ARX788 Displays Activity in HER2+ Advanced Breast Cancer

Treatment with ARX788 led to a significant progression-free survival (PFS) benefit vs lapatinib (Tykerb) plus capecitabine for the treatment of patients with HER2-positive advanced breast cancer who experienced disease progression after a trastuzumab (Herceptin)-based regimen, according to results from the phase 3 ACE-Breast-02 trial (CTR20201708) published in Signal Transduction and Targeted Therapy.1

At a data cutoff of December 21, 2022, findings from the second interim analysis of ACE-Breast-02 demonstrated that patients who received ARX788 (n = 221) achieved a median PFS of 11.3 months (95% CI, 8.4-13.8) compared with 8.2 months (95% CI, 6.9-8.7) months in the lapatinib/capecitabine group (n = 220; HR, 0.64; 95% CI, 0.49-0.82; log-rank P = .0006). The 1-year PFS rates were 49.3% (95% CI, 41.3%-56.8%) and 30.7% (95% CI, 23.3%-38.3%), respectively.

“ARX788 is 1 of the first site-specific construct-homogeneous antibody-drug conjugates [ADCs] and the first to be assessed in a phase 3 trial,” Xichun Hu, MD, PhD, chief physician and doctoral supervisor, Fudan University, and director, Department of Medical Oncology, Fudan University Shanghai Cancer Center, in China, and his coauthors wrote. “Given its potency and distinct safety profile, ARX788 has the potential to be an alternative second-line treatment option for patients.”

ARX788 is composed of an anti-HER2 monoclonal antibody site-specifically conjugated with AS269 and a monomethyl auristatin F payload. Preclinical data from patient-derived breast xenograft models showed that the agent had more potent anti-tumor activity compared with ado-trastuzumab emtansine (T-DM1; Kadcyla) in HER2-positive and HER2-low tumors, and in a model that was resistant to T-DM1.

Data from a phase 1 study conducted in China demonstrated that efficacy-evaluable patients (n = 29) with HER2-positive metastatic breast cancer treated with the recommended phase 2 dose of ARX788 (1.5 mg/kg every 3 weeks) experienced an objective response rate (ORR) of 65.5% (95% CI, 45.7%-82.1%).2 The disease control rate (DCR) was 100% (95% CI, 81.2-100) and the median PFS was 17.02 months (95% CI, 10.09-not reached). No dose-limiting toxicities or treatment-related deaths were reported.

Baseline Characteristics and Study Design in ACE-Breast-02

ACE-Breast-02 was an open-label trial conducted across 83 centers in China which enrolled patients 18 to 75 years of age with HER2-positive recurrent or metastatic breast cancer or locally advanced breast cancer not amenable to radical local surgery or radiation.1 Eligible patients needed to have experienced disease progression following at least 1 line of a trastuzumab-based regimen for recurrent or metastatic disease or had relapsed or experienced disease progression during or within 12 months after neoadjuvant or adjuvant trastuzumab lasting at least 9 weeks. Prior treatment with a taxane, at least 1 measurable lesion per RECIST 1.1, an ECOG performance status of 0 or 1, and adequate organ function were also required. Patients who received T-DM1 or other HER2-directed ADCs were not eligible for enrollment.

Eligible patients were randomly assigned 1:1 to receive intravenous ARX788 every 3 weeks at a dose of 1.5 mg/kg or 1250 mg of lapatinib once a day plus capecitabine at 1000 mg/m2 twice daily on days 1 through 14 every 3 weeks. Patients were assigned to a given arm using a stratified permuted block method of size 4; the stratification factors were the number of prior chemotherapy lines (0-1 vs > 1) and the presence of visceral metastasis (yes vs no). Treatment in both arms continued until disease progression, intolerable toxicity, or patient withdrawal.

The primary end point was PFS by blinded independent central review. Secondary end points included overall survival (OS), investigator-assessed PFS, ORR, DCR, duration of response (DOR), and safety.

