Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: Updated results from a phase I/II trial
Authors: K. Yonemori, N. Masuda, S. Takahashi, T. Kogawa, T. Nakayama, Y. Yamamoto, M. Takahashi, T. Toyama, T. Saeki, H. Iwata
Journal: Annals of Oncology (2019)

Background: Human epidermal growth factor receptor 3 (HER3) is overexpressed in a variety of solid tumors, including breast cancer. U3-1402 is a HER3-targeted antibody drug conjugate with a novel peptide-based cleavable linker and a potent topoisomerase I inhibitor payload. The ongoing, phase 1/2 study (NCT02980341) is evaluating the safety, tolerability, and efficacy of U3-1402 in HER3-overexpressing metastatic breast cancer (MBC). Here, we report updated results from Dose Escalation and Dose Finding. Methods: In Dose Escalation, the U3-1402 dose was escalated between 1.6 and 8.0 mg/kg based on dose-limiting toxicity (DLT) data and guided by the modified Continuous Reassessment Method. In Dose Finding, patients received 1 of 2 doses (4.8 or 6.4 mg/kg). The primary objectives were to determine the safety/tolerability, the maximum tolerated dose (MTD), and the recommended dose for expansion. Efficacy assessments included investigator-assessed objective response rate (ORR) and disease control rate (DCR) per RECIST v1.1. Pharmacokinetics and the anti-drug antibodies were also assessed. Results: As of 6 Nov 2018, 42 patients received U3-1402 across Dose Escalation and Dose Finding (34 and 8, respectively). Overall, 21 patients have discontinued treatment. The median age was 54.5, and the median prior anticancer regimens was 6. ORR was 42.9% (18/42) and the DCR was 90.5% (38/42). With a 7.6-month median exposure, 14 (33.3%) patients had serious treatment-emergent adverse events (TEAEs) regardless of causality; 7 (16.7%) were drug-related. One patient discontinued treatment due to TEAEs; no TEAEs led to death. Grade ≥3 TEAEs (≥15%) regardless of causality included thrombocytopenia (35.7%), neutropenia (28.6%), leukopenia (21.4%) and anemia (16.7%). MTD was not reached; DLTs 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. (Encore from SABCS2018). Editorial acknowledgement: Nicole Seneca, PhD; and Stefan Kolata, PhD, of AlphaBioCom, LLC, King of Prussia, PA, USA. Clinical trial identification: NCT02980341, release date December 2, 2016; Clinicaltrials.jp: JapicCTI-163401, release date October 12, 2016. Legal entity responsible for the study: Daiichi Sankyo Co., Ltd., and Daiichi Sankyo, Inc. Funding: Daiichi Sankyo Co., Ltd. Disclosure: N. Masuda: Personal fees in the form of honoraria, research funding paid to the institution: Chugai, AstraZeneca, Pfizer, Eli Lilly, Eisai, Takeda, Kyowa-Kirin, Novartis, Daiichi Sankyo; Research funding paid to the institution: MSD. S. Takahashi: Personal fees for non-CME services: Eisai, BMS; Research funding: Novartis, AstraZeneca, Daiichi Sankyo, MSD, Taiho, Bayer, Chugai. T. Kogawa: Personal fees for non-CME services: Taiho, AstraZeneca, Daiichi Sankyo Co., Ltd; Research funding: Daiichi Sankyo Co. Y. Yamamoto: Personal fees: Chugai, AstraZeneca, Novartis, Pfizer, Kyowa Hakko-Kirin, Eisai, Daiichi-Sankyo, Lilly, Sysmex, Taiho, Takeda. T. Toyama: Personal fees for non-CME services: Daiichi Sankyo. T. Saeki: Grants, personal fees: Eisai, Daiichi Sankyo, Chugai, Taiho, Ono Pharma. H. Iwata: Research funds (Inst), consulting, personal fee: AstraZeneca, Chugai, Daiichi Sankyo, Pfizer; Research funds (Inst), consulting: Kyowa Hakko Kirin, Lilly Japan; Personal fee: Eisai; Research funds (Inst): Bayer, Eisai, GSK, MSD, Nihonkayaku, Novartis. All other authors have declared no conflicts of interest.