ARX788 Demonstrates Significant PFS Benefit in HER2-Positive Breast Cancer

ARX788, a next-generation antibody-drug conjugate (ADC), has demonstrated a significant improvement in progression-free survival (PFS) compared to lapatinib plus capecitabine (LC) in patients with HER2-positive advanced breast cancer (ABC) pretreated with trastuzumab and taxane. The phase III trial, conducted in China, showed a median PFS of 11.3 months in the ARX788 group compared to 8.2 months in the LC group (HR 0.64, p = 0.0006). This study marks ARX788 as one of the first site-specific construct-homogeneous ADCs to be assessed in a phase III trial.

The global standard of care for second-line treatment of HER2-positive metastatic breast cancer is trastuzumab deruxtecan (T-DXd). In China, treatment options have included capecitabine plus tyrosine kinase inhibitors (lapatinib or pyrotinib), or trastuzumab emtansine (T-DM1) since 2022 or T-DXd since 2023.

Efficacy Results

The interim analysis, with a data cutoff of December 21, 2022, included 441 patients randomized to either ARX788 or LC. The blinded independent central review (BICR) assessment showed a significantly longer median PFS in the ARX788 group (11.3 months, 95% CI: 8.4-13.8) compared to the LC group (8.2 months, 95% CI: 6.9-8.7) (HR 0.64, 95% CI: 0.49-0.82, p = 0.0006). One-year PFS rates were 49.3% and 30.7% for ARX788 and LC, respectively.

The objective response rate (ORR) was 63.8% in the ARX788 group and 52.7% in the LC group (p = 0.0186). Complete response (CR) was observed in 5.4% and 3.6% of patients in the ARX788 and LC groups, respectively. The median duration of response (DoR) was significantly longer in the ARX788 group at 12.5 months compared to 8.3 months in the LC group (p = 0.0017).

Safety Profile

Treatment-related adverse events (TRAEs) were reported in 98.6% of patients in the ARX788 group and 99.1% in the LC group. Grade ≥3 TRAEs occurred in 41.4% and 40.0% of patients in the ARX788 and LC groups, respectively. Dose reduction due to TRAEs occurred in 23.6% and 37.7% of patients, respectively. Discontinuation due to TRAEs occurred in 6.8% of patients in the ARX788 group, primarily due to interstitial lung disease (ILD, 3.2%) and lung infection (2.7%).

The most frequently reported TRAEs in the ARX788 group included hepatic enzyme increase, dry eye, blurred vision, alopecia, and ILD. Ocular toxicity related to ARX788 occurred in 74.5% of patients, mainly as dry eye (55%), blurred vision (35%), and keratopathy (28.2%). ILD was reported in 32.7% of patients in the ARX788 group and 0.5% in the LC group.

Study Design

The ACE-Breast-02 trial was a multicenter, open-label, randomized, controlled phase III trial conducted in 83 centers in China. Eligible patients were aged 18-75 years with recurrent or metastatic HER2-positive breast cancer who had progressed on at least one line of trastuzumab-based regimen and had been pretreated with taxane. Patients were randomized 1:1 to ARX788 (1.5 mg/kg every three weeks) or lapatinib plus capecitabine. The primary outcome was PFS assessed by BICR, with secondary outcomes including OS, ORR, DoR, and safety.

Implications

ARX788 demonstrated a statistically significant and clinically meaningful improvement in PFS compared to lapatinib plus capecitabine in patients with HER2-positive ABC. The manageable safety profile and promising efficacy results suggest that ARX788 has the potential to be an alternative second-line treatment option for these patients. Ongoing trials are exploring ARX788 in HER2-low and brain metastatic patients, as well as in post-T-DXd settings and neoadjuvant use.