Targeting HER2-Low Breast Cancer: the ARX788 Phase 2 Clinical Trial

Laura Huppert, MD, UCSF, discusses the design and rationale for a single-arm, open-label phase 2 clinical trial (NCT06224673) evaluating the safety and efficacy of ARX788 as a monotherapy for patients with HER2-low breast cancer.

ARX788 is a next-generation, site-specific antibody-drug conjugate (ADC). Its mechanism of action involves a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), conjugated via a specialized non-natural amino acid linker to AS269, a potent tubulin inhibitor payload.

While previous phase 1 studies (ACE-Breast-01 and ACE-Pan Tumor-01) successfully demonstrated efficacy in HER2-positive cases, they also identified associated ocular adverse events. Given the high unmet clinical need for novel treatments in HER2-low populations (defined as HER2 IHC 1+ or 2+ and FISH/ISH negative)—specifically those who have progressed on prior therapies—investigators hypothesize that ARX788 will prove safe and effective for this specific subgroup.

The study targets patients with locally advanced unresectable or metastatic breast cancer who have received at least 1 prior line of chemotherapy or ADC therapy in the metastatic setting. Patients will receive ARX788 intravenously at a dose of 1.5 mg/kg every 2 weeks until disease progression or intolerable toxicity occurs.

Enrollment, set to begin in the third quarter of 2025, aims to recruit 30 to 36 patients divided into 2 specific cohorts based on hormone receptor (HR) status:

• Cohort 1: HR-positive/HER2-low (n = 20–24)
• Cohort 2: HR-negative/HER2-low (n = 10–12)

The primary end point of the study is the objective response rate (ORR). The sample size is statistically powered to estimate ORR with a specific margin of error at a 90% confidence level, anticipating a 25% response rate.

Secondary end points are comprehensive, evaluating both survival metrics and specific safety protocols:

• Duration of Response (DOR), Disease Control Rate (DCR), and Best Overall Response (BOR).
• Progression-Free Survival (PFS) and Overall Survival (OS).
• Safety Efficacy: Specifically, the efficacy of a prophylactic regimen designed to prevent grade 2 or higher ocular toxicity, addressing the adverse effects noted in phase 1.

Exploratory end points will further investigate patient-reported outcomes and blood/tumor-based biomarker analyses to deepen the understanding of ARX788’s impact.