Abstract P3-09-06: Bintrafusp alfa (M7824), a bifunctional fusion protein targeting transforming growth factor-β and programmed death ligand 1, in advanced triple-negative breast cancer: Preliminary results from a phase 1 cohort
Authors: Spira Alexander , Awada Ahmad , Isambert Nicolas , Estellés David Lorente , Nemunaitis John , Penel Nicolas , Ojalvo Laureen S , Helwig Christoph , Borel Christian 
Published: March 2020

Abstract
Background: Approximately 10%-20% of breast cancers (BCs) are classified as triple-negative breast cancer (TNBC). TNBC lacks targeted treatment options and has a poor prognosis. 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. We report interim results in patients with advanced TNBC treated with bintrafusp alfa in an expansion cohort of an ongoing, open-label, phase 1 trial (NCT02517398).
Methods: Eligible patients had confirmed TNBC (ER: IHC &lt;1%; PR: IHC &lt;1%; HER2: FISH non-amplified, IHC 0/1+, or IHC 2+ and FISH non-amplified) that progressed during or after first-line chemotherapy with an ECOG performance status of ≤1 and measurable disease by RECIST 1.1. Prior treatment with immune checkpoint inhibitors was not permitted. Patients received bintrafusp alfa 1200 mg every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal. The primary endpoint was confirmed best overall response (BOR) as assessed by independent review committee (IRC) according to RECIST 1.1. Key secondary endpoints included investigator-assessed BOR and safety. Exploratory endpoints included an extensive integrated biomarker evaluation of patient samples. These data are presented in a separate, submitted abstract.
Results: As of August 24, 2018, 33 patients with heavily pretreated TNBC (54.5% of patients had ≥4 prior regimens) were enrolled in this study of bintrafusp alfa. Patients received a median of 3 doses of bintrafusp alfa (range, 1-24). Confirmed responses as assessed by IRC and investigator occurred in 3 patients (1 complete response and 2 partial responses as assessed by IRC; ORR, 9.1% [95% CI, 1.9%-24.3%]); disease control was achieved in a total of 5 patients (15.2% [95% CI, 5.1%-31.9%]) by both IRC and investigator read. The median progression-free survival per IRC was 1.3 months (95% CI, 1.2-1.4 months), and the median overall survival was 7.8 months (95% CI, 2.1-12.8 months). Importantly, a biomarker related to TGF-β biology was identified via RNAseq analysis of tumor samples with 32.0-fold higher expression in patients who experienced disease control (response or stable disease) compared with those who had progressive disease (biomarker results for this expansion cohort are presented in a separate abstract). PD-L1 expression was not associated with response to treatment. In the entire cohort, 6 patients (18.2%) experienced ≥1 grade 3 treatment-related adverse event (TRAE), including anemia (n=3), asthenia, decreased appetite, generalized rash, hypophysitis, and increased transaminases (all n=1). No grade 4 TRAEs were reported. Three patients discontinued treatment due to TRAEs, including 1 death that was assessed by the investigator as related to treatment. Dyspnea, hemolysis, and thrombocytopenia were reported as grade 5 TRAEs in this patient, who had extensive disease at trial entry and was noted to have multiple pulmonary emboli, progressive disease, and expanding pleural effusion after 3 doses. No autoantibodies mediating hemolysis or thrombocytopenia were identified on workup.
Conclusions: In summary, bintrafusp alfa was well tolerated, with a safety profile consistent with expectations in this heavily pretreated, advanced TNBC cohort. We identified high expression of a potential predictive biomarker of response in patients with advanced TNBC treated with bintrafusp alfa. Detailed biomarker data are presented in the separate abstract and warrant further investigation of bintrafusp alfa in TNBC.
Citation Format: Alexander Spira, Ahmad Awada, Nicolas Isambert, David Lorente Estellés, John Nemunaitis, Nicolas Penel, Laureen S Ojalvo, Christoph Helwig, Christian Borel. Bintrafusp alfa (M7824), a bifunctional fusion protein targeting transforming growth factor-β and programmed death ligand 1, in advanced triple-negative breast cancer: Preliminary results from a phase 1 cohort [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 P3-09-06.