Abstract OT-32-01: A phase 2, open-label study of bintrafusp alfa monotherapy in patients withHMGA2-expressing triple-negative breast cancer

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with few targeted treatment options and a poor prognosis. Despite approvals of the anti-PD-L1 monoclonal antibody (mAb) atezolizumab in combination with nab-paclitaxel for unresectable, locally advanced/metastatic TNBC that expresses PD-L1 (tumor-infiltrating immune cells ≥1% of tumor area), many recent studies of other anti-PD-(L)1 therapies in advanced TNBC have shown limited efficacy, likely due to intrinsic therapeutic resistance. Transforming growth factor β (TGF-β), which promotes cancer progression by inducing angiogenesis, fibrosis, and epithelial-mesenchymal transition (EMT), may attenuate the efficacy of or promote resistance to anti-PD-(L)1 therapies. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In a cohort of 33 patients with heavily pretreated, advanced TNBC that progressed during/after first-line therapy, bintrafusp alfa was safe and resulted in antitumor activity (NCT02517398). Exploratory biomarker analysis showed that high mobility group AT-hook 2 (HMGA2) expression was 32-fold higher in tumor samples from patients who experienced disease control than from patients who had progressive disease in that cohort. Elevated expression of HMGA2, a protein associated with TGF-β signaling and a known regulator of EMT, is associated with metastasis and poor survival in breast cancer. We present the study design of a phase 2 trial to evaluate the efficacy and safety of bintrafusp alfa in patients with pretreated metastatic TNBC that expresses high levels of HMGA2. Trial Design: This phase 2, multicenter, open-label study will evaluate bintrafusp alfa monotherapy in patients with HMGA2-expressing TNBC that progressed on ≥1 line of systemic therapy for their metastatic disease. Patients will receive bintrafusp alfa 1200 mg every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal. Eligibility Criteria: Patients must have histologically confirmed TNBC defined by ASCO-CAP guidelines (estrogen receptor: immunohistochemistry [IHC] Citation Format: Leisha A Emens, Margaret E. Gatti-Mays, Joyce O’Shaughnessy, Luc Dirix, Giovanni Faggioni, Andrea Fontana, Jerome Martin-Babau, Christoph Helwig, Alice Huang, Riham Iadevaia, Laureen S Ojalvo. A phase 2, open-label study of bintrafusp alfa monotherapy in patients with HMGA2-expressing triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-32-01.