687P - A CRUK phase I/IIA, first in human dose-escalation and expansion trial of HMBD-001 (an anti-HER3 antibody) in patients with advanced HER3 positive solid tumours

Background

Human epidermal growth factor receptor (HER)3 is a HER family transmembrane protein. Overexpression of HER3 is observed in multiple solid tumour types and are associated with poor clinical outcome. HMBD-001 is an IgG1 humanized monoclonal antibody specifically targeting HER3 with a unique mechanism of action, inhibiting both ligand-dependent and independent activation.

Methods

HMBD-001 is being evaluated in a first in human, multi-centre, open-label, non-randomised phase 1/IIA trial: Part A dose-escalation, with an initial intra-patient dose escalation, followed by inter-patient dose escalation utilising a one-stage Bayesian continuous reassessment design in advanced solid tumours commonly overexpressing HER3; and Part B, a dose-expansion phase in combination in metastatic castration-resistant prostate cancer (mCRPC) (NCT05057013). The primary objectives of Part A are to determine safety and tolerability and the recommended dose and schedule for phase 2 evaluation (RP2D). The pharmacokinetic profile, clinical and pharmacodynamic activity of HMBD-001 as a single agent and potential predictive and pharmacodynamic biomarkers are being evaluated.

Results

As of 11 April 2023, 17 patients with advanced solid tumours have received weekly infusions of HMBD-001 monotherapy across 6 cohorts (150mg-3000mg). In total, 70 HMBD-001 treatment related adverse events (TRAEs) have been reported. 14 (82.4%) patients have had ≥1 TRAE. No grade ≥3 TRAEs nor DLTs have been observed. More TRAEs have been observed at higher doses. Gastrointestinal disorder TRAEs are the most frequently reported (45.7%, 32/70); 13 patients (76.5%) experienced grade ≤ 2 diarrhoea. 4 patients (23.6%) have experienced trial-specific events of special interest; grade ≤2 infusion related reactions. Stable disease has been recorded in 4/12 evaluable heavily pre-treated patients.

Conclusions

Preliminary data supports a highly tolerable safety profile, supporting combination therapy. HMBD-001 will next be evaluated in Part B in biomarker selected mCRPC with Enzalutamide. Trials of HMBD-001 in squamous NSCLC and NRG1 fusions are also planned for Q3/4 2023.

Clinical trial identification

NCT05057013.

Editorial acknowledgement

Legal entity responsible for the study

Cancer Research UK.

Funding

Cancer Research UK.

Disclosure

J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Menarini Silicon Biosystems, ImCheck Therapeutics, Crescendo; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi Sankyo, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics, Menarini Silicon Biosystems; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Crescendo, ImCheck Therapeutics; Non-Financial Interests, Institutional, Product Samples: Daiichi Sankyo, Bayer, Merck Serono, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GSK. S. Lord: Financial Interests, Personal, Advisory Board: Sanofi, Rejuversen; Financial Interests, Personal, Invited Speaker: Sanofi, Prosigna, Eisai, Roche, Pfizer, Novartis; Financial Interests, Personal, Ownership Interest, Co-founder of company: Mitox Therapeutics; Financial Interests, Institutional, Local PI: Boehringer Ingelheim, Piqur Therapeutics, AstraZeneca, Merck KGaA, Carrick Therapeutics, Sanofi, RS Oncology, Synthon; Financial Interests, Institutional, Research Grant: Pathios Therapeutics; Financial Interests, Institutional, Coordinating PI: Roche, BioInvent International; Non-Financial Interests, Advisory Role: Carrick Therapeutics. C. Yap: Financial Interests, Personal, Advisory Board, Statistical Consultant: Faron Pharmaceutical; Financial Interests, Personal, Invited Speaker, Speaker at a Training Workshop: Bayer; Financial Interests, Institutional, Research Grant: AstraZeneca, Celgene, Novartis; Financial Interests, Personal and Institutional, Research Grant: Faron Pharmaceuticals. C. Peron: Financial Interests, Institutional, Full or part-time Employment, Clinical Research Fellow: Churchill Hospital-University of Oxford; Financial Interests, Institutional, Full or part-time Employment, PhD Student in Oncology: University of Oxford-Department of Oncology; Financial Interests, Personal, Ownership Interest, Start-up focused on the etiological diagnosis of infectious diseases: Oxbridge Clinical. P.J. Ingram: Financial Interests, Personal, Member of Board of Directors: Hummingbird Bioscience. K.Y. Kwek: Financial Interests, Advisory Board: Hummingbird Bioscience. J.D. Boyd-Kirkup: Financial Interests, Member of Board of Directors: Hummingbird Bioscience. H.S. Walter: Financial Interests, Personal and Institutional, Advisory Board: BeiGene, Lily, Genmab; Financial Interests, Institutional, Research Grant: Gilead, Pfizer; Financial Interests, Personal and Institutional, Training: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca. All other authors have declared no conflicts of interest.