At baseline, the median age in both the investigational and control arms was 52 years. Most patients in both arms had an ECOG performance status of 1 (53.4% vs 55.5%), visceral metastasis (76.0% vs 77.7%), HER2 immunohistochemistry 3+ (61.1% vs 63.6%), and 1 prior line of treatment in the metastatic setting (66.5% vs 66.4%). The median number of prior lines of chemotherapy in both arms was 1 (range, 1-4). Beyond trastuzumab and taxane therapy, patients in both arms received previous pertuzumab (Perjeta; 34.4% vs 28.2%), anthracyclines (64.3% vs 66.8%), capecitabine (10.0% vs 11.4%), anti-HER2 TKIs (3.2% vs 2.7%), other targeted therapy (2.7% vs 2.3%), and hormone therapy (40.3% vs 34.5%).

Additional Safety and Efficacy Data Confirm Benefit With ARX788

The investigator-assessed median PFS was 10.7 months (95% CI, 9.1-13.7) in the investigational arm compared with 7.1 months (95% CI, 6.9-8.6) in the control arm (HR, 0.64; 95% CI, 0.50-0.82; log-rank P = .0004). Moreover, the PFS benefit observed with ARX788 was broadly observed in all key subgroups that were examined.

Patients who received ARX788 also experienced a trend toward an OS benefit compared with those in the control arm (HR, 0.71; 95% CI, 0.46-1.10). The 1-year OS rates were 87.3% (95% CI, 81.8%-91.3%) and 82.4% (95% CI, 75.9%-87.3%), respectively.

The ORR in the ARX788 arm was 63.8% (95% CI, 57.1%-70.1%) compared with 52.7% (95% CI, 45.9%-59.5%) in the control arm. The respective complete response rates were 5.4% and 3.6%. The median DOR was 12.5 months (95% CI, 10.9-15.1) vs 8.3 months (95% CI, 6.9-11.1), respectively (P = .0017).

In terms of safety, 2.7% of patients in the ARX788 experienced grade 5 treatment-related adverse effects (TRAEs), including 3 cases of interstitial lung disease, 2 of respiratory failure, and 1 of pneumonitis; no treatment-related deaths occurred in the control arm. Common any-grade TRAEs in the ARX788 arm included increased aspartate aminotransferase (AST; 70.9%), increased alanine aminotransferase (59.5%), and dry eye (55.0%). In the control arm, common any-grade TRAEs included hand foot syndrome (59.5%), increased blood bilirubin (53.0%), and increased AST (52.6%). Dose reduction (23.6% vs 37.7%) and discontinuation (6.8% vs 1.8%) due to TRAEs was reported in both arms.

“In conclusion, ARX788, a site-specific construct-homogeneous ADC, demonstrated a significant PFS benefit in the second-line treatment of HER2-positive patients [with] advanced breast cancer who had progressed on 1 line of [a] trastuzumab-based regimen and had been pretreated with [a] taxane,” study authors wrote in conclusion. “Trials focusing on HER2-low and brain metastatic patients in China [CTR20222247, NCT05018702], as well as post-trastuzumab deruxtecan [T-DXd; Enhertu] and neoadjuvant use in the I-SPY II platform in the USA [NCT04829604, NCT01042379] are all actively ongoing.”

References

1. Hu X, Zhang Q, Wang L, et al. ACE-Breast-02: a randomized phase III trial of ARX788 versus lapatinib plus capecitabine for HER2-positive advanced breast cancer. Signal Transduct Target Ther. 2025;10(1):56. doi:10.1038/s41392-025-02149-3
2. Zhang J, Ji D, Shen W, et al. Phase I trial of a novel anti-HER2 antibody-drug conjugate, ARX788, for the treatment of HER2-positive metastatic breast cancer. Clin Cancer Res. Published online June 29, 2022. doi:10.1158/1078-0432.CCR-22-0456