Abstract PD1-09: Safety and efficacy results from the phase 1/2 study of U3-1402, a human epidermal growth factor receptor 3 (HER3)-directed antibody drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC)
Authors: Krop Ian , Yonemori Kan , Takahashi Shunji , Inoue Kenichi , Nakayama Takahiro , Iwata Hiroji , Toyama Tatsuya , Yamamoto Yutaka , Takahashi Masato , Osaki Akihiko , Saji Shigehira , Sagara Yasuaki , O’Shaughnessy Joyce , Traina Tiffany , Ohwada Shoichi , Qi Zhenhao , Qiu Yang , Onuma Hiroshi , Sharma Om , Mekan Sabeen , Masuda Norikazu 
Published: February 2021

Abstract
Introduction: U3-1402 is a novel, investigational ADC directed against HER3, which is widely expressed in breast cancer. Safety and preliminary antitumor activity of U3-1402 was previously reported in this ongoing, phase 1/2 clinical trial (NCT02980341/JapicCTI-163401). Here we report updated safety data from the dose escalation/dose finding (DE/DF) and phase 2 dose expansion parts, and we present for the first time efficacy data for patients in the expansion part with HR+/HER2− MBC with high or low levels of HER3 expression. Methods: In DE/DF, U3-1402 was administered intravenously (IV) Q2W or Q3W at doses ranging from 1.6 to 8.0 mg/kg. Patients had HER3-expressing advanced/unresectable disease refractory/intolerant to standard treatment or for which no standard treatment was available. In the expansion part, U3-1402 was administered IV Q3W to patients with HER3-high (4.8 or 6.4 mg/kg) or HER3-low (6.4 mg/kg) HR+/HER2− MBC or with HER3-high triple-negative breast cancer (TNBC; 6.4 mg/kg). Primary objectives included safety and efficacy of U3-1402; secondary objectives included correlative biomarker and pharmacokinetics analyses. Archival or pretreatment tissue obtained in the 6 months prior to U3-1402 treatment was analyzed by IHC for HER3 expression. Results: As of March 2020, all 4 expansion cohorts had completed enrollment. In the DE/DF and expansion parts combined, 172 patients received ≥1 dose of U3-1402 (114 [66%] had HR+/HER2− MBC). Median age was 56 y (range, 30-83 y); 123 (72%) and 49 (28%) patients had an ECOG PS of 0 or 1, respectively. Patients received a median of 6 (range, 1-14) prior systemic therapies. Median treatment duration of U3-1402 was 5 mo (range, 1-30 mo). 101 patients (59%) discontinued because of progressive disease, and 15 (9%) discontinued because of an AE. The most common grade ≥3 treatment-emergent AEs reported were decreased neutrophil count (43 patients [25%]), decreased platelet count (39 patients [23%]), decreased white blood cell count (28 patients [16%]), and anemia (31 patients [18%]). Nine patients (5%) experienced treatment-related interstitial lung disease according to central adjudication, including one grade 5 event. At data cutoff, 85 patients in the HR+/HER2− expansion part were evaluable for efficacy by blinded independent central review. Among 33 patients with HR+/HER2− HER3-high MBC treated with 4.8 mg/kg, 10 (30%) had a response (all partial responses [PRs]), with a clinical benefit rate (CBR; complete response + PR + stable disease for ≥6 mo) of 45% (15/33). Among 31 patients with HER3-high MBC treated with 6.4 mg/kg, 3 (10%) had a response (all PR) with a CBR of 16% (5/31). Among 21 patients with HER3-low MBC treated with 6.4 mg/kg, 6 (29%) had a response (all PRs) with a CBR of 33% (7/21). TNBC data are immature at the time of abstract data cutoff; efficacy by HR status will be provided in the presentation. Membrane HER3 expression levels were dynamic; they varied between archival and pretreatment biopsies and decreased on treatment with U3-1402. Across the doses evaluated, the U3-1402 AUC and Cmax of the total antibody, intact ADC, and released payload were approximately dose proportional, with minimal accumulation after multiple doses; the released payload Cmax was highest in cycle 1 and decreased in later cycles. Conclusions: In this heavily pretreated MBC population, U3-1402 demonstrated clinically meaningful antitumor activity in HR+/HER2− MBC with high or low levels of HER3 expression. The safety profile of U3-1402 was consistent with that previously reported, with 9% of patients discontinuing because of AEs. Clinical data pertaining to patients with TNBC and correlative analyses (including association of HER3 expression with response) will be presented.
Citation Format: Ian Krop, Kan Yonemori, Shunji Takahashi, Kenichi Inoue, Takahiro Nakayama, Hiroji Iwata, Tatsuya Toyama, Yutaka Yamamoto, Masato Takahashi, Akihiko Osaki, Shigehira Saji, Yasuaki Sagara, Joyce O’Shaughnessy, Tiffany Traina, Shoichi Ohwada, Zhenhao Qi, Yang Qiu, Hiroshi Onuma, Om Sharma, Sabeen Mekan, Norikazu Masuda. Safety and efficacy results from the phase 1/2 study of U3-1402, a human epidermal growth factor receptor 3 (HER3)-directed antibody drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-09.