Bispecific ADC Iza-Bren Extends Survival in Advanced TNBC

The investigational bispecific antibody-drug conjugate (ADC) izalontamab brengitecan (iza-bren) significantly improved progression-free survival (PFS) and overall survival (OS) vs physician's choice of chemotherapy in patients with pretreated, unresectable locally advanced or metastatic triple-negative breast cancer (TNBC), according to data from the phase 3 PANKU-Breast02 trial (NCT06382142) presented at the 2026 American Society of Clinical Oncology Annual Meeting.

Results from the multicenter randomized study demonstrated a 71% reduction in the risk of disease progression or death in patients treated with iza-bren.

“The results from this phase 3 study support iza-bren as a new standard of care for patients with pretreated metastatic triple-negative breast cancer,” Jiong Wu, MD, PhD, a distinguished professor at Fudan University Cancer Institute in Shanghai, China, said during the presentation.

Dual Primary End Points Met at Interim Analysis

In the open-label trial conducted across 81 centers in China, 418 patients who progressed after 1 to 2 prior lines of systemic therapy—including taxanes—were randomly assigned 1:1 to receive either iza-bren (2.5 mg/kg on days 1 and 8 every 3 weeks) or physician's choice of standard chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine).

At a prespecified interim analysis, the study met both of its dual primary end points. Blinded independent central review revealed a median PFS of 8.5 months (95% CI, 6.9-9.8) for the iza-bren cohort vs 3.1 months (95% CI, 2.7-4.1) for the chemotherapy cohort. This represented a statistically significant and clinically meaningful efficacy advantage (HR, 0.29; 95% CI, 0.22-0.38; P < .0001). The 6-month PFS probabilities were 62.0% and 17.6% for the bispecific ADC and chemotherapy arms, respectively.

The survival benefit extended to OS, evaluated after 53.2% of the required information fraction was reached. Median OS was 15.9 months (95% CI, 13.3-not reached [NR]) with iza-bren compared with 12.5 months (95% CI, 11.4-NR) with standard chemotherapy. This reflects a 40% reduction in the risk of death (HR, 0.60; 95% CI, 0.42-0.85; P = .0019).

Tumor Response and Subgroup Consistency

Iza-bren is a potentially first-in-class bispecific ADC targeting both EGFR and HER3. It features high affinity for EGFR, low affinity for HER3, and carries a potent topoisomerase I inhibitor payload via a cathepsin B-cleavable linker, maintaining a drug-to-antibody ratio of 8.

This mechanism yielded a confirmed objective response rate of 51.7% in the investigational arm—including a 3.9% complete response rate—compared with 20.5% in the chemotherapy arm (P < .0001). The disease control rate was also higher with the ADC (83.1% vs 59.0%), and the median duration of response was more than doubled at 8.3 months vs 4.0 months.

Prespecified subgroup analyses confirmed that the PFS benefit remained consistent regardless of baseline clinical characteristics. Notably, the therapeutic effect was sustained across varying levels of HER2 expression. In patients classified as HER2 immunohistochemistry (IHC) 0, the median PFS was 8.3 months with the ADC vs 2.6 months with chemotherapy (HR, 0.28). In the HER2-low cohort (IHC 1+ or IHC 2+/in situ hybridization negative), median PFS was 9.7 months vs 4.1 months, respectively (HR, 0.32). Efficacy was also maintained in patients with baseline liver metastases and those who had received prior anti–PD-L1 immunotherapy.

Safety: Myelosuppression Is Frequent but Manageable

Treatment-emergent adverse events (TEAEs) occurred in 100% of patients receiving iza-bren and 98.5% of those receiving chemotherapy. Grade 3 or higher TEAEs were more prevalent in the ADC arm (88.9% vs 62.9%), as were serious adverse events (44.0% vs 19.0%).

The toxicity profile of iza-bren was predominantly hematologic. The most frequent grade 3 or higher toxicities included as follows:

• Decreased neutrophil count (58.0%)
• Decreased white blood cell count (56.0%)
• Decreased platelet count (52.7%)
• Anemia (46.9%)

Febrile neutropenia was reported in 5.3% of patients treated with the ADC compared with 0.5% in the control arm. However, the median time to resolution for grade 3 or 4 neutropenia was brief (4 days), and these hematologic toxicities were successfully managed using standard supportive care.

Dose modifications were common in the investigational arm: 63.3% of patients required dose reductions, and 63.3% required dose interruptions. Despite the high rate of high-grade laboratory abnormalities, toxicities rarely led to treatment failure; the discontinuation rate due to TEAEs was low at 1.9% for iza-bren compared with 0.5% for chemotherapy.

Crucially, given the classwide risks associated with topoisomerase I inhibitor payloads, the incidence of interstitial lung disease (ILD) was low. Independent adjudication confirmed only 1 case (0.5%) of ILD in the iza-bren arm, which was grade 2. No grade 3 or higher ILD events were observed.

These data suggest that although the bispecific ADC requires proactive monitoring for myelosuppression and appropriate dose adjustments, its toxicity profile remains clinically manageable, given its substantial survival benefits.

DISCLOSURES: Wu reported having a consulting or advisory role with Lilly.

REFERENCE

Wu J, Zhang J, Ouyang O, et al. Izalontamab brengitecan (iza-bren) versus physician’s choice of chemotherapy in patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC): a randomized phase III study. J Clin Oncol. 2026;44(suppl 17):LBA1003. doi:10.1200/JCO.2026.44.17_suppl.LBA1003