Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in breast cancer patients: Phase 1 dose escalation study.

Abstract

2512 Background: U3-1402 is a human epidermal growth factor receptor 3 (HER3)-targeting antibody-drug conjugate (ADC) of high drug-to-antibody-ratio (DAR: 7 to 8) with a novel linker and topoisomerase I inhibitor payload. HER3 is overexpressed in a variety of cancers, including breast, lung, colorectal, ovarian, prostate and urothelial cancer. This ongoing, Phase 1/2 study (NCT02980341) of U3-1402 in HER3-expressing metastatic breast cancer (MBC) is divided into three parts: dose escalation (Part 1), dose finding (Part 2), and dose expansion (Part 3). Methods: In Part 1 of the ongoing study, the dose of U3-1402 was escalated based on dose-limiting toxicity data, guided by the modified Continuous Reassessment Method (mCRM). U3-1402 was administered via intravenous (IV) infusion in 21-day cycles. The primary objectives are to determine safety and tolerability of U3-1402, the maximum tolerated dose (MTD), and the recommended dose for Phase 2. AEs, PK, ORR per RECIST v1.1, and durability of responses were assessed. Efficacy-evaluable patients (pts) received at least one dose of U3-1402 and had pre- and post-treatment tumor assessments. Results: As of December 28, 2017, 21-evaluable pts (female, median age 59 years, ECOG 0-1, and ≥ 2 previous treatment regimens) have received U3-1402 at dose levels between 1.6 mg/kg to 8.0 mg/kg. Reversible Grade 3/4 thrombocytopenia, and Grade 3/4 liver enzyme increase as dose-limiting toxicities were observed in 4 (19%) and 2 (9.5%) pts respectively. The most common treatment-related adverse events were nausea (71.4%), vomiting (47.6%), and decreased appetite (47.6%). ORR was 33% and DCR (CR+PR+SD) was 95%. Three pts (14%) discontinued due to PD and 1 pt discontinued due to Grade 2 pneumonitis. Seventeen pts (80%) remain on treatment, including 6 pts (28%) who have remained on treatment for more than 6 months. HER3 IHC has been evaluated in 294 breast cancer pts, 87 (30%) showed high levels of HER3 expression. Conclusions: In a preliminary analysis of 21 pts, U3-1402 exhibits antitumor activity in previously treated HER3 expressing MBC pts and treatment is associated with a manageable safety profile. Clinical trial information: NCT02980341.