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PD-1 inhibitor (BI 754091)

BI 754091: A programmed cell death protein-1 inhibitor

BI 754091* is a humanised programmed cell death protein-1 (PD-1)-targeting monoclonal antibody (mAb) that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, which can inactivate T cells.1 In doing so, BI 754091 allows T cells to remain active against tumour cells.1

Clinical trials (monotherapy and combinations): BI 754091 is currently being investigated as a monotherapy in a Phase I trial in solid tumours.2 Trials of BI 754091 in combination with BI 891065*3 (a second mitochondria-derived activator of caspase [SMAC] mimetic), BI 754111*4–7 (a lymphocyte activation gene 3 [LAG-3] inhibitor) and BI 836880*8,9 (a vascular endothelial growth factor/angiopoietin-2 growth factor [VEGF/Ang2] inhibitor) are also ongoing.

Additionally, BI 754091 is being investigated in combination with both BI 754111 (a LAG-3 inhibitor) and BI 907828* (a murine double minute 2 [MDM2]-p53 antagonist).10

Role of PD-1

PD-1 is an inhibitory cell surface receptor that is activated by inflammatory signals. It has two known ligands, PD-L1 and PD-L2, which are both expressed on antigen-presenting cells (APCs). In normal tissues, binding of PD-L1 or PD-L2 to PD-1 inhibits T-cell receptor signalling, limiting T-cell function and preventing immune-mediated damage to healthy cells and tissues.11

Tumour cells can avoid destruction by host-immune surveillance. One mechanism that tumour cells use to avoid immune-mediated destruction is to upregulate PD-L1 expression, which leads to inactivation of PD-1-expressing T cells.12

Preclinical studies and clinical trials have shown that immunotherapeutic approaches using antibodies to block pathways, such as the PD-1 pathway, can facilitate the immune system’s antitumour activity in the treatment of cancers.12

About BI 754091

Mechanism of action

The PD-1 receptor is found on T cells, B cells, monocytes and natural killer cells. Activation of the PD-1 pathway by its ligands PD-L1 and PD-L2 negatively regulates immune response.1 Binding of PD-L1 or PD-L2, inactivates T cells and downregulates the expression of pro-inflammatory cytokines, enabling tumours to evade elimination.11

BI 754091 is a humanised PD-1-targeting mAb that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2,1 thereby inhibiting downstream PD-1 signalling. This allows T cells to remain active and to carry out their role in the destruction of tumour cells by secreting molecules such as perforin and granzyme B.1,13

Mechanism of action involving immune checkpoint inhibition1

PD-1 inhibitor mechanism of action

MHC, major histocompatibility complex; PD-1, programmed cell death protein-1; PD-L1, programmed death ligand-1; TCR, T-cell receptor.

Combination therapy

There is mechanistic rationale and/or preclinical data to suggest the potential for synergistic effects of PD-1 inhibitor BI 754091 when used in combination with: the potent SMAC mimetic BI 891065,14,15  with the humanised LAG-3-targeting mAb BI 754111,16,17 and with the humanised bispecific nanobody® BI 836880 (which comprises blocking domains for VEGF and Ang2).18

Clinical development

BI 754091 is currently being investigated as a monotherapy in patients with solid tumours and as part of the following combination regimens across a range of tumour types:

  • In combination with the SMAC mimetic BI 891065 in patients with solid tumours3
  • In combination with the LAG-3 inhibitor BI 754111 in patients with non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) and other solid tumours4-7
  • In combination with both the LAG-3 inhibitor BI 754111 and the MDM2-p53 antagonist BI 907828 in patients with solid tumours10
  • In combination with the VEGF/Ang2 inhibitor BI 836880 in patients with NSCLC and other solid tumours8,9

Solid tumours

Clinical trials of a PD-1 inhibitor as a monotherapy and as part of combination regimens in patients with solid tumours

NSCLC and solid tumours

Clinical trial of a PD-1 inhibitor in combination with a VEGF/Ang2 inhibitor in patients with solid tumours

NSCLC and HNSCC

Clinical trial of a PD-1 inhibitor in combination with a LAG-3 inhibitor in patients with NSCLC or HNSCC

*Exploratory advanced NSCLC cohort.

AE, adverse event; Ang2, angiopoietin 2; APC, antigen-presenting cell; DCR, disease control; DCR, disease control rate; DLT, dose-limiting toxicity; DoR, duration of response; LAG-3, a lymphocyte activation gene 3; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; OR, objective response; PD-1, programmed death-1 receptor; PD-L1, programmed death-1 receptor ligand; PFS, progression-free survival; PK/PD, pharmacokinetics/pharmacodynamics; SMAC, second mitochondria-derived activator of caspase; VEGF, vascular endothelial growth factor; 89Zr, isotope of zirconium.

References

1

Zettl M, et al. Cancer Res 2018;78(Suppl. 13): Abstract 4558 and poster.

2

ClinicalTrials.gov. NCT02952248. https://clinicaltrials.gov/ct2/show/NCT02952248 (Accessed: November 2019).

3

ClinicalTrials.gov. NCT03166631. https://clinicaltrials.gov/ct2/show/NCT03166631 (Accessed: November 2019).

4

ClinicalTrials.gov. NCT03156114. https://clinicaltrials.gov/ct2/show/NCT03156114 (Accessed: November 2019).

5

ClinicalTrials.gov. NCT03433898. https://clinicaltrials.gov/ct2/show/NCT03433898 (Accessed: November 2019).

6

ClinicalTrials.gov. NCT03780725. https://clinicaltrials.gov/ct2/show/NCT03780725 (Accessed: November 2019).

7

ClinicalTrials.gov. NCT03697304. https://clinicaltrials.gov/ct2/show/NCT03468426 (Accessed: November 2019).

8

ClinicalTrials.gov. NCT03468426. https://clinicaltrials.gov/ct2/show/NCT03468426 (Accessed: November 2019).

9

ClinicalTrials.gov. NCT03972150. http://clinicaltrials.gov/ct2/show/NCT03972150 (Accessed:November 2019).

10

ClinicalTrials.gov. NCT03964233. https://clinicaltrials.gov/ct2/show/NCT03964233 (Accessed: November 2019).

11

McDermott DF, et al. Cancer Med 2013;2(5):662–73.

12

He J, et al. Sci Rep 2015;5:13110.

13

Martinez-Lostao L, et al. Clin Cancer Res 2015;21(22):5047–56.

14

Beug ST, et al. Nat Commun 2017;8:14278.

15

Impagnatiello MA, et al. Cancer Res 2017;77(Suppl. 13):2330.

16

Zettl M, et al. Annual Meeting of the American Association for Cancer Research 2018; Abstract 4547.

17

Andrews LP, et al. Immunol Rev 2017;276(1):80–96.

18

Hofmann I, et al. Poster presentation at the 8th Euro Global Summit on Cancer Therapy 2015.

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*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: November 2019