P2.13-43 Phase 1 Study of the Anti-HER3 Antibody Drug Conjugate U3-1402 in Metastatic or Unresectable EGFR-Mutant NSCLC

Abstract

While outcomes for patients with EGFR-mutant NSCLC have significantly improved with the use of EGFR tyrosine kinase inhibitors, there remain limited treatment options for many patients once they develop resistance to these agents. The HER3/ERBB3 oncogene is overexpressed in many cancers, including NSCLC, and higher expression is correlated with poor outcomes. U3-1402 is a novel HER3-targeting antibody-drug conjugate (ADC) comprised of a recombinant fully human anti-HER3 antibody (patritumab) covalently conjugated via a cleavable peptide linker to a derivative of the topoisomerase I inhibitor exatecan. After U3-1402 binds to HER3 on the tumor cell surface, it is internalized and leads to apoptosis via inhibition of topoisomerase I. This ADC achieves a high drug-to-antibody ratio (DAR) of ∼8:1. In vivo xenograft mouse model studies with human tumor cell lines indicate that U3-1402 exhibits HER3 expression-dependent tumor growth inhibition activity. This is a multicenter Phase 1, Dose Escalation and Dose Expansion study of U3-1402 in metastatic or unresectable adenocarcinoma NSCLC subjects harboring EGFR-activating mutation who (a) are T790M mutation-negative after disease progression during treatment with erlotinib, gefitinib, or afatinib or (b) develop disease progression while on osimertinib. Eligible subjects are at least 18 years of age, have ECOG PS 0 or 1, have radiological documentation of disease progression while receiving continuous treatment with an EGFR TKI, have at least one measurable lesion per RECIST v1.1, have adequate bone marrow and organ function, do not have LVEF < 45%, do not have QTc prolongation, and do not have spinal cord compression or clinically active brain metastases. In Dose Escalation, subjects receive U3-1402 via intravenous infusion in 21-day cycles. In Dose Escalation, escalation of U3-1402 dosing is based on dose-limiting toxicity data in subjects, guided by the modified Continuous Reassessment Method (mCRM) using a Bayesian logistic regression model (BLRM) following the escalation with overdose control (EWOC) principle. Additionally, intra-subject dose escalation may be considered in subjects who have completed at least 4 cycles of treatment without ≥ Grade 2 treatment-emergent adverse events. In Dose Expansion, subjects receive U3-1402 at the recommended dose for expansion (RDE) determined in Dose Escalation. Primary objectives are to determine the safety, tolerability, and RDE of U3-1402. Secondary objectives are to assess the pharmacokinetic parameters of U3-1402 and its components, and to assess antitumor activity of U3-1402 (RECIST v1.1). Enrollment to Dose Escalation cohort 1 was completed in April 2018. Clinicaltrials.gov identifier: NCT03260491 Section not applicable - CTIP Section no applicable