Abstract P3-02-03: A phase Ib trial of bintrafusp alfa and eribulin in patients with metastatic triple negative breast cancer (TNBC)
Authors: Damodaran Senthil , Liu Diane , Schwartz Jill , Valero Vicente , Ramirez David , Saleem Sadia , Ueno Naoto T. , Ibrahim Nuhad K. , Karuturi Meghan S. , Murthy Rashmi K. , Moulder Stacy , Litton Jennifer K. 
Published: March 2023

Abstract
Background: Metastatic TNBC is an aggressive breast cancer subtype with poor prognosis and limited systemic therapy options. While pembrolizumab in combination with chemotherapy is approved for PD-L1 positive TNBC, limited immunotherapy options exist for patients with progressive and/or PD-L1 negative disease. TGFβ released by cancer cells and stromal fibroblasts attenuates the intrinsic antitumor potential of immune cells within the tumor microenvironment mediating resistance to immunotherapy. Consequently, inhibition of TGFβ signaling could potentially enhance antitumor responses to anti-PD-L1/PD-1 therapies. Bintrafusp alfa is a bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody blocking programmed cell death ligand 1. Preclinical studies have shown that eribulin downregulates TGFβ by phosphorylation of Smad proteins. Therefore, combining eribulin with bintrafusp alfa may have a synergistic effect. This study evaluated the combination of bintrafusp alfa with eribulin in patients with metastatic TNBC. Methods: This is a phase 1b, open label, single center study evaluating bintrafusp alfa in combination with eribulin in patients with metastatic TNBC who had relapsed/progressed on prior therapies. Patients with ER/PR ≤10% with measurable disease were enrolled. Patients who received prior anti-PD-1/PD-L1 therapies in the metastatic setting were excluded. Patients received bintrafusp alfa 1200 mg intravenously every 2 weeks in combination with eribulin (1.4 mg/m2 (dose level 1), 1.1 mg/m2, or 0.7 mg/m2) on days 1, 8, 22, 29 on every 6-week cycle. Primary objectives were to determine the recommended phase II dose (RP2D) as well as to evaluate the safety and tolerability of eribulin in combination with the fixed dose of bintrafusp alfa. Secondary objective was to determine the overall response rate (ORR) according to RECIST 1.1. Bayesian optimal interval (BOIN) design was employed to identify the RP2D. Toxicities assessed using CTCAE v4.03. Tumor assessments were performed every 6 weeks. Results: A total of 25 patients were enrolled on the study. Twenty-one patients were evaluable (3 screen failures, 1 received only one dose of study treatment). Median age 59 (range 27-85). Median number of prior therapies 2 (range 0-8). The most common reason for protocol discontinuation was disease progression (n = 15, 71%). Four patients experienced dose limiting toxicities (DLTs); 3 with decreased neutrophil count and 1 with increased aspartate aminotransferase. Five patients (24%) experienced grade 4 toxicities (increased aspartate aminotransferase, hypokalemia, hypophosphatemia, neutropenia). Nine patients (43%) experienced grade 3 toxicities. Three patients (14%) discontinued study due to toxicity. Total of 2 deaths were observed, none related to treatment. Most common toxicities (any grade) include anemia (n = 13 patients), elevated aspartate aminotransferase (11), neutropenia (n = 10), elevated aminotransferase (9), headache (n = 9), hypokalemia (n = 8), hyperglycemia (n = 8), leukopenia (n = 8), and fatigue (n = 8). RP2D was eribulin 1.1 mg/m2 with bintrafusp alfa 1200 mg. Six patients had PR (28.6%), 2 had SD (9.5%) and 12 had PD (57.1%) as the best response. One patient withdrew before response evaluation. Median PFS was 1.7 months (95% CI: (1.2, 5.9) and median OS was 11.1 months (95%CI: (5.2, 15.7). Conclusions: The combination of bintrafusp alfa with eribulin has manageable safety profile with meaningful clinical activity in patients with TNBC. Further studies evaluating TGF inhibitors in breast cancer are warranted.
Citation Format: Senthil Damodaran, Diane Liu, Jill Schwartz, Vicente Valero, David Ramirez, Sadia Saleem, Naoto T. Ueno, Nuhad K. Ibrahim, Meghan S. Karuturi, Rashmi K. Murthy, Stacy Moulder, Jennifer K. Litton. A phase Ib trial of bintrafusp alfa and eribulin in patients with metastatic triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-02-03.