Izalontamab Brengitecan Improves OS/PFS in Advanced/Metastatic TNBC

Findings from the phase 3 PANKU-Breast02 trial (NCT06382142) presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting showed significant improvements in progression-free survival (PFS) and overall survival (OS) with izalontamab brengitecan (iza-bren), an investigational bispecific antibody-drug conjugate (ADC), over chemotherapy among those with previously treated unresected locally advanced or metastatic triple-negative breast cancer (TNBC).

Results from the multicenter study demonstrate 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,” said Jiong Wu, MD, PhD, Fudan University Cancer Institute, 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 randomized 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, which included eribulin, capecitabine, gemcitabine, or vinorelbine.

At a prespecified interim analysis, the study met both of its dual primary end points. Blinded independent central review (BICR) 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 designed to target 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 (DAR) of 8.

This mechanism yielded a confirmed objective response rate (ORR) 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-(L)1 immunotherapy.

Safety: Myelosuppression 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:

• 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 at 4 days, and these hematologic toxicities were successfully managed using standard supportive care.

Dose modifications were common in the investigational arm, with 63.3% of patients requiring dose reductions and 63.3% requiring 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 class-wide 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 restricted to grade 2 severity. No grade 3 or higher ILD events were observed.

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

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

Reference

Wu J 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. 44, 2026 (suppl 17; abstr LBA1003). doi:10.1200/JCO.2026.44.17_suppl.LBA1003