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Mini Oral session: Developmental therapeutics

460MO - Preliminary results from a phase I study using the bispecific, human epidermal growth factor 2 (HER2)-targeting antibody-drug conjugate (ADC) zanidatamab zovodotin (ZW49) in solid cancers

Date

12 Sep 2022

Session

Mini Oral session: Developmental therapeutics

Topics

Clinical Research;  Therapy

Tumour Site

Presenters

Komal Jhaveri

Citation

Annals of Oncology (2022) 33 (suppl_7): S197-S224. 10.1016/annonc/annonc1049

Authors

K. Jhaveri1, H. Han2, E. Dotan3, D. Oh4, C. Ferrario5, A.W. Tolcher6, K. Lee7, C. Liao8, Y. Kang9, Y.H. Kim10, E.P. Hamilton11, A. Spira12, N. Patel13, C.S. Karapetis14, S.Y. Rha15, L.A. Boyken16, J. Woolery16, P.L. Bedard17

Author affiliations

  • 1 Medical Oncology, Memorial Sloan Kettering Cancer Center, 10065 - New York, NY/US
  • 2 Breast Oncology, Moffitt Cancer Center, 33612 - Tampa/US
  • 3 Medical Oncology, Fox Chase Cancer Center, 19111-2497 - Philadelphia/US
  • 4 Internal Medicine Dept., Seoul National University Hospital, 110-744 - Seoul/KR
  • 5 Oncology, Jewish General Hospital, H3T 1E2 - Montreal/CA
  • 6 Clinical Research Director, NEXT Oncology, 78229 - San Antonio/US
  • 7 Internal Medicine Dept, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 463-707 - Seongnam/KR
  • 8 Medicine - Hematology/oncology Section, University of Chicago Medicine, 60637-1470 - Chicago/US
  • 9 Oncology Dept, Asan Medical Center, 138-931 - Seoul/KR
  • 10 Medical Oncology, Korea University Anam Hospital, 136-701 - Seoul/KR
  • 11 Drug Development Unit, Sarah Cannon Research Institute, Tennessee Oncology, 37203 - Nashville/US
  • 12 Research Institute, Virginia Cancer Specialists, 22031 - Fairfax/US
  • 13 Medical Oncology, City of Hope, 91010 - Duarte/US
  • 14 Medical Oncology, Flinders Medical Centre and Flinders University, 5042 - Bedford Park/AU
  • 15 Medical Oncology Department, Yonsei Cancer Center, Yonsei University Health System, 03722 - Seoul/KR
  • 16 Clinical Development, Zymeworks Inc., Vancouver/CA
  • 17 Division Of Medical Oncology & Hematology, Princess Margaret Cancer Centre, M5G 2M9 - Toronto/CA
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Resources

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Abstract 460MO

Background

ZW49 is a novel ADC comprised of a HER2-targeting bispecific antibody (directed against 2 non-overlapping HER2 epitopes) attached to a proprietary auristatin toxin with a protease-cleavable linker. The results from this ongoing, first-in-human, dose escalation (DE) and dose expansion (DX) study (NCT03821233) are presented.

Methods

DE: In a 3+3 design, patients (pts) with HER2+ cancers were dosed with ZW49 IV QW (3 weeks on, 1 off; 1-1.75 mg/kg), Q2W (1-2 mg/kg) or Q3W (2-3 mg/kg). DX: Pts with centrally confirmed HER2+ cancers and measurable disease received ZW49 at the recommended dose(s)(RD[s]) determined in DE. Primary endpoints are safety and tolerability assessments; secondary endpoints include response assessments per RECIST v1.1.

Results

As of 10 Mar 2022, 76 pts (DE [51] and DX [25]; female: 58%; median age: 59 years [range, 24-83]) have been treated with ZW49. Overall, the most common histologies were gastric (28%) and breast (22%) cancers; 70% received prior HER2-targeted therapy; median number of prior metastatic therapies was 3 (range: 1-16). A RD of 2.5 mg/kg was identified for the Q3W schedule. One dose-limiting toxicity of Grade [Gr] 2 keratitis > 14 days was observed in 1 pt and resolved to Gr 1 (2.5 mg/kg Q3W DX cohort). 68 (89%) pts had treatment-related adverse events (TRAEs); majority were Gr 1 or 2 in severity. The most common TRAEs (≥ 20% pts) included keratitis (42%), alopecia (25%), and diarrhea (21%). 7 (9%) pts had Gr ≥ 3 TRAEs, including 2 Gr 4 events (infusion-related reaction [1 pt] and decreased neutrophil count [1 pt]). Serious TRAEs were reported in 3 pts, leading to 1 discontinuation (D/C); 2 other pts had D/C due to TRAE. No interstitial lung disease nor TR deaths were reported. Among 29 response-evaluable pts treated with ZW49 at 2.5 mg/kg Q3W, the confirmed objective response rate across multiple cancer types was 28% and disease control rate was 72%.

Conclusions

ZW49 has a manageable safety profile with encouraging single-agent antitumor activity in heavily pretreated pts with HER2+ cancers. Enrollment continues at 1.75 mg/kg QW in DE and 1.5 mg/kg QW in DX.

