Multicenter phase 3 trial of izalontamab brengitecan for unresectable locally advanced or metastatic triple-negative breast cancer

Izalontamab brengitecan (iza-bren) is a first-in-class bispecific antibody-drug conjugate targeting EGFRxHER3 with a topoisomerase I inhibitor payload. A multicenter phase 3 trial in China evaluated iza-bren versus physician's choice of chemotherapy (TPC; erubilin, capecitabine, gemcitabine, or vinorelbine) in patients with unresectable locally advanced or metastatic triple-negative breast cancer (aTNBC) who had disease progression after one or two lines of systemic therapy for advanced disease. Randomization was stratified by prior lines of therapy (1 versus 2), prior anti-PD-(L)1 (yes versus no), and HER2 IHC (0 versus 1+/2+ ISH-). The dual primary endpoints were PFS by BICR and OS. A total of 412 patients were treated (iza-bren 207, TPC 205). At the planned interim analysis (median follow-up 11.0 months), median BIRC-PFS was 8.5 months with iza-bren versus 3.1 months with TPC (HR 0.29; 95% CI 0.22-0.38) and median OS was 15.9 months versus 12.5 months (0.60; 0.42-0.85). Confirmed objective response rate assessed by BIRC was 51.7% with iza-bren versus 20.5% with TPC (OR 4.28; 95% CI 2.75-6.66). Most common grade ≥ 3 treatment-emergent adverse events (iza-bren versus TPC) were decreased neutrophil count (58.0% versus 46.8%), decreased white blood cell count (56.0% versus 33.2%), decreased platelet count (52.7% versus 2.4%), and anemia (46.9% versus 2.9%); all-grade interstitial lung disease was reported in 3 versus 0 patients; and treatment discontinuation due to TEAEs in 4 versus 1 patients. The authors conclude that at this planned interim analysis both primary endpoints were met. Iza-bren demonstrated significant improvement in both PFS and OS compared with chemotherapy, with a manageable safety profile in heavily pretreated aTNBC patients.