Abstract OT-32-01: A phase 2, open-label study of bintrafusp alfa monotherapy in patients with HMGA2-expressing triple-negative breast cancer
Authors: Emens Leisha A , Gatti-Mays Margaret E. , O’Shaughnessy Joyce , Dirix Luc , Faggioni Giovanni , Fontana Andrea , Martin-Babau Jerome , Helwig Christoph , Huang Alice , Iadevaia Riham , Ojalvo Laureen S 
Published: February 2021

Abstract
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] &lt;1%; progesterone receptor: IHC &lt;1%; human epidermal growth factor receptor 2: in situ hybridization nonamplified or IHC 0/1), high tumor HMGA2 expression, ECOG performance status ≤1, and measurable disease by RECIST 1.1. Patients must have experienced disease progression while receiving the most recent therapy prior to enrollment. HMGA2 expression will be centrally determined on archival or fresh tumor tissue by RT-PCR. Prescreening for HMGA2 expression while receiving preceding treatment is allowed; a fresh tumor biopsy prior to study entry may be requested for exploratory biomarker analysis. Patients with prior exposure to immunotherapy are not eligible. Specific Aims: The primary endpoint is independent review committee-assessed objective response rate per RECIST 1.1. Key secondary endpoints include safety, duration of response, durable response rate, progression-free survival, and overall survival. Additional exploratory biomarker characteristics will also be investigated. Statistical Methods: Descriptive statistics, including mean, median, standard deviation, and range, will be used to characterize continuous variables. Frequency counts and percentages will be used to characterize categorical variables. Accrual: Planned enrollment is 29 patients. Contact Information: Leisha A. Emens, MD, PhD Email: emensla@upmc.edu
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.