Bispecific antibodies in breast cancer: A systematic landscape analysis of clinical trials.

Abstract

e14503 Background: Bispecific antibodies (BsAbs) engage two targets to enhance antitumor activity and potentially overcome resistance in breast cancer, but their mechanistic diversity has not been systematically mapped. Methods: ClinicalTrials.gov was systematically searched for therapeutic trials evaluating BsAbs with breast cancer as an eligible cohort. Studies were excluded if breast cancer was ineligible, the agent was not bispecific, or the study was non-therapeutic. Trials were categorized by target pair, class, and phase. Descriptive analyses were performed. Results: We identified 34 clinical trials evaluating 21 BsAbs that included patients with breast cancer. HER2 was the most frequently targeted pathway (n = 18), with HER2×HER2 constructs most common (n = 8; 3 BsAbs). Immune checkpoint BsAbs were prominent, particularly PD-1×CTLA-4 (n = 8; 4 BsAbs). CD3×HER2 T-cell–engaging BsAbs were also frequently studied (n = 7; 3 BsAbs). Clinical efficacy/safety outcomes were reported in a limited subset. Across three phase II HER2-directed BsAb studies, objective response rates ranged 27–76%, with complete responses observed in at least five patients (zenocutuzumab n = 2, KN026 n = 3). Partial responses comprised most responses, with at least 47 patients achieving partial response. Median progression-free survival ranged 5.5–27.7 months. Grade ≥3 treatment-related adverse events occurred in approximately 51–67%, most commonly neutropenia and diarrhea. Additionally, a phase II immune checkpoint BsAb targeting PD-L1×CTLA-4 demonstrated ORR 44% and mPFS 7.3 months in metastatic triple-negative breast cancer. Conclusions: The BsAb clinical landscape in breast cancer is rapidly expanding with marked mechanistic heterogeneity and enrichment of HER2-directed strategies. Early outcomes from select agents show meaningful antitumor activity, supporting continued development of oncogene-targeted and immune-modulating BsAbs. Distribution of bispecific antibody clinical trials in breast cancer by target combination and phase. Target N Phase Example agents HER2×HER2 8 I–III Zanidatamab; KN026;TQB2930 CD3×HER2 7 I–II Ertumaxomab; ISB1302; HER2Bi HER2×HER3 1 II Zenocutuzumab 4-1BB×HER2 1 I YH32367 PD-1×CTLA-4 8 I–II QL1706; SI-B003; KN046; Vudalimab CTLA-4×LAG-3 1 I Pavunalimab CD3×MUC1 1 II Anti-CD3×MUC1 Other PD-1-based 5 I–III See footnote† CD47-based 2 I See footnote* †PD-1–based checkpoint bispecific antibodies include: PD-1×TIGIT: Rilvegostomig; PD-1×VEGF: Ivonescimab; PD-L1×VEGF-A: Pumitamig; PD-1×CD73: AK131; ICOS×PD-1: XmAb23104. *CD47-based include: CD47×HER2: IMM2902; CD47×MSLN: NI1801.