Abstract PD1-03: Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: Updated results of a phase 1/2 trial
Authors: Masuda N , Yonemori K , Takahashi S , Kogawa T , Nakayama T , Iwase H , Takahashi M , Toyama T , Saeki T , Saji S , Inoue K , Onuma H , Tajima N , Shiose Y , Chen S , Guevara F , Yu C , Ueno S , Iwata H 
Published: May 2019

Abstract
Background: Human epidermal growth factor receptor 3 (HER3) is overexpressed in a variety of solid tumors, including breast cancer. However, there are no approved HER3-targeted anti-cancer therapies. U3-1402 is a HER3-targeted antibody drug conjugate with a novel peptide-based cleavable linker attached to a potent topoisomerase I inhibitor payload. It has a high drug-to-antibody ratio (7:1 to 8:1), a novel linker which is stable in plasma and selectively cleaved by lysosomal cathepsins up-regulated in cancer cells, and a payload with a short systemic half-life. The ongoing, phase 1/2 study (NCT02980341) was initiated to evaluate the safety, tolerability, and efficacy of U3-1402 in HER3-overexpressing metastatic breast cancer (MBC). The study has 3 parts: Dose Escalation, Dose Finding, and Dose Expansion. Here we report updated results from Dose Escalation and Dose Finding.
Methods: In Dose Escalation, the dose of U3-1402 was escalated based on dose-limiting toxicity data (between 1.6 and 8.0 mg/kg) and guided by the modified Continuous Reassessment Method. In Dose Finding, patients were treated with 1 of 2 doses (4.8 mg/kg or 6.4 mg/kg) identified during Dose Escalation. In both parts, U3-1402 was administered via IV infusion in 21-day cycles. The primary objectives were to determine the safety and tolerability of U3-1402, the maximum tolerated dose (MTD), and the recommended dose for expansion. Efficacy assessments included investigator-assessed objective response rate (ORR; proportion of complete response [CR] + partial response [PR]) per RECIST v1.1 and disease control rate (DCR; proportion of CR + PR + stable disease). Efficacy-evaluable patients received ≥1 dose of U3-1402 and had pre- and post-treatment tumor assessments. Pharmacokinetics and the anti-drug antibodies were also assessed.
Results: As of 1 June 2018, a total of 42 patients received U3-1402 across Dose Escalation and Dose Finding (34 and 8 patients, respectively). Overall, 12 patients have discontinued treatment (9 due to progressive disease, 1 due to clinical progression, 1 due to Grade 2 pneumonitis, and 1 due to withdrawal of consent). A total of 30 patients remain on treatment (33.3% [14/42] for ≥6 months). The median (range) age was 54.5 (30–81), and majorities of patients had an ECOG performance status of 0 (76.2%; 32/42) and had received ≥5 prior anti-cancer regimens (78.6%; 33/42). Among efficacy-evaluable patients, the ORR was 46.3% (19/41) and the DCR was 90.2% (37/41). Grade ≥3 treatment-related AEs (TEAEs) were reported in 61.9% (26/42) patients. TEAEs (&gt;50% in treated patients) regardless of causality (any grade, Grade ≥3) included nausea (83.3%, 4.8%), thrombocytopenia (71.4%, 33.3%), decreased appetite (64.3%, 7.1%), neutropenia (59.5%, 26.2%), and leukopenia (57.1%, 19.0%). The MTD was not reached; dose limiting toxicities included events of decreased platelet count and increases in AST or ALT.
Conclusions: In a preliminary analysis of this ongoing phase 1/2 clinical trial, U3-1402 demonstrated antitumor activity in a substantial number of heavily pretreated HER3-expressing MBC patients, and U3-1402 treatment was associated with a manageable safety profile.
Citation Format: Masuda N, Yonemori K, Takahashi S, Kogawa T, Nakayama T, Iwase H, Takahashi M, Toyama T, Saeki T, Saji S, Inoue K, Onuma H, Tajima N, Shiose Y, Chen S, Guevara F, Yu C, Ueno S, Iwata H. Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: Updated results of a phase 1/2 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-03.