About nintedanib

Nintedanib* is an angiokinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR) 1–3, platelet-derived growth factor receptors (PDGFR) α and ß and fibroblast growth factor receptors (FGFR) 1–3.1 This page details nintedanib’s licensing and MoA.

Nintedanib licensing

Nintedanib (VARGATEF®) is approved in the EU and in other countries worldwide in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumor histology after first-line chemotherapy.1

The role of angiogenesis in cancer

Angiogenesis plays a crucial role in the development of cancer, with tumor growth and metastatic spread dependent on it.2 Angiogenesis is stimulated when tissues or tumor cells require oxygen and nutrients, and is regulated by growth factors that bind to and activate growth factor receptor tyrosine kinases to drive downstream signaling.2–5 Angiokinase inhibitors may block components of the angiogenesis signaling pathway, and thus may limit tumor growth.4,6

There is also an increasing body of preclinical and clinical evidence to suggest that sustained angiogenesis can result in immunosuppression, which can facilitate immune evasion.7 Anti-angiogenic drugs may, therefore, help convert an immunosuppressive microenvironment to an immunosupportive microenvironment, as well as normalizing the tumor vasculature.7

Nintedanib’s mechanism of action

Nintedanib is a triple angiokinase inhibitor that simultaneously inhibits the kinase activity of VEGFRs 1–3, PDGFRs α and β, and FGFRs 1–3.1,8,9 In doing so, nintedanib blocks the following functions of its target kinases:

  • VEGFR: stimulates growth, division, survival and migration of cells10
  • PDGFR: promotes the migration and adherence of cells, which contributes to the development and stabilization of new blood vessels11
  • FGFR: promotes the proliferation, differentiation and the secretion of angiogenic factors6,12

Intracellular signaling via these receptors is necessary for the proliferation and survival of endothelial cells and perivascular cells (pericytes and vascular smooth muscle cells).1 Nintedanib competitively binds to the adenosine triphosphate (ATP) binding pocket of these receptors in the cleft between the NH2- and the COOH-terminal lobes of the kinase domain.9 By binding to these receptors and blocking intracellular signaling, nintedanib hinders the formation of new tumor blood vessels, inhibits vessel maturation and disrupts the maintenance of vascular integrity, which may impact tumor growth.6,8,12

Nintedanib mechanism of action: triple angiokinase inhibition1,6,8–12 

Figure for nintedanib mechanism of action

FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Preclinical studies have shown that nintedanib blocks VEGFR-2 activation for up to 32 hours, providing sustained inhibition of receptor activation.9  Preclinical data also show that nintedanib inhibits Akt and MAPK phosphorylation in endothelial and vascular smooth muscle cells and pericytes. It also induces rapid changes in tumor perfusion and permeability, as measured by DCE-MRI, in xenograft models of different tumor types. The antitumor activity of nintedanib was reported in a number of different tumor xenograft models, including a Calu-6 NSCLC model. In addition, the combination of nintedanib with docetaxel or pemetrexed has also been shown to increase antitumor activity in xenograft models.13

Nintedanib does not induce epithelial-to-mesenchymal transition (EMT) and does not induce an invasive phenotype in vitro;14 indeed, it has been shown to potentially reverse EMT in vitro.15

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References

1

Nintedanib (VARGATEF®) summary of product characteristics, December 2019 (Accessed: June 2020).

2

de Mello RA, et al. Recent Pat Anticancer Drug Discov 2012;7(1):118-31.

3

Nishida N, et al. Vasc Health Risk Manag 2006;2(3):213-9.

4

Papetti M, et al. Am J Physiol Cell Physiol 2002;282(5):C947-70.

5

Hanahan D, et al. Cell 2011;144(5):646-74.

6

Carmeliet P, et al. Nature 2011;473(7347):298-307.

7

Popat S, et al. Lung Cancer 2020;144:76–84.

8

Rashdan S, et al. Expert Opin Pharmacother 2014;15(5):729–39.

9

Hilberg F, et al. Cancer Res 2008;68(12):4774–82.

10

Ferrara N, et al. Nat Med 2003;9(6):669–76.

11

Andrae J, et al. Genes Dev 2008;22(10):1276–312.

12

Ahmad I, et al. Biochim Biophys Acta 2012;1823(4):850–60.

13

Hilberg F, et al. J Thorac Oncol 2007;2(8):S380.

14

Kutluk Cenik B, et al. Mol Cancer Ther 2013;12(6):992–1001.

15

Huang RY, et al. Oncotarget 2015;6(26):22098–113.

*Nintedanib is approved in the EU under the brand name VARGATEF® for use in combination with docetaxel in adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. For the full list of country-specific information please click here. Nintedanib is not approved in other oncology indications.

 

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Page last updated: August 2020