Clinical trial identification

NCT03821233.

Editorial acknowledgement

Legal entity responsible for the study

Zymeworks Inc.

Funding

Zymeworks Inc.

Disclosure

K. Jhaveri: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, AbbVie, Taiho Oncology, Seattle Genetics, Daiichi Sankyo, Loxo Oncology, Gilead, Blueprint Medicines, Biotheranostics; Financial Interests, Personal, Other, Consultant: Pfizer, Genentech, Sun Pharma Pvt Ltd; Financial Interests, Institutional, Invited Speaker: Novartis, Pfizer, AstraZeneca, Lilly Pharmaceuticals, Genentech, Zymeworks, Gilead, Puma Biotechnology, Merck Pharmaceuticals; Non-Financial Interests, Leadership Role: Lilly/Loxo Oncology. H. Han: Financial Interests, Personal, Advisory Board: Novartis, Gilead, AstraZeneca; Financial Interests, Personal, Other, Speaker's Bureau: Lilly; Financial Interests, Institutional, Invited Speaker: Zymeworks, arvinas, AbbVie, Daiichi Sankyo, Marker therapeutics, Pfizer, SeaGen, Quantum Leap Healthcare Collaborative. E. Dotan: Financial Interests, Personal, Advisory Board: Incyte, Helsinn, QED, Basilea; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Research Grant, Research Grant: Pfizer; Financial Interests, Institutional, Invited Speaker, Clinical trial: Zymeworks, Incyte, Medimmune, Relay, NGM Biopharmaceuticals, Inc., AstraZeneca; Financial Interests, Institutional, Invited Speaker, Clinical trial chair: Ipsen. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono , Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. C. Ferrario: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bayer, Merck, Knights Therapeutics; Financial Interests, Institutional, Invited Speaker: Astellas, AstraZeneca, Lilly, Merck, Novartis, Roche - Genetech, Sanofi, Seattle Genetics, Sermonix, Zymeworks; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Funding: Bayer; Non-Financial Interests, Advisory Role: AstraZeneca, Knights Therapeutics, Merck. A.W. Tolcher: Financial Interests, Institutional, Advisory Board, Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is the CEO and Founder.: Adagene, Inc., ARO Biotherapeutics, BIOINVENT, Boehringer Ingelheim International GmbH, Deka Biosciences, Eleven Bio, ELUCIDA, EMD Serono/ MERK KGaA, IMMUNOME, NBE Therapeutics, Pelican, Pieris Pharma, Pyxis Oncology, Vincerx, Zymeworks Inc., MIRATI; Financial Interests, Institutional, Other, Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is the CEO and Founder.: Asana BioSciences, LLC., Axlmmune, Bayer, Gilde Healthcare Partners, HBM Partners, Immunomet Therapeutics, Inc., Karma Oncology, Menarini Ricerche, Mersana, NANOBIOTIX, Partner Therapeutics, Pfizer Inc., Pierre Fabre, RYVU Therapeutics, Seattle Genetics, SOTIO Biotechnology Co., Spirea Limited Inc., Transcenta Therapeutics Inc., Trillium Therapeutics Inc., AbbVie, Inc, AGENUS, Inc., Ascentage, Mekanistic Therapeutics; Financial Interests, Institutional, Other, Fees for consulting for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is the President and Founder.: Aclaris Therapeutics; Financial Interests, Institutional, Other, Fees for consulting for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder.: Daiichi Sankyo, Inc.; Financial Interests, Institutional, Other, NOTE: Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder.: Immuneering, Impact Therapeutics US, Inc., Ocellaris Pharma, Inc. & Eli Lilly, SK Life Science, Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd; Financial Interests, Institutional, Advisory Board, NOTE: Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is President and Founder.: ZielBio, Inc., Ikena Oncology, Hiber Cell, Inc.; Financial Interests, Institutional, Invited Speaker, Dr. Tolcher is the Director of Research, CEO and Founder of NEXT Oncology: NEXT Oncology; Financial Interests, Personal, Stocks/Shares: Pyxis Oncology; Financial Interests, Institutional, Invited Speaker, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which Dr. Anthony Tolcher is CEO and Founder: Adagene Inc, Apros Therapeutics, Inc., AbbVie, Inc, Aminex Therapeutics, Inc., Amphivena Therapeutics, Inc., Arcellx, Inc., ARMO Biosciences, Arrys Therapeutics, Inc., Artios Pharma Limited, Asana BioSciences, LLC., Ascentage Pharma Group Inc., Astex Pharmaceuticals, Basilea Pharmaceutica International Ltd, BioInvent International AB, BioNTech RNA Pharmaceuticals GmbH, BioNTech RNA Pharmaceuticals GmbH, Birdie Biopharmaceuticals, HK Ltd., BJ Bioscience Inc., Codiak BioSciences, Inc., Boehringer Ingelheim Pharmaceutical, Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., CStone Pharmaceuticals (Suzhou) Co., Ltd., Cybrexa Therapeutics, Inc., Daiichi Sankyo Inc., Deciphera Pharmaceuticals, LLC, eFFECTOR Therapeutics, Inc, Eli Lilly and Company, EMD Serono, Gilead Sciences, Inc., GlaxoSmithKline