Novel ADC IBI354 Drives Responses in Pretreated HER2+ Advanced Breast Cancer

HER2+ Breast Cancer |
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Treatment with the novel antibody-drug conjugate (ADC) IBI354 was safe and had antitumor activity in patients with pretreated HER2-positive advanced breast cancer, according to updated findings from a phase 1 trial (NCT05636215).

Data presented at the 2025 ASCO Annual Meeting demonstrated that evaluable patients with HER2-positive breast cancer (n = 88) achieved an overall response rate (ORR) of 59.1% (95% CI, 48.1%-69.5%), including a complete response rate of 4.5% and a partial response (PR) rate of 54.5%. The stable disease (SD) and progressive disease (PD) rates were 31.8% and 9.1%, respectively. The disease control rate (DCR) was 90.9% (95% CI, 82.9%-96.0%).

In patients with HER2-positive breast cancer treated with IBI354 at a dose of 9 mg/kg once every 3 weeks (n = 29), the ORR was 72.4% (95% CI, 52.8%-87.3%), comprised exclusively of PRs. The respective SD and PD rates were 17.2% and 10.3%, and the DCR was 89.7% (95% CI, 72.6%-97.8%).

In the trial’s safety population (n = 368), which included patients with breast cancer and other HER2-positive solid tumors, any-grade treatment-emergent adverse effects (TEAEs) occurred in 97.6% of patients, and 39.1% of patients had grade 3 or higher TEAEs. The rates of any-grade and grade 3 or higher treatment-related AEs (TRAEs) were 90.8% and 27.4%, respectively. The respective rates of serious AEs and treatment-related serious AEs were 20.7% and 9.0%.

TEAEs led to treatment interruption, treatment reduction, and treatment discontinuation in 26.9%, 2.7%, and 1.9% of patients, respectively. TEAEs led to death in 1 patient (0.3%), and no patients died due to TRAEs. Treatment-related interstitial lung disease was reported in 1.9% of patients.

“IBI354 continues to demonstrate favorable safety profiles with no new safety signals,” lead study author Charlotte Rose Lemech, BSc, FRACP, MBBS, of Scientia Clinical Research at UNSW Sydney in Australia, and colleagues wrote in a poster presentation of the data. “Encouraging efficacy of IBI354 was observed in HER2-positive breast cancer.”

IBI354 Background and Phase 1 Design

The novel ADC is comprised of trastuzumab (Herceptin) conjugated to a camptothecin derivative. The unique mechanisms of action of IBI354 include selective binding of the antibody to the tumor; NT1 internalization of the agent, lysosomal degradation, and release of the cytotoxic payload NT1; inhibition of the activity of topoisomerase 1 to produce DNA damage and cell apoptosis; and a bystander effect to kill neighboring cancer cells.

In the global, multicenter, phase 1 study, investigators enrolled patients with advanced breast cancer and other solid tumors with HER2 expression or gene alterations who had progressed on or were intolerant to standard therapies. Patients with breast cancer needed to have a HER2 expression of immunohistochemistry (IHC) 2+/in situ hybridization+ or IHC 3+.

Enrolled patients received IBI354 at doses ranging from 0.8 mg/kg to 18 mg/kg given every 2 or 3 weeks.

Safety was the study’s primary end point. Secondary end points included ORR, DCR, duration of response (DOR), progression-free survival (PFS), and overall survival.

In the overall breast cancer population, the median age was 53 years (range, 32-78), and most patients were female (98.9%), Asian (100%), had an ECOG performance status of 1 (75.0%), had stage IV disease (97.7%), had IHC 3+ HER2 expression (80.7%), and had received at least 3 prior lines of therapy (73.9%).

In the overall breast cancer cohort, most patients also had hormone receptor–positive disease (56.8%) and had received prior treatment with taxanes (96.6%) and trastuzumab or a biosimilar (100%). Other prior treatments included pertuzumab (Perjeta; 37.5%), ado-trastuzumab emtansine (Kadcyla; 37.5%), and a HER2 TKI (81.8%).

Additional Data

In patients with HER2-positive breast cancer, DOR data remained immature. The 12-month DOR rate was 61.2% (95% CI, 43.7%-74.8%).

In the 9-mg/kg group, patients with breast cancer achieved a median PFS of 14.1 months (95% CI, 8.3-not calculable). OS data were also immature, with events reported in 3.4% of patients.

Reference

Lemech C, Sun Y, Nagrial A, et al. IBI354 (anti-HER2 antibody-drug conjugate [ADC]) in patients (pts) with HER2-positive breast cancer (BC) and other solid tumors: Updates from a phase 1 study. J Clin Oncol. 2025;43(suppl 16):1029. doi:10.1200/JCO.2025.43.16_suppl.1029