Trial Launches to Evaluate Novel ADC in Previously Treated HER2+ Breast Cancer

The phase 2 ACE-Breast03 trial (NCT04829604) has been launched to evaluate the efficacy and safety of ARX788, an investigational antibody-drug conjugate (ADC), in patients with metastatic HER2-positive breast cancer who have progressed on prior HER2-directed therapies, according to a news release from Keck Medicine of the University of Southern California (USC).¹

The global registration study is currently enrolling patients who experienced resistance to or disease progression on regimens containing ado-trastuzumab emtansine (T-DM1; Kadcyla), fam-trastuzumab deruxtecan-nxki (Enhertu), and/or tucatinib (Tukysa).

“At USC Norris [Comprehensive Cancer Center], we treat a large volume of patients with HER2-positive, metastatic breast cancer and we have found that resistance to existing therapies is a major issue,” said global lead principal investigator Janice Lu, MD, PhD, a medical oncologist with Keck Medicine and medical director of the USC Comprehensive Breast Oncology Program, in the news release.¹ “We are excited to lead this effort in assessing a possible alternative solution for breast cancer patients and hope to expand our ability to provide effective personalized care.”

ARX788 is an ADC that combines a HER2-directed monoclonal antibody with Amberstatin269, which can destroy cancer cells and prevent new cell growth.

Prior findings from phase 1 trials demonstrated encouraging antitumor activity with ARX788 in patients with HER2-overexpressing solid tumors.² The overall response rate (ORR) was 74% with 1.5 mg/kg of ARX788 in patients with HER2-positive breast cancer and 67% in patients with HER2-overexpressing solid tumors. Across both populations, the disease control rate (DCR) was 100%.

In the phase 2 trial, patients will receive an intravenous infusion of ARX788 every 4 weeks.³ Two hundred patients are estimated to enroll.

The primary end point of the study is ORR by RECIST v1.1 criteria over 2 years; secondary end points include duration of response, best percent change in the sum of the longest diameters of measurable tumors, best overall response, DCR, progression-free survival, overall survival, number of patients experiencing treatment-emergent adverse effects, maximum serum concentration for ARX788, total antibody, and pAF-AS269, trough concentration for ARX788, total antibody, and pAF-AS269, area under the serum concentration-time curve for ARX788, total antibody, and pAF-AS269, and incidence of anti-drug antibodies following administration of ADX788.

Eligible patients must be 18 years of age or older with a life expectancy of at least 3 months, an ECOG performance status of 1 or lower, and adequate organ function. Patients must have at least 1 measurable lesion per RECIST v1.1 criteria and adequate tumor samples available for HER2 status confirmation. Patients with stable brain metastases are eligible for enrollment.

Patients with a history of interstitial lung disease, pneumonitis, or other clinically significant lung diseases within 12 months of enrollment, ocular events or active ocular infections, or congestive heart failure, unstable angina pectoris, unstable atrial fibrillation, or cardiac arrhythmia within 12 months of enrollment are not eligible for the study.

Currently, patients are being recruited from over 20 sites in the United States and Australia. An additional 150 sites are planned to open worldwide, including Europe and Asia.¹

Additionally, the trial will be presented during the 2021 San Antonio Breast Cancer Symposium as an ongoing trial.

“If this drug is effective, it could provide a hopeful alternative to patients with a difficult prognosis and help them maintain a quality of life in ways that chemotherapy cannot,” Lu concluded.

References

1. USC Norris Comprehensive Cancer Center launches global clinical trial testing potential therapy for aggressive type of breast cancer. News release. Keck Medicine of USC. October 11, 2021. Accessed October 14, 2021. https://bit.ly/3lJiAgM
2. Hurvitz SA, Park H, Frentzas S, et al. Safety and unique pharmacokinetic profile of ARX788, a site-specific ADC, in heavily pretreated patients with HER2-overexpresing solid tumors: results from two phase 1 clinical trials. J Clin Oncol. 2021;39(suppl 15):1038. doi:10.1200/JCO.2021.39.15_suppl.1038
3. ARX788 in HER2-positive, metastatic breast cancer subjects (ACE-Breast-03) (ACE-Breast03). ClinicalTrials.gov. Updated October 6, 2021. Accessed October 14, 2021. https://clinicaltrials.gov/ct2/show/NCT04829604