Research & Development Limited, IDEAYA Biosciences, Haihe Biopharma Co., Ltd., Heat Biologics, IDEAYA Biosciences, ImmuneOncia Therapeutics, Inc., IMPACT Therapeutics, Inc., Inhibrx, Inc., Innate Pharma SA, Janssen Research & Development, K-Group Beta, Inc., KeChow Pharma, Inc., Kiromic Biopharma, Inc, Mabspace Biosciences (Suzhou) Co., Limited, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Mersana Therapeutics, Inc.; Financial Interests, Institutional, Invited Speaker: ADC Therapeutics SA, Agenus Inc.; Financial Interests, Institutional, : Mirati Therapeutics, Inc. K. Lee: Financial Interests, Personal, Advisory Board: Bayer, Daiichi Sankyo, BMS; Financial Interests, Personal, Other, Consultation: ISU ABXIS; Financial Interests, Institutional, Invited Speaker: Merck Sharp & Dohme, Ono pharmaceutical, AstraZeneca, Merck KGaA, Pfizer, BeiGene, ALX Oncology, Zymeworks, Macrogenics, Five Prime Therapeutics, Oncologie, Pharmacyclics, Green Cross Corp, ABLBIO, Y-BIOLOGICS, Genexine, LSK BioPharma, Daiichi Sankyo, Taiho Pharmaceutical. C. Liao: Financial Interests, Personal, Advisory Board: AstraZeneca, FirstThought LLC, Transthera, BluePrints Medicine, QED, Genentech, Cancer Experts Now, Histosonics, Ipsen, Exelixis; Financial Interests, Personal, Other, Speaker Bureau: Eisai, Incyte; Financial Interests, Personal, Invited Speaker: OncLive; Financial Interests, Institutional, Invited Speaker, Research funding for investigator initiated trial: BMS. Y. Kang: Financial Interests, Personal, Advisory Board: ALX Oncology, Zymeworks, Amgen, Novartis, Macrogenics, Daehwa, Blueprint, Surface Oncology, BMS, Merck, Roche. Y.H. Kim: Financial Interests, Personal, Ownership Interest: OncoMASTER; Financial Interests, Institutional, Invited Speaker: MSD Oncology, Ono Pharmaceutical, Macrogenics, Korea Astellas, Zymeworks. E.P. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, Seagen, Arcus, iTeos, Janssen, Loxo, Relay Therapeutics; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, SeaGen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Orinove, Leap Therapeutics, Zenith Epigenetics, Harpoon, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, ImmunoGen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses, Incyte, Jacobio, Mabspace Biosciences, Myraid Genetic Labs, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Vincerx Pharma. A. 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; 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, Invited Speaker: LAM Therapeutics, Roche, AstraZeneca, Novartis, Boehringer Ingelheim, Astellas Pharma, MedImmune, 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, Mersana, Mirati Therapeutics, Rubius, Synthekine, Blueprint Medicines. N. Patel: Financial Interests, Institutional, Invited Speaker, Updates in Breast Cancer talk annually: OncLive; Financial Interests, Personal, Other, Consultant to trial breast cancer guideline based treatment platform: Node.Health. C.S. Karapetis: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, BMS, Ipsen, Eli Lilly, Eisai, Roche, Takeda, Beigene; Financial Interests, Institutional, Invited Speaker: Takeda, Roche, Mirati, Daiichi Sankyo; Non-Financial Interests, Member: Medical Oncology Group of Australia, American Society of Clinical Oncology. L.A. Boyken: Financial Interests, Institutional, Full or part-time Employment: Zymeworks; Financial Interests, Personal, Stocks/Shares: Zymeworks. J. Woolery: Financial Interests, Personal, Full or part-time Employment, I am a full-time employee: Zymeworks Biopharmaceuticals; Financial Interests, Personal, Stocks/Shares: Zymeworks Biopharmaceuticals, Seagen. P.L. Bedard: Financial Interests, Institutional, Invited Speaker: AstraZeneca, Bicara, BMS, Amgen, Novartis, Genentech/Roche, Sanofi, Merck, Pfizer, Zymeworks, Nektar Therapeutics, Lilly, SeaGen; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Funding: Servier; Non-Financial Interests, Invited Speaker, Executive Board Member: Breast International Group; Non-Financial Interests, Leadership Role, Chair: AACR Project GENIE; Non-Financial Interests, Leadership Role, Past Chair IND Committee Member, Breast Site Steering Committee: Canadian Clinical Trials Group; Non-Financial Interests, Advisory Role: SeaGen, Lilly, Amgen, Merck, BMS, Pfizer, Gilead. S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, MSD, Amgen, LG biochemical, GSK; Financial Interests, Personal, Invited Speaker: Lilly, Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daichii Sankyo; Financial Interests, Institutional, Invited Speaker: Indivumed, zy,meworks, Beigine; Financial Interests, Other, Durg supply for clinical trial: Merck; Financial Interests, Institutional, Invited Speaker, Drug supply for clincal trial: MSD.

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