Abstract P3-09-13: Identification of a tumor biomarker in advanced triple-negative breast cancer that predicts response to bintrafusp alfa (M7824), a bifunctional fusion protein targeting transforming growth factor-β and programmed death ligand 1
Authors: Locke George , Zhang Yue , Ojalvo Laureen S , Helwig Christoph , Rolfe Alex , Christensen Olaf , Dussault Isabelle 
Published: March 2020

Abstract
Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Identification of biomarkers that are predictive of response to investigational therapies will help identify patients that are more likely to clinically benefit from treatment. Bintrafusp alfa (M7824) is an innovative 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 this expansion cohort of a global, phase 1, open-label trial (NCT02517398), an extensive tumor biomarker analysis was conducted to identify potential markers correlating with efficacy in patients with advanced TNBC treated with bintrafusp alfa.
Methods: Patients received infusions of bintrafusp alfa 1200 mg every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal. Tumor archival material was collected from each patient for biomarker analysis. All biomarker analyses were exploratory. PD-L1 expression and immune phenotype were determined by immunohistochemistry. Tumor samples were also processed for RNA sequencing (RNAseq) and resulting data were analyzed to identify potential associations between gene expression and efficacy of bintrafusp alfa treatment.
Results: As of August 24, 2018, 33 patients with heavily pretreated TNBC were treated with bintrafusp alfa (54.5% of patients received ≥4 prior regimens). The objective response rate was 9.1% (n=3) and the disease control rate was 15.2% in a total of 5 patients. PD-L1 expression levels in tumor cells and in the tumor microenvironment were generally low in this cohort with the majority of patients having 0% PD-L1+ tumor cells and/or ≤10% PD-L1+ immune cells in their tumor microenvironment. Moreover, several patients had an immune desert phenotype. PD-L1 expression was not associated with response to treatment. Importantly, exploratory analysis of RNAseq data (n=26 passing quality control) identified differential expression of the high mobility group AT-hook 2 (HMGA2) gene with 32.0-fold higher expression (as computed by DESeq2; q=2.23e−13) in patients who experienced disease control (response or stable disease) compared to those who had progressive disease. HMGA2 is a transcriptional regulator whose expression is upregulated by TGF-β signaling. Furthermore, HMGA2 is known to be an important factor in mediating TGF-β-induced epithelial-mesenchymal transition. In The Cancer Genome Atlas dataset, approximately 12% of subjects annotated as TNBC have high expression of HMGA2. Clinical efficacy and safety data for this expansion cohort are presented in a separate abstract.
Conclusions: We identified high expression of HMGA2 as a potential predictive biomarker of response in TNBC patients treated with bintrafusp alfa. HMGA2 assay development is on-going to confirm this finding in a future clinical trial.
Citation Format: George Locke, Yue Zhang, Laureen S Ojalvo, Christoph Helwig, Alex Rolfe, Olaf Christensen, Isabelle Dussault. Identification of a tumor biomarker in advanced triple-negative breast cancer that predicts response to bintrafusp alfa (M7824), a bifunctional fusion protein targeting transforming growth factor-β and programmed death ligand 1 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-13.