Abstract B057: Preclinical intracranial activity of NVL-330, a selective HER2 tyrosine kinase inhibitor

Abstract Background: Oncogenic mutations and gene amplifications in the HER2 receptor tyrosine kinase are detected in 2–4% and 1–5% of non-small cell lung cancers (NSCLC) in the US, respectively. Exon 20 insertion mutations (exon20ins) are the predominant HER2 mutations in NSCLC, and ∼50% of patients with HER2-mutant metastatic NSCLC develop brain metastases. The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has received FDA accelerated approval for HER2-mutant NSCLC, and several tyrosine kinase inhibitors (TKIs) are under investigation for this indication, including zongertinib and sevabertinib. NVL-330 is an investigational TKI designed to address the combined medical needs of targeting HER2-mutant tumors and treating brain metastases, while minimizing treatment related adverse events due to off-target inhibition of wild-type EGFR. Here we characterized the preclinical pharmacological profile of NVL-330, including brain penetrance, in comparison to T-DXd and other HER2 TKIs. Methods: TKIs were profiled in cellular phospho-HER2, phospho-EGFR, and viability assays. Efflux ratio was determined using an MDR1-MDCKI permeability assay. The unbound brain-to-plasma partitioning ratio (Kp,uu) was determined at one hour after oral 10 mg/kg dosing in Wistar Han rats. Intracranial efficacy studies were performed in nude mice, with administration of T-DXd intravenously once every three weeks (Q3W) and TKIs orally twice daily (BID). Results: In this preclinical study, NVL-330 broadly inhibited HER2 oncogenic alterations, with similar potency and selectivity over wild-type EGFR as the HER2-selective TKI zongertinib. By contrast, sevabertinib did not broadly demonstrate selectivity over wild-type EGFR. Low efflux ratio in cell permeability assays and high Kp,uu in rats are generally considered predictors of favorable brain penetrance in humans. NVL-330 demonstrated a lower efflux ratio and a higher Kp,uu, compared with zongertinib and sevabertinib. In the HER2 amp NCI-N87 intracranial xenograft model, treatment with NVL-330 at 30 mg/kg BID induced tumor regression. By contrast, neither treatment with T-DXd at 10 mg/kg Q3W nor zongertinib at 30 mg/kg BID induced tumor regression. Furthermore, when mice with intracranial tumors that progressed on zongertinib were switched to treatment with NVL-330, rapid intracranial tumor regression was observed. Pharmacokinetic analyses in intracranial tumor bearing mice indicated that NVL-330 had significantly higher brain penetrance than T-DXd or zongertinib, consistent with its intracranial antitumor activity. Conclusions: In this preclinical study, NVL-330 was broadly and selectively active against HER2 oncogenic alterations and demonstrated favorable brain penetrance and/or intracranial activity compared to T-DXd, zongertinib, and sevabertinib. This differentiated preclinical profile supports the potential for NVL-330 to address a medical need for patients with HER2-driven cancers, including those with brain metastases. Citation Format: Yuting Sun, Kristin L. Andrews, Anupong Tangpeerachaikul, Michael J. Walsh, Nancy E. Kohl, Joshua C. Horan, Henry E. Pelish. Preclinical intracranial activity of NVL-330, a selective HER2 tyrosine kinase inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B057.