About nintedanib

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 tumour histology after first-line chemotherapy.1

The role of angiogenesis in cancer

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

Nintedanib’s mechanism of action

Nintedanib is a triple angiokinase inhibitor that simultaneously inhibits the kinase activity of vascular endothelial growth factor receptors (VEGFRs) 1–3, platelet-derived growth factor receptors (PDGFRs) α and β, and fibroblast growth factor receptors (FGFRs) 1–3.1,7,8 In doing so, nintedanib blocks the following functions of its target kinases:

  • VEGFR: stimulates growth, division, survival and migration of cells9
  • PDGFR: promotes the migration and adherence of cells, which contributes to the development and stabilisation of new blood vessels10
  • FGFR: promotes the proliferation, differentiation and the secretion of angiogenic factors6,11

Intracellular signalling via these receptors is crucial 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.8 Nintedanib also inhibits Fms-like tyrosine protein kinase (Flt)-3, lymphocyte-specific tyrosine protein kinase (Lck), proto-oncogene tyrosine protein kinase Src (Src) and Abelson tyrosine protein kinase (Abl).8,12 By binding to these receptors and blocking intracellular signalling, nintedanib hinders the formation of new tumour blood vessels, inhibits vessel maturation and disrupts the maintenance of vascular integrity, which impacts upon tumour growth.6,7,11

Triple angiokinase inhibition and target cells of nintedanib.

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

Watch nintedanib’s mechanism of action

Preclinical studies have shown that nintedanib blocks VEGFR-2 activation for up to 32 hours, providing sustained inhibition of receptor activation.8 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 tumour perfusion and permeability, as measured by DCE-MRI, in xenograft models of different tumour types. The antitumour activity of nintedanib was reported in a number of different tumour xenograft models, including a Calu-6 NSCLC model.  In addition, the combination of nintedanib with docetaxel or pemetrexed has also been shown to increase antitumour activity in xenograft models.13  Preclinical investigations in malignant pleural mesothelioma (MPM) showed antitumour activity of nintedanib in cell lines – in which nintedanib inhibited cell proliferation and reduced migratory activity – and in vivo, in a MPM xenograft mouse model.14 

Nintedanib does not induce epithelial-to-mesenchymal transition (EMT) and does not induce an invasive phenotype in vitro;15 indeed, it has been shown to potentially reverse EMT in vitro.16

In addition to NSCLC,17 nintedanib has also been investigated in patients with various solid tumours, including MPM,18 colorectal cancer,19 ovarian cancer,20 hepatocellular carcinoma21 and renal cell carcinoma.22

Return to top

References: 
  1. Nintedanib (VARGATEF®) summary of product characteristics - January 2015. Accessed: April 2017.
  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. Rashdan S, et al. Expert Opin Pharmacother 2014;15(5):729–39.
  8. Hilberg F, et al. Cancer Res 2008;68(12):4774–82.
  9. Ferrara N, et al. Nat Med 2003;9(6):669–76.
  10. Andrae J, et al. Genes Dev 2008;22(10):1276–312.
  11. Ahmad I, et al. Biochim Biophys Acta 2012;1823(4):850–60.
  12. Boehringer Ingelheim Data on File.
  13. Hilberg F, et al. J Thorac Oncol 2007;2(8):S380.
  14. Laszlo V, et al. J Thorac Oncol 2015;10(9):S202 (ORAL14.07).
  15. Kutluk Cenik B, et al. Mol Cancer Ther 2013;12(6):992-1001.
  16. Huang RY, et al. Oncotarget 2015;6(26):22098-113.
  17. Reck M, et al. Lancet Oncol 2014;15(2):143–55.
  18. ClinicalTrials.gov. NCT01907100. http://clinicaltrials.gov/ct2/show/NCT01907100. Accessed: April 2017.
  19. Cutsem EV, et al. Ann Oncol 2016;29(Suppl 6):Abstract LBA20_PR.
  20. du Bois A, et al. Lancet Oncol 2016;17(1):78–89.
  21. Meyer T, et al. J Clin Oncol 2015;33(Suppl):Abstract 4074.
  22. Eisen T, et al. Br J Cancer 2015;113(8):1140-7.
X