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.

Abstract

LBA1003 Background: Triple-negative breast cancer (TNBC) remains a therapeutic challenge due to its aggressive biology and limited treatment options beyond first-line immunotherapy plus chemotherapy. Patients who progress after taxane-containing regimens face poor outcomes and have a high unmet need. Izalontamab brengitecan (iza-bren) is a first-in-class bispecific antibody–drug conjugate (ADC) targeting EGFRxHER3 with a potent topoisomerase I inhibitor payload. Here we report the results of a pre-planned interim analysis from a phase III study of iza-bren in patients with TNBC. Methods: This randomized, multicenter, open-label, phase III study enrolled patients with unresectable locally advanced or metastatic TNBC who had disease progression after 1–2 prior lines of systemic therapy for advanced disease—including prior taxanes. Patients were randomized 1:1 to receive iza-bren (2.5 mg/kg D1D8 Q3W) or treatment of physician’s choice (TPC) (eribulin, capecitabine, gemcitabine, or vinorelbine). Randomization was stratified by prior lines of therapy (1 vs. 2), prior anti-PD-(L)1 (yes vs. no), and HER2 IHC (0 vs. 1+/2+ ISH-). The dual-primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Results: A total of 418 patients were randomized (iza-bren/TPC: 207/211) and 412 were treated (iza-bren/TPC: 207/205). As of the data cutoff (Jan 13, 2026), median follow-up was 11.0 months. The median PFS by BICR was 8.5 months with iza-bren and 3.1 months with TPC (HR, 0.29 [95% CI, 0.22-0.38]; stratified log-rank P<0.0001). The median OS was 15.9 months with iza-bren and 12.5 months with TPC (HR, 0.60 [95% CI, 0.42-0.85]; stratified log-rank P=0.0019). The confirmed objective response rate (cORR) assessed by BICR was 51.7% with iza-bren and 20.5% with TPC (odds ratio, 4.28 [95% CI, 2.75-6.66]). Most common grade ≥3 TEAEs (iza-bren vs TPC) were neutrophil count decreased (58.0% vs 46.8%), white blood cell count decreased (56.0% vs 33.2%), platelet count decreased (52.7% vs 2.4%), and anemia (46.9% vs 3.9%). All-grade ILD was reported in 3 (1.4%) and 0 patients in the iza-bren and TPC arms, respectively. Treatment discontinuation due to TEAEs occurred in 4 (1.9%) patients in the iza-bren arm and 1 (0.5%) patient in the TPC arm. No new safety signals were observed. Conclusions: This pre-planned interim analysis met both dual-primary endpoints of PFS by BICR and OS. Iza-bren demonstrated a statistically significant and clinically meaningful improvement in both PFS and OS compared with chemotherapy, with a manageable safety profile in heavily pre-treated TNBC patients, supporting iza-bren as a new standard of care in this population. Clinical trial information: NCT06382142 .