Abstract OT1-07-06: Phase 1/2 first-in-human study of U3-1402, an anti-human epidermal growth factor receptor 3 (HER3) antibody-drug conjugate, in HER3-expressing advanced/unresectable or metastatic breast cancer, including those with triple negative breast cancer (TNBC) or HER3-low disease
Authors: Krop Ian , Masuda Norikazu , Kogawa Takahiro , Takahashi Shunji , Yonemori Kan , Inoue Kenichi , Nakayama Takahiro , Yamamoto Yutaka , Alvarez Ricardo , Toyama Tatsuya , Osaki Akihiko , Takahashi Masato , O'Shaughnessy Joyce , Sagara Yasuaki , Saji Shigehira , Kaklamani Virginia , Oh Sun Young , Gradishar William , Haley Barbara , Iwasa Tsutomu , Traina Tiffany , Ueno Naoto , Isakoff Steve , Ohwada Shoichi , Tanaka Yoshimi , Mekan Sabeen , Onuma Hiroshi , Sharma Om , Iwata Hiroji 
Published: March 2020

Abstract
Background: The HER3 protein is expressed in multiple solid tumor types, including breast cancer, and high expression of HER3 is associated with poor prognosis. U3-1402 is a novel HER3-targeted antibody-drug conjugate designed with a peptide-based cleavable linker and a topoisomerase I inhibitor payload. U3-1402 has a high drug-to-antibody ratio (~ 8:1), and the stable linker is selectively cleaved by lysosomal enzymes upregulated in tumor cells. In addition, high cell membrane cross-penetration allows for potential payload activity against neighboring tumor cells with antigen heterogeneity. This ongoing phase 1/2, multicenter, open-label, first-in-human study was initiated in Japan and expanded to the United States to evaluate the safety and efficacy of U3-1402 in HER2-negative (including hormone receptor [HR]-positive disease and TNBC), HER3-expressing advanced/unresectable or metastatic breast cancer (NCT02980341/JapicCTI-163401). The study comprises 3 parts: dose escalation, dose finding, and dose expansion. Preliminary results from the phase 1 dose-escalation and dose-finding parts demonstrated the recommended dose for expansion, with antitumor activity of U3-1402 in this heavily pretreated patient population (Masuda, et al. SABCS 2018).
Methods: In the ongoing, phase 2, dose-expansion part of this trial, U3-1402 is administered via intravenous infusion every 3 weeks to patients with HER3-expressing advanced/unresectable or metastatic breast cancer. Approximately 110 patients will be treated in the dose-expansion part within cohorts based on breast cancer molecular subtype and HER3 protein expression: patients with HER3-high, HER2-negative, HR-positive disease will receive 4.8 or 6.4 mg/kg U3-1402; patients with HER3-low, HER2-negative, HR-positive disease will receive 6.4 mg/kg U3-1402; and patients with HER3-high, TNBC will receive 6.4 mg/kg U3-1402. Eligible patients for dose expansion are aged ≥ 18 years in the United States (≥ 20 years in Japan); have documented HER3-positive disease, as measured by immunohistochemistry; must undergo fresh tumor biopsy prior to starting treatment, if a sample has not already been submitted for assessment of HER3 expression. For all cohorts except TNBC, patients must have received ≥ 2 and ≤ 6 prior chemotherapy regimens, including ≥ 2 regimens for advanced/unresectable or metastatic disease. For the TNBC cohort, patients must have progressed after receiving 1 to 2 prior chemotherapy regimens in the advanced setting. Patients with previously treated or asymptomatic untreated brain metastases are eligible. Treatment will continue until progression, unacceptable toxicity, death, withdrawal of consent, or termination of the study. The primary objective of dose expansion is to evaluate the safety and efficacy of U3-1402; the secondary objectives are to evaluate the relationship between the efficacy of U3-1402 and HER3 expression and to assess pharmacokinetics and antidrug antibodies. Efficacy assessments include investigator-assessed objective response rate per RECIST v1.1, response duration, time to response, clinical benefit rate, progression-free survival, overall survival, and percent change in target lesion(s). Patients receiving at least 1 dose of U3-1402 with pretreatment and posttreatment tumor assessments will be evaluated for efficacy.
Citation Format: Ian Krop, Norikazu Masuda, Takahiro Kogawa, Shunji Takahashi, Kan Yonemori, Kenichi Inoue, Takahiro Nakayama, Yutaka Yamamoto, Ricardo Alvarez, Tatsuya Toyama, Akihiko Osaki, Masato Takahashi, Joyce O'Shaughnessy, Yasuaki Sagara, Shigehira Saji, Virginia Kaklamani, Sun Young Oh, William Gradishar, Barbara Haley, Tsutomu Iwasa, Tiffany Traina, Naoto Ueno, Steve Isakoff, Shoichi Ohwada, Yoshimi Tanaka, Sabeen Mekan, Hiroshi Onuma, Om Sharma, Hiroji Iwata. Phase 1/2 first-in-human study of U3-1402, an anti-human epidermal growth factor receptor 3 (HER3) antibody-drug conjugate, in HER3-expressing advanced/unresectable or metastatic breast cancer, including those with triple negative breast cancer (TNBC) or HER3-low disease [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-07-06.