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HER3 activation, through NRG1 ligand-dependent and independent heterodimerization with HER2 or EGFR, can drive tumor growth and survival via potent PI3K pathway signaling. HER3 activation has emerged as an important mechanism for both tumor progression and acquired resistance to standard of care therapies in multiple indications. With an effective biomarker strategy to select for patients with HER3 driven cancer, potent inhibition of HER3-driven heterodimerization has the potential to confer profound clinical impact. HER3 targeting approaches to date have not shown expected clinical efficacy. Suboptimal HER3 inhibition is one possible explanation; to prevent downstream PI3K signalling, it is critical to fully block both ligand-dependent and independent HER3 activation. Further, despite the clinical evaluation of several anti-HER3 antibodies, only limited progress has been made to establish predictive biomarkers of response to HER3 inhibition. The most thoroughly studied biomarkers predicting response have been increased expression and genomic rearrangements of the HER3 ligand, NRG1. For example, oncogenic NRG1-fusions have been identified as tumor drivers in up to 0.2% of all solid cancers. Few biomarkers predicting lack of response have been reported to date. HMBD-001, is an unique anti-HER3 antibody rationally developed to bind the dimerization interface of HER3 in order to block all HER3 heterodimerization. In contrast to other anti-HER3 antibodies that predominantly bind to the NRG1 binding domain, we observed potent and superior in vitro and in vivo tumor growth inhibition for HMBD-001 in multiple cancer models, including NRG1-fusion driven models. We show that HMBD-001 binds to HER3 with high affinity even in the presence of high concentrations of NRG1, in contrast to other antibodies in which NRG1 competes for the HER3 ligand binding site, thereby decreasing affinity and likely potency. Notably, HMBD-001 treatment of an NRG1-fusion ovarian PDX model showed superior tumor growth inhibition compared with anti-HER3 and anti-HER2/HER3 bispecific antibodies targeting the NRG1 binding domain of HER3. To develop a robust biomarker signature for patient selection beyond NRG1-fusions, we interrogated the genomic and transcriptomic data of all preclinical models for which HMBD-001 efficacy data was available, including in vitro and in vivo models representing multiple HER3 associated cancer sub-types. We identified a novel gene signature that was robustly predictive of HMBD-001 response across a wide range of cancers, including loss of function and gain of function mutations in specific downstream mediators of the MAPK and PI3K signaling pathways. In conclusion, the superior potency of HMBD-001 in preclinical models predicts more complete inhibition of HER3 and better responses in HER3 driven cancers that can be identified using a novel gene signature biomarker. Clinical trials of HMBD-001 in HER3 driven cancers, including those with NRG1-fusions, are expected to commence in 2021. Citation Format: Dipti Thakkar, Shalini Paliwal, Shreya Kar, Namita Gandhi, Konrad Paszkiewicz, Piers Ingram, Jerome Boyd-Kirkup. An anti-HER3 antibody, HMBD-001, that uniquely binds to and blocks the HER3 heterodimerization interface, shows superior tumor growth inhibition in biomarker-defined preclinical cancer models including NRG1-fusion driven cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P197.