Abstract Background: TNBC, accounting for 15-25% of breast cancer cases, is an aggressive subtype with poor prognosis, and metastatic TNBC remains challenging to treat with current standard of care (SOC). PD-(L)1 inhibitors combined with chemo have improved outcomes in pts with high PD-L1 expression in the 1L setting, but outcomes remain poor in pts with PD-L1 negative tumors. Novel therapies are needed to provide effective treatment with long-lasting clinical benefits for locally recurrent or metastatic TNBC, particularly for pts ineligible for anti-PD-(L)1 treatment. BNT327 is an investigational bispecific antibody, targeting PD-L1 and VEGF-A. Dual targeting of PD-L1 and VEGF-A combines two complementary modalities, aiming to improve outcomes. PD-L1 is often upregulated in tumor cells and tumor-infiltrating immune cells. By simultaneously binding to PD-L1 and VEGF-A, BNT327 is hypothesized to co-localize immunostimulatory and anti-angiogenic activities to the tumor microenvironment, reversing the negative impact of VEGF signaling on immune cell infiltration and activation, and normalizing tumor vasculature, leading to tumor growth inhibition. A Phase II trial (NCT05918133) of BNT327 plus nab-paclitaxel conducted in China in 1L locally advanced/metastatic (la/m) TNBC showed encouraging efficacy across PD-L1 levels and a manageable safety profile (Wu et al. 2023, Wu et al. 2024). Trial design: ROSETTA Breast-01 is a global, randomized, double-blind Phase III trial evaluating the safety and efficacy of BNT327 plus chemo in pts with PD-L1 negative, previously untreated, locally recurrent inoperable or metastatic TNBC. Pts are stratified by prior treatment with cancer immunotherapy in the neoadjuvant/adjuvant setting, on-trial chemo regimen, and geography, and randomized 1:1 to receive a combination treatment with BNT327 or placebo plus physician´s choice chemo (paclitaxel/nab-paclitaxel, gemcitabine plus carboplatin, or eribulin). Chemo is administered per SOC. Pts will receive treatment until disease progression, intolerable toxicity, death, withdrawal, or trial termination. Eligibility criteria: Eligible pts are aged ≥18 yrs, with locally recurrent inoperable or metastatic PD-L1 negative TNBC in the 1L setting, adequate hematologic and organ function, and ECOG PS of 0 or 1. Endpoints: The primary endpoints are overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) per RECIST v1.1. Secondary endpoints include PFS by investigator, objective response rate, duration of response, disease control rate, OS and PFS rates, occurrence of treatment emergent adverse events (TEAEs), dose interruption, reduction, and discontinuation due to TEAEs, and changes in pt-reported outcomes. Statistical methods: The primary endpoints, PFS per BICR and OS, will be compared between treatment arms using a stratified log-rank test. The hazard ratio for PFS and OS will be estimated via a Cox proportional hazards model, adjusted for the randomization stratification factors. Accrual: The trial aims to randomize ∼558 pts across sites in North and South America, Europe, Asia, and Australia. Contact information: For more information or to refer pts, please contact: patients@biontech.com. Acknowledgment: The trial is sponsored by BioNTech. BNT327 is being jointly developed by BioNTech and Bristol Myers Squibb. Writing assistance was provided by Kordula Heinen, of BioNTech SE. Citation Format: P. Schmid, R. Dent, P. Razavi, P. Rietschel, S. Günther, L. Li, Ö. Türeci, U. Şahin. A global Phase III, randomized, double-blind trial of BNT327 plus chemotherapy (chemo) vs placebo plus chemo in patients (pts) with previously untreated locally recurrent inoperable or metastatic, PD-L1 negative triple negative breast cancer (TNBC) (ROSETTA Breast-01) 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 PS5-09-20.
Schmid et al. (Tue,) studied this question.