Abstract PD8-04: Safety and anti-tumor activity of ARX788 in HER2-positive metastatic breast cancer patients whose disease is resistant/refractory to HER2 targeted agents (trastuzumab, ADCs, TKIs, and bispecific antibodies): ACE-Breast-01 trial results

Abstract Introduction: HER2 is overexpressed on 15-20% of breast cancers and is a clinically important cancer driver. In spite of the HER2 targeted therapy’s success, most patients in the metastatic setting will eventually experience disease progression. ARX788 is an antibody drug conjugate (ADC) that consists of an anti-HER2 mAb and a potent tubulin inhibitor payload AS269, that is site-specifically conjugated to the antibody via a non-natural amino acid incorporated into antibody by using a proprietary EuCODE technology platform. The phase 1 study ACE-Breast-01 (ZMC-ARX788-111 [CTR20171162]) evaluates the safety, pharmacokinetics, and efficacy of ARX788 in patients in China with metastatic HER2-positive breast cancer. Methods: ACE-Breast-01 is an open label, single site, dose escalation study using a 3+3 study design in 69 heavily pretreated patients (median of 6 prior lines of therapy, range: 2-17) with metastatic HER2-positive breast cancer who received intravenous ARX788. While the ARX788 MTD has not been determined, the 1.5 mg/kg of ARX788 dose is reported herein. Eligible patients had histologically documented, incurable, locally advanced or metastatic HER2+ (IHC 3+ and/or FISH positive) breast cancer whose disease had failed prior anti-HER2 treatments in the advanced disease setting; ECOG performance ≤1; adequate organ function; no history of interstitial lung disease or other significant lung disease; no radiotherapy for pulmonary diseases including lung parenchyma; no history of keratitis, corneal disease, or active ocular infection; no unstable brain or spinal cord metastasis; and no history of hypersensitivity to trastuzumab or any component of ARX788. The DLT assessment period was 84 days for pulmonary toxicity and one cycle of duration for all other toxicities. Investigators assessed efficacy using RECIST 1.1 and evaluated safety using NCI-CTCAE V.4.1. Results: Nineteen patients showed clinical response in the 1.5 mg/kg Q3W cohort, with the confirmed objective response rate of 66% (19/29, exact 95% CI, 45.7% to 82.1%), with median duration of response of 14.4 months [95% CI (9.0, NA)]. The disease control rate (CR + PR + SD) among the 29 patients treated was 100%. All patients (29/29, 100%) received prior trastuzumab in addition to other anti-HER2 treatments. Patients were heavily treated with prior HER2-targeted therapies and demonstrated robust ORR ranging from 65-80% (Table 1). ARX788 was generally well tolerated with most adverse events being grade 1 or 2 and were manageable. Low systemic toxicity (low incidence and low grade of neutropenia, thrombocytopenia, anemia, decrease WBC counts, nausea, vomiting, constipation, fatigue, etc.) was observed. No DLT or drug-related deaths occurred, as of data cut-off of 30-Jun-2021. Conclusion: At the 1.5 mg/kg dose level, ARX788 had robust anti-tumor activity in patients whose disease was resistant/refractory to other HER2 targeted therapies and was generally well tolerated with low systemic toxicity. Table 1.Summary of ACE-Breast-01 Confirmed ORR in patients whose disease is resistant or refractory to prior HER2 treatment (trastuzumab, ADCs, TKIs, and bispecific antibodies) at ARX788 1.5 mg/kg Q3WPrior anti-HER2 therapy*Confirmed ORRTrastuzumab containing regimens*19/29 (66%)HER2 ADCs (T-DM1, DX126-262, A166, BAT8001, and HS630) regimens**4/5 (80%)​HER2 TKIs (lapatinib, pyrotinib, neratinib, AST-1306, and Hemay-022) regimens15/23 (65%)​Both HER2 ADC and HER2 TKI regimens3/4 (75%)Bispecific antibodies (KN026 and M802) containing regimens3/4 (75%)*All patients (29/29) received prior trastuzumab-containing regimens.**One patient who received prior pertuzumab also achieved confirmed PR. Citation Format: Jiang Zhang, Dongmei Ji, Weina Shen, Qin Xiao, Yajia Gu, Joyce O’Shaughnessy, Gang Xia, Yanping Ji, Gaozhun Xiong, Matt Li, Dong Xu, Robert Cartmell, Cynthia Song, Jinchun Yan, Xichun Hu. Safety and anti-tumor activity of ARX788 in HER2-positive metastatic breast cancer patients whose disease is resistant/refractory to HER2 targeted agents (trastuzumab, ADCs, TKIs, and bispecific antibodies): ACE-Breast-01 trial results [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-04.