NVL-330, a selective HER2 tyrosine kinase inhibitor, in patients with advanced or metastatic HER2-altered non-small cell lung cancer: The phase 1 HEROEX-1 study

Document Type

Conference Proceeding

Publication Date

5-28-2025

Publication Title

J Clin Oncol

Keywords

antibody drug conjugate, epidermal growth factor receptor, protein tyrosine kinase, protein tyrosine kinase inhibitor, trastuzumab deruxtecan, adult, brain metastasis, conference abstract, controlled study, drug concentration, drug therapy, exon, female, Food and Drug Administration, gene amplification, gene insertion, human, insertion mutation, maximum tolerated dose, metastasis, neoplastic cell transformation, non small cell lung cancer, oral drug administration, pharmacodynamics, pharmacokinetics, phase 1 clinical trial, systemic therapy, therapy

Abstract

Background: Oncogenic mutations and gene amplifications in the HER2 receptor tyrosine kinase are detected in approximately 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 (ADC) trastuzumab deruxtecan (T-DXd) has received FDA accelerated approval for HER2-mutant NSCLC, but no tyrosine kinase inhibitors (TKIs) are currently approved for this indication. NVL-330 is a novel, brain-penetrant, HER2-selective investigational TKI, designed to address the medical need of targeting HER2-mutant tumors, and treating brain metastases, while minimizing treatment related adverse events due to off-target inhibition of wild-type EGFR. Methods: HEROEX-1 (NCT06521554) is a first-inhuman, Phase 1a/1b trial. The Phase 1a dose escalation portion employs a Bayesian optimal interval design with a 3+3 run-in, followed by a Phase 1b dose expansion. The study population includes adult patients with advanced or metastatic NSCLC with a HER2 oncogenic mutation (Phase 1a/1b) or amplification (Phase 1a only) determined by local testing. Eligible patients must have received at least one prior systemic therapy including platinum-based chemotherapy with or without immunotherapy, or are unsuitable candidates for available therapies. Prior HER2-directed antibodies and HER2-directed ADCs are allowed. Prior HER2 TKIs are allowed in Phase 1a only. Patients will receive NVL-330 by oral administration once or twice daily. The primary objectives are to evaluate safety and tolerability, determine the recommended Phase 2 dose, and, if applicable, the maximum tolerated dose of NVL-330. Additional objectives include assessment of preliminary activity and characterization of the pharmacokinetic and pharmacodynamic profiles of NVL-330. Analyses will be performed to evaluate tumor and blood-based biomarkers of response and other relevant biomarkers. The study is open to accrual.

PubMed ID

Not assigned.

Volume

43

Issue

16_suppl

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