Abstract P1-18-16: A phase 1 study of ARX788, a HER2-targeting antibody-drug conjugate, in patients with metastatic HER2-positive breast cancer
Authors: Hu Xichun , Zhang Jian , Ji Dongmei , Xia Gang , Ji Yanping , Xiong Gaozhun , Liang Xuejun 
Published: March 2020

Abstract
Background: ARX788 is a novel site-specific antibody drug conjugate (ADC) that consists of a human epidermal growth factor receptor 2 (HER2) targeting monoclonal antibody (mAb) linked to the cytotoxic payload AS269, a highly potent tubulin inhibitor. Through a proprietary technology, a non-natural amino acid is precisely incorporated into the pre-determined site on the heavy chain of the mAb, and AS269 is specifically conjugated to the non-natural amino acid. In the first-in-human study in Australia/New Zealand (NCT02512237), delayed drug-induced pneumonitis, which occurred after 4-5 cycles of administration, were observed in participants at dose levels of 1.3 mg/kg Q3W or higher. Here, we present results of a phase I study (CTR20171162) to evaluate safety, pharmacokinetics, and preliminary antitumor effect of ARX788 in Chinese patients with metastatic HER2-positive breast cancer, with special focus on the delayed pneumonitis.
Methods: Patients with metastatic HER2-positive breast cancer received intravenous ARX788 at doses of 0.33, 0.66, 0.88, 1.1, 1.3, 1.5 mg/kg Q3W or 0.88, 1.1, 1.3 mg/kg Q4W. The DLT assessment period was set to be 21 days in 0.33, 0.66 mg/kg Q3W cohorts, and additional 63 days (total 84 days) in other dose cohorts for the pulmonary toxicity. Dose cohorts were expanded at 1.1 and 1.3 mg/kg Q3W. Safety and tolerability were assessed by monitoring adverse events (AEs) and antitumor effects were evaluated according to the RECIST v1.1 criteria. Pulmonary toxicity of special interest was assessed every 2 cycles of therapy by CT imaging. Serum concentrations of ARX788 ADC, total antibody, and metabolite pAF-AS269 were measured and PK parameters were calculated.
Results: As of 3 July 2019, 45 female Chinese participants with age range from 30 to 67 received ARX788, with 31 of whom had been treated for at least 84 days. No dose-limiting toxicities and treatment-related serious adverse events were observed. Serious blood and liver toxicity that are commonly associated with ADCs were rarely observed (only one participant experienced Grade 4 neutrophil count decreased on cycle 18 and none for ≥Grade 3 liver toxicity). Adverse events that required special attentions were ocular and pulmonary toxicity. Ocular events were mostly mild to moderate in severity and were reversible. Three participants experienced Grade 2 drug-related pneumonitis observed on days 130, 172 and 224, all of whom resolved after steroid treatment and re-started ARX788 treatment with dose reduction. ARX788 ADC serum exposure increased with dose increment and the mean terminal phase half-life ranged between 2.3 and 4.9 days. Among 42 evaluated participants, the overall response rate was 31% (13/42) and 42% (5/12) in 1.3 mg/kg Q3W cohort. One participant in 0.88 mg/kg Q3W cohort has undergone the treatment for more than 17 months.
Conclusions: ARX788 was well tolerated in heavily-pretreated patients with HER2-positive metastatic breast cancer without evidence of Grade 3 or greater pneumonitis. Encouraging overall response rate was observed in 1.3 mg/kg Q3W cohort. Considering the predicted benefit/risk profile, 1.3 mg/kg Q3W is the recommended dose for further development of ARX788 in HER2-positive breast cancer.
Citation Format: Xichun Hu, Jian Zhang, Dongmei Ji, Gang Xia, Yanping Ji, Gaozhun Xiong, Xuejun Liang. A phase 1 study of ARX788, a HER2-targeting antibody-drug conjugate, in patients with metastatic HER2-positive breast cancer [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 P1-18-16.