436TiP - DYNASTY-Breast02: A phase III trial of BNT323/DB-1303 vs investigator's choice chemotherapy in HER2-low, hormone receptor positive, metastatic breast cancer

Background

The current standard of care for Growth Factor Receptor 2 (HER2)-low, Hormone Receptor Positive (HR+) Metastatic Breast Cancer is endocrine therapy (ET) with a CDK4/6 inhibitor as first line therapy, but patients typically progress after a median ∼ two years, underlying the need for new treatment options. BNT323/DB-1303 is a third-generation HER2-targeting antibody-drug conjugate (ADC) comprising a humanized anti-HER2 IgG1 monoclonal antibody, conjugated to a DNA topoisomerase I inhibitor via a cathepsin-cleavable maleimide tetrapeptide (GGFG) linker, with a drug-to-antibody ratio of ∼8. Preclinically, BNT323/DB-1303 displays potent antitumor activity in HER2-positive and HER2-low tumor models. The phase 1 NCT05150691 trial showed promising antitumor responses in HER2 low BC patients (unconfirmed overall response rate 38.5%, n=5/13) alongside a favorable toxicity profile across 85 pts with advanced/metastatic solid tumors, with no dose limiting toxicities observed up to 10 mg/kg (ASCO 2023 abstract #3023).

Trial design

Dynasty-Breast02 (NCT06018337) is a phase 3, 1:1 randomized, multi-center, open-label trial comparing BNT323/DB-1303, dosed intravenously Q3W as monotherapy at 8 mg/kg, to physician’s choice of chemotherapy (capecitabine, paclitaxel or nab-paclitaxel). The trial will recruit 532 patients at 230 centers with advanced/metastatic HER2 low, hormone receptor positive advanced or metastatic breast cancer that have progressed after 2 lines of endocrine therapy (ET) or within 6 months of first-line ET+CDK4/6 therapy with ECOG 0-1. Patients are stratified according to prior treatment (CDK4/6; taxane in non-metastatic setting) and HER2 expression status (ICH 1+ or IHC2+/ISH- per central lab assessment). The primary endpoint is PFS per RECIST 1.1, with OS (key secondary endpoint), safety and patient reported outcomes as secondary endpoints. Exploratory endpoints include assessment of pharmacokinetics including free DNA topoisomerase I inhibitor and the immunogenicity of BNT323/DB-1303, and to identify potential markers of response. The primary analysis will occur after approximately 337 events. Enrollment is currently open.

Clinical trial identification

NCT06018337.

Editorial acknowledgement

The authors would like to acknowledge Andrew Finlayson of BioNTech SE for medical writing assistance.

Legal entity responsible for the study

Duality biologics.

Funding

Duality biologics.

Disclosure

J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: Abbvie, Agendia, Amgen, Aptitude Health, AstraZeneca, Eisai, G1 Therapeutics, Lilly, Merck, Novartis, Pfizer, Puma, Roche, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre Pharmaceuticals, Samsung Bioepis, Sanofi, BioNtech, Byondis, Dava Oncology, Fishawack Health, Genzyme, GSK, Genentech, Loxo Oncology, Seagen, Stemline Therapeutics, Taiho Oncology, Veru; Financial Interests, Personal, Other, Advisory Board: BioNTech, Duality. J. Cortés: Financial Interests, Personal, Advisory Board, consulting/advisor: Roche, Astrazeneca, Seattle Genetics, Daiichi Sankyo, Lilly, MERCK SHARP& DOHME, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies, Jazz Pharmaceuticals, Abbvie, Scorpion Therapeutics, Bridgebio, Biocon, Biontech; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Eisai, Pfizer, Lilly, Merck Sharp& Dohme, Daiichi Sankyo, Astrazeneca, Gilead, Steamline Therapeutics; Financial Interests, Personal, Stocks/Shares: MAJ3 Capital; Financial Interests, Personal, Stocks/Shares, (relative): Leuko; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, Astrazeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Queen Mary University of London, Iqvia; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, Astrazeneca, Steamline Therapeutics; Other, travel cost and expenses: Merck Sharp&Dhome. P. Schmid: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Pfizer, Roche, Gilead, Eisai, MSD, Seagen, Lilly; Financial Interests, Institutional, Research Grant: AstraZeneca, Genentech, Roche. S. Kim: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Lilly, DaeHwa Pharma, ISU Abx, Daiich-Sankyo, BeiGene, Samsung Bioepics, OBI pharma; Financial Interests, Personal, Invited Speaker: Legochem Bioscience; Financial Interests, Personal, Ownership Interest: Genopeaks; Financial Interests, Institutional, Research Grant: Novartis, Sanofi-Genzyme, DongKook Pharm Co. M.A. Colleoni: Financial Interests, Institutional, Research Grant: ROCHE; Non-Financial Interests, Leadership Role, CO-Chair Scientific Committee: International Breast Cancer Study Group. M. Wenger: Financial Interests, Personal, Full or part-time Employment: BioNTech; Financial Interests, Personal, Leadership Role: BioNTech; Financial Interests, Personal, Stocks/Shares: BioNTech. J.H. Lee: Financial Interests, Personal, Full or part-time Employment: BioNTech; Financial Interests, Personal, Stocks/Shares: BioNTech. V. Gu: Financial Interests, Personal, Full or part-time Employment: Duality Biologics; Financial Interests, Personal, Stocks/Shares: Duality Biologics. Y. Qiu: Financial Interests, Personal, Full or part-time Employment: Duality biologics; Financial Interests, Personal, Stocks/Shares: Duality biologics; Financial Interests, Personal, Member of Board of Directors: Duality biologics. S. Liu: Financial Interests, Personal, Full or part-time Employment: Duality biologics; Financial Interests, Personal, Stocks/Shares: Duality biologics. H. Fang: Financial Interests, Personal, Full or part-time Employment: Duality biologics; Financial Interests, Personal, Stocks/Shares: Duality biologics. R. Shi: Financial Interests, Personal, Full or part-time Employment: Duality biologics; Financial Interests, Personal, Stocks/Shares: Duality biologics. Z. Zhu: Financial Interests, Personal, Leadership Role: Duality biologics; Financial Interests, Personal, Member of Board of Directors: Duality biologics; Financial Interests, Personal, Stocks or ownership: Duality biologics. E.P. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pfizer, Mersana, Olema Pharmaceuticals, Stemline Therapeutics, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Tubulis, Verascity Science, Theratechnologies; Financial Interests, Institutional, Other, Consulting: Accutar Biotechnology, Entos, Fosun Pharma, Gilead Sciences, Jazz Pharmaceuticals, Jefferies LLC, Medical Pharma Services, Tempus Labs, Zentalis Pharmaceuticals; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Molecular Templates, Dana Farber Cancer Inst, 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, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses Pharma, Incyte, Jacobio, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals, Cascadian Therapeutics, Context Therapeutics, Cullinan, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Relay Therapeutics, Tolmar, Torque Therapeutics; Financial Interests, Institutional, Local PI: Bristol-Myers Squibb, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetic Laboratories, Silverback Therapeutics, Stemline Therapeutics. All other authors have declared no conflicts of interest.