BI 1387446* is a small molecule that binds to the stimulator of interferon (IFN) genes (STING).1 STING functions as a DNA sensor and induces the production of IFNβ by tumor-associated stromal cells, leading to the activation of dendritic cells (DCs), thereby driving T-cell priming and recruitment into the tumor microenvironment.2,3
Clinical trials (monotherapy and combination therapy): BI 1387446 is currently being investigated in a Phase I trial as monotherapy and in combination with ezabenlimab (BI 754091)*, a programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced solid tumors.4
STING is a 379-amino-acid protein that is expressed in various endothelial and epithelial cell types, as well as in hematopoietic cells, such as T cells, macrophages and DCs.5 STING is part of the innate immune response to cytosolic nucleic acids and functions as a DNA sensor and signaling molecule.6 STING is essential for controlling the transcription of numerous host defence genes, including type I IFNs and pro-inflammatory cytokines, following the recognition of cyclic dinucleotides in the cytosol of the cell.5
The production of type I IFNs leads to the activation of DCs, effective cross-priming of CD8+ T cells against tumor antigens and migration of tumor-specific CD8+ T cells into the tumor.7 Thus, therapeutic strategies that activate the STING innate immune-sensing pathway to restore type I IFN signaling may have the potential to increase tumor immunogenicity – ‘heating up’ immune cold tumors that do not respond to checkpoint inhibitor therapy due to low numbers of tumor-infiltrating lymphocytes.8
Mechanism of action
BI 1387446 induces type 1 IFN (α/β) secretion in tumor-associated DCs, leading to improved cross-priming and activation of tumor-specific cytotoxic CD8+ T cells and increased CD8+ T-cell infiltration into the tumor.1
Preclinical data have shown that BI 1387446 potently and highly selectively activates the STING pathway, resulting in dose-dependent local tumor control and the induction of a tumor-specific immune response.9
In mice, administration of BI 1387466 results in a systemic anti-tumor response, which is enhanced by combination with a PD-1 inhibitor.9
BI 1387466 is currently undergoing clinical investigation as a monotherapy and in combination with ezabenlimab in patients with advanced solid tumors in a Phase I study.4,10
|Trial number||Phase||Treatment||Patient population||Status|
(monotherapy and in combination with
ezabenlimab [BI 754091])
Advanced solid tumors
A Phase I, open-label, dose-escalation study of a STING agonist (BI 1387446) with or without ezabenlimab (BI 754091) in patients with advanced solid tumors (NCT04147234)4
DLT, dose-limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; MTD, maximum tolerated dose; OR, objective response; STING, stimulator of interferon genes.
Boehringer Ingelheim. Data on file.
Woo SR. Immunity 2014;41(5):830–42.
Foote JB, et al. Cancer Immunol Res 2017;5(6):468–79.
ClinicalTrials.gov. NCT04147234. https://clinicaltrials.gov/ct2/show/NCT04147234 (Accessed: February 2021).
Barber GN. Nat Rev Immunol 2015;15(12):760–70.
Burdette DL, Vance RE. Nature Immunol 2013;14(1):19–26.
Corrales L. Cell Rep 2015;11(7):1018–30.
Jing W. J Immunother Cancer 2019;7(1):115
Gremel G, et al. Cancer Res 2020;80(16 Suppl.): Abstract 4522.
Harrington K, et al. J Immunother Cancer 2020;8(3): Abstract 408.
*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.
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Page last updated: March 2021
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