88TiP - A phase Ib study of HMBD-001, a monoclonal antibody targeting HER3, with or without chemotherapy in patients with genetic aberrations in HER3 signaling

Background

Human epidermal growth factor receptor (HER) 3 is a member of the ErbB/HER family of receptor tyrosine kinases. HER3 lacks kinase activity and must be transactivated by dimerization with a kinase-active partner (e.g. HER2 or EGFR) for signal transduction. Rare neuregulin-1 gene (NRG1) fusions and mutations in the extracellular domain (ECD) of HER3 can result in HER3-mediated oncogenesis across solid tumors. HMBD-001 is a humanized IgG1 monoclonal antibody specifically targeting the HER3 dimerization interface, thereby inhibiting both ligand-dependent and -independent HER3 activation. Targeting aberrant HER3 signaling in pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) with HMBD-001 plus chemotherapy is believed to maximize clinical benefit to these patients. Initial data from the first-in-human dose escalation study supports a highly tolerable safety profile, suggesting that HMBD-001 can be combined with other targeted agents and/or standard of care chemotherapy.

Trial design

HMBD-001 is being evaluated in a multicenter, open label, phase Ib trial in patients with genetic aberrations in HER3 signaling, including NRG1 gene fusions and selected HER3 ECD mutations across solid tumors. The study evaluates HMBD-001 in combination with standard of care chemotherapy in two cohorts: NRG1 fusions in PDAC (HMBD-001 + nab-paclitaxel + gemcitabine) and in NSCLC (HMBD-001 + docetaxel) and HMBD-001 monotherapy in two other cohorts: NRG1 fusions in other solid tumors and selected HER3 ECD mutations across solid tumors. A Simon 2-stage minimax design is employed for the three NRG1 fusion cohorts, with an initial safety lead-in using a 3+3 design for the two novel chemotherapy combinations. The primary objectives are to determine the safety and tolerability of all combination regimens and to assess the preliminary anti-tumor activity in terms of objective response rate (ORR) by RECIST v1.1 for all regimens. Secondary endpoints include duration of response (DOR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and pharmacokinetic (PK) and immunogenicity profile analysis.

Clinical trial identification

NCT05919537.

Legal entity responsible for the study

Hummingbird Bioscience Australia Pty Ltd.

Funding

Hummingbird Bioscience Australia Pty Ltd.

Disclosure

M. Millward: Financial Interests, Personal, Advisory Board: BeiGene Australia Pty Ltd, Bristol Myers Squibb Australia Pty Ltd, AstraZeneca Australia Pty Ltd, The Limbic, Eli Lilly Australia Pty Ltd, IQVIA Australia Pty Ltd, Amgen Australia Pty Ltd, Merck Pte Ltd, Pfizer Australia Pty Ltd, Guardant Health, Roche Products Pty Ltd; Financial Interests, Personal, Full or part-time Employment, Employee: University of Western Australia; Financial Interests, Personal, Other, Consultant: Linear Clinical Research; Financial Interests, Institutional, Local PI, Trial payments to Institution: Bristol Myers Squibb, Genentech/Roche, BeiGene, Eli Lilly, Albion Laboratories, Akeso Biopharma, AbbVie, Five Prime Therapeutics, Dizal Pharma, Maxinovel, Amgen, Atridia, INXMED, Alpine Immune Sciences, Turning Point Therapeutics, IMPACT Therapeutics, Kinnate Biopharma, Rely Therapeutics, GenFleet Therapeutics, Vivace Therapeutics, Eucure Biopahrma, InventisBio, Cullinan Oncology, Tyra Biosciences, Axelia Oncology; Non-Financial Interests, Personal, Other, Scientific Advisory Committee member: Thoracic Oncology Group Australasia. 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, Neoleukin Therapeutics, PharmAbcine Australia Pty Ltd, Remegen, Seattle Genetics, Surface Oncology, Eucure Biopharma, Janssen Oncology, Therapim, LaNova Australia Pty Ltd, Medicenna Therapeutics Inc, Minghui Pharmaceutical, ImmunGen Inc, Imugene Ltd, Agenus. A. Mas Fernandez, D. Thakkar, T. Arbabzade, C.H. Goey, Q. Seet, W. Toy, K. Paszkiewicz, P.J. Ingram, J.D. Boyd-Kirkup, K.Y. Kwek: Financial Interests, Personal, Full or part-time Employment: Hummingbird Bioscience. All other authors have declared no conflicts of interest.