institutional, Speaker, Consultant, Advisor: AstraZeneca, Pfizer, Seagen, EMD Serono, Daiichi Sankyo, Ipsen, Jazz Pharmaceuticals, Arcus Biosciences; Financial Interests, Institutional, Financially compensated role: Astellas, Codiak Biosciences, BeiGene, CytomX, Eisai, GSK, OncXerna, Takeda. J.W. Goldman: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Genentech, Eli Lilly, Janssen, AbbVie, Gritstone; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Eli Lilly; Financial Interests, Institutional, Local PI: Genentech, Janssen, BMS, AbbVie. D. Morgensztern: Financial Interests, Personal, Speaker, Consultant, Advisor: AbbVie, Lilly, Mirati, Arcus; Financial Interests, Personal, Other, Patents: Genprex; Financial Interests, Personal, Advisory Board: AbbVie. S. Kondo: Financial Interests, Personal, Speaker, Consultant, Advisor: Chugai, Eisai; Financial Interests, Personal, Expert Testimony: Sanofi; Financial Interests, Personal, Other, Support for attending meetings and/or travel: Eisai. P.A. Jänne: Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, Voronoi, Daiichi Sankyo, Novartis, Sanofi, Takeda Oncology, Mirati Therapeutics, Trasncenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie, Duality Biologics, Blueprint Medicines, Dizal Pharma; Financial Interests, Personal, Advisory Board, Consulting fees for advice on diagnostic development: Biocartis; Financial Interests, Personal, Advisory Board, Consulting fee for advice on drug development: Merus, Frontier Medicines; Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: Hongyun Biotechnology; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals, Allorion Therapeutics, Frontier Medicines; Financial Interests, Personal, Royalties, I receive post-marketing royalties from being an inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp; Financial Interests, Institutional, Research Grant, Sponsored research agreement with my institution: AstraZeneca, Daiichi Sankyo, Puma, Eli Lilly, Boehringer Ingelheim, Revolution Medicines, Takeda Oncology. H. Fujii: Financial Interests, Personal, Full or part-time Employment: Astellas; Financial Interests, Personal, Stocks/Shares: Astellas. S. Gill, A. Saci: Financial Interests, Personal, Full or part-time Employment: Astellas. P. Lorusso: Financial Interests, Personal, Advisory Board: Takeda, Pfizer, Kineta, Molecular Templates, I-Mab, Mekanistic, Mersana Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen, Roivant Sciences, NeuroTrials, Actuate Therapeutics, Atreca Development, Amgen CodeBreak 202, Cullinan, DrenBio, Quanta Therapeutics, Schrodinger, Boehrigner Ingelheim. A.W. Tolcher: Financial Interests, Institutional, Advisory Role: AbbVie; Financial Interests, Institutional, Advisory Board: Aclaris Therapeutics, Agenus, Aro Biotherapeutics, Ascentage Pharma, Aximmune, Bayer, BioInvent, BluPrint Oncology, Boehringer Ingelheim, Bright Peak Therapeutics, Daiichi Sankyo, Inc., Deka Biosciences, Eleven Biotherapeutics, Elucida Oncology, EMD Serono, Gilde Healthcare, IMPAC Medical Systems, Janssen, Jazz Pharmaceuticals, Karma Oncology, Kirilys Therapeutics, Lengo Therapeutics, Lilly, Link Immunotherapeutics, Mekanistic Therapeutics, Menarini, Mersana, Mirati Therapeutics, Nanobiotix, NBE Therapeutics, Nerviano Medical Sciences, Novo Nordisk, Nurix, Ocellaris Pharma, Partner Therapeutics, Pelican Therapeutics, Pfizer, Pieris Pharmaceuticals, Pierre Fabre, Pyxis, Qualigen Therapeutics, Roche, Ryvu Therapeutics, Seagen, Senti Biosciences, SK Life Sciences, Sotio, Spirea, Sunshine Guojian, Transcenta, Transgene, Trillium Therapeutics, Verastem, Vincerx Pharma, VRise Therapeutics, Zentalis, ZielBio, Zymeworks; Financial Interests, Institutional, Research Funding: AbbVie, ABL Bio, Adagene, ADC Therapeutics, Agenus, Aminex, Amphivena, Apros Therapeutics, Arcellx, ARMO BioSciences, Arrys Therapeutics, Artios, Asana Biosciences, Ascentage Pharma, Astex Pharmaceuticals, Basilea, Bioinvent, Birdie, BJ Bioscience, Boehringer Ingelheim, Boston Biomedical, CStone Pharmaceuticals, Daiichi Sankyo, Inc., Deciphera, eFfector Therapeutics, EMD Serono, Gilead Sciences, GSK, ImmuneOncia, Inhibrx, Innate Pharma, Janssen Research & Development, K-Group Beta, Kechow Pharma, Kiromic, Merck Sharp & Dohme, Mersana, Mirati Therapeutics, Naturewise, NBE Therapeutics, Sound Biotherapeutics, Samumed, Seagen, Shanghai HaiHe Pharmaceutical, Spring Bank, Sunshine Guojian, Symphogen, Syndax, Synthorx, Takeda, Tizona Therapeutics, Inc., Zymeworks. All other authors have declared no conflicts of interest.