Abstract PS5-03-09: Trial in progress: A phase 2/3 trial of iza-bren (BMS986507/BL-B01D1), an EGFRxHER3 antibody-drug conjugate, vs standard-of-care chemotherapy in patients with previously untreated, locally advanced, recurrent inoperable, or metastatic triple negative breast cancer ineligible for anti-PD-(L)1 treatment (IZABRIGHT-Breast01)

Abstract Background: The epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER) 3 are well-established oncogenic drivers frequently overexpressed in advanced cancers, including triple-negative breast cancer (TNBC) and HER2-negative BC. Their prevalence and critical role in tumor progression make these receptors suitable targets for iza-bren. Iza-bren is a potentially first-in-class antibody-drug conjugate (ADC) composed of an EGFR×HER3 bispecific antibody, conjugated to a novel topoisomerase 1 inhibitor payload (Ed-04) via a cleavable stable linker. Iza-bren has shown promising clinical activity and a manageable safety profile in early-phase clinical trials across various solid tumors, including pre-treated metastatic BC. Methods: IZABRIGHT-Breast01 (NCT06926868) is an open-label, randomized phase 2/3 trial evaluating the efficacy and safety of iza-bren vs chemotherapy of investigator’s choice (paclitaxel, nab-paclitaxel, capecitabine, or carboplatin plus gemcitabine) in patients with previously untreated, locally advanced, recurrent inoperable or metastatic TNBC or estrogen receptor (ER)-low, HER2-negative BC who are ineligible for approved anti-programmed death-1/programmed death ligand 1 (PD-L1)-based treatment combinations or endocrine therapy-based treatments, respectively. Key inclusion criteria include ≥ 18 years of age, ECOG performance status 0-1, measurable disease by RECIST v1.1, and either histologically or cytologically confirmed locally advanced, recurrent inoperable, or metastatic TNBC or ER-low, HER2-negative BC. Additional eligibility criteria include recent tumor biopsy collected (≤ 6 months), brain MRI or CT scan ≤ 28 days pre-randomization, and eligibility for ≥ 1 chemotherapy option. Key exclusion criteria include known germline BRCA 1/2 mutation with PARP inhibitor as best treatment option, untreated symptomatic CNS metastases, known bleeding disorders or conditions affecting bone marrow reserve, history of interstitial lung disease or pneumonitis, and prior therapy with iza-bren or any other ADC targeting EGFR and/or HER3 or containing a topoisomerase 1 inhibitor payload. In phase 2, patients will be randomized 1:1:1 to receive iza-bren at dose 1 (arm A1) or dose 2 (arm A2) on days 1 and 8 of each 3-week cycle, or chemotherapy of investigator’s choice (arm B). After a dose is selected, the study will proceed to phase 3 to confirm efficacy and safety with the selected dose of iza-bren. In phase 3, patients will continue to be randomized 1:1 into arms A and B. Randomization will be stratified by early recurrence (6-12 months after last treatment with curative intent) vs late recurrence ( 12 months) vs de novo disease presentation (no prior early-stage breast cancer), hormone receptor status (ER-low 1%-10% and/or progesterone receptor PgR-low 1%-10% vs negative ER and PgR 1%), and intended chemotherapy (taxanes nab-paclitaxel or paclitaxel vs capecitabine vs carboplatin plus gemcitabine). Treatment will continue until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) per blinded independent central review using RECIST v1.1. The key secondary endpoint is overall survival. Other secondary endpoints include investigator-assessed PFS, objective response, disease control rate, duration of response, time to response, time to subsequent treatment, PFS after next line of treatment, safety, and health-related quality of life. Citation Format: S. Loi, G. Werutsky, Y. Park, S. Loibl, G. Curigliano, D. Eiger, J. Spiridigliozzi, A. K. Dubey, J. Cheng, S. M. Tolaney. Trial in progress: A phase 2/3 trial of iza-bren (BMS986507/BL-B01D1), an EGFRxHER3 antibody-drug conjugate, vs standard-of-care chemotherapy in patients with previously untreated, locally advanced, recurrent inoperable, or metastatic triple negative breast cancer ineligible for anti-PD-(L)1 treatment (IZABRIGHT-Breast01 abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-03-09.