1. Nintedanib: preclinical data
Chapter 4
Nintedanib: preclinical data

2. Angiogenesis in NSCLC ANGIOGENESIS
Angiogenesis is a critical requirement for sustaining the tumour microenvironment, growth and metastasis1,2
A delicate balance exists between proangiogenic and antiangiogenic factors, which can be hijacked by tumour cells to cause aberrant angiogenesis and ensure tumour survival and spread2
Tyrosine kinase receptors are involved in signalling cascades that result in the creation of new blood vessels that help tumour survival and metastasis2,3
VEGFs and FGFs act via their receptors to stimulate endothelial cell-mediated secretion of proteases, allowing cells to invade the surrounding matrix
After the formation of new lumen-containing vessels, endothelial cells secrete growth factors, including a PDGF, which attracts supporting cells that stabilise the new vessel
VEGFR
FGFR
PDGFR
ANGIOGENESIS
FGF(R), fibroblast growth factor (receptor); NSCLC, non-small cell lung cancer; PDGF(R), platelet-derived growth factor (receptor); VEGF(R), vascular endothelial growth factor (receptor). This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK).
1. Folkman J. N Engl J Med 1971;285(21):1182–6; 2. Manzo A, et al. Int J Mol Sci 2017;18(10):2021; 3. Cross MJ, Claesson-Welsh L. Trends Pharmacol Sci 2001;22(4):201–7.

3. Nintedanib: a triple angiokinase inhibitor
Nintedanib is a triple angiokinase inhibitor targeting VEGFR 1–3, PDGFR α/β and FGFRs 1–31,2
By targeting angiogenesis, nintedanib is thought to inhibit the creation of new blood vessels that help tumour survival and metastasis3
Studies have reported functional improvement in tumour blood perfusion after treatment with angiogenesis inhibitors, leading to increased intratumoural delivery of cytotoxic drugs during combination therapy4
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.
FGF(R), fibroblast growth factor (receptor); NSCLC, non-small cell lung cancer; PDGF(R), platelet-derived growth factor (receptor); VEGF(R), vascular endothelial growth factor (receptor). This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK).
1. Hilberg F, et al. Cancer Res 2008;68(12):4774–82; 2. Popat S, et al. Poster presented at the 7th European Lung Cancer Conference. Geneva, Switzerland, 5–8 May 2017; 3. Manzo A, et al. Int J Mol Sci 2017;18(10):2021; 4. Nerini IF, et al. Chin J Cancer 2016;35:61.

4. Antiangiogenic effects of nintedanib in preclinical studies
Sustained inhibition of receptor activation
Nintedanib blocks VEGFR2 activation for up to 32 hours
Inhibition of downstream signalling in vascular cells
Nintedanib inhibits AKT and MAPK phosphorylation in endothelial and vascular smooth muscle cells and pericytes
Reduction of vascular permeability
Ktrans is significantly reduced in tumours treated with nintedanib for 72 hours
Nintedanib induces rapid changes in tumour perfusion and permeability, as measured by DCE-MRI, in xenograft models of different tumour types
In preclinical studies, nintedanib has demonstrated antiangiogenic effects.
After 1-hour exposure in cultured cells, nintedanib results in sustained inhibition of receptor activation for 32 hours
Nintedanib has shown inhibition of downstream signalling in vascular cells: MAPK and AKT signalling pathways in three cell types that contribute to angiogenesis (endothelial cells, pericytes and smooth muscle cells), resulting in inhibition of cell proliferation and apoptosis
Nintedanib has been shown to have effects on vascular permeability:
Tumour perfusion and vascular permeability can be quantified using the Toft’s model transfer constant or Ktrans. The lower the Ktrans value, the less tumour perfusion and vascular permeability has occurred. After 3 days (72 hours) of nintedanib treatment, Ktrans values decreased significantly in nintedanib-treated tumours. This shows that nintedanib is highly effective at reducing tumour blood flow by inhibiting angiogenesis
Nintedanib induces rapid changes in tumour perfusion and permeability in xenograft models of different tumour types, as measured by dynamic contrast-enhanced magnetic resonance imaging
AKT, protein kinase B; DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging; Ktrans, transfer constant; MAPK, mitogen-activated protein kinase; VEGFR, vascular endothelial growth factor receptor. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK).
1. Hilberg F, et al. Cancer Res 2008;68(12):4774–82.

5. Antitumour activity of nintedanib in xenograft models
Effective at well-tolerated doses
Calu-6 (NSCLC)
HT-29 (small and large colon tumours)
FaDu (head and neck carcinoma)
SKOV-3 (ovarian carcinoma)
PAC-120 (prostate cancer)
Caki-1 (renal cancer)
GS-9L (glioma; syngeneic rat model)
Nintedanib
50–100 mg/kg/day showed inhibitory action in:
The antitumour activity of nintedanib has been investigated in a number of xenograph models
Mice with established xenographs were treated with continuous oral once- daily nintedanib (50 or 100 mg/kg)
Nintedanib showed significant inhibition of tumour growth compared to controls in the xerograph models shown
NSCLC, non-small cell lung cancer. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK).
1. Hilberg F, et al. Cancer Res 2008;68(12):4774–82.

6. Combination of nintedanib with docetaxel or pemetrexed in xenograft models
Combination of suboptimal doses of nintedanib with docetaxel or pemetrexed increases antitumour activity versus single agents
NCI-H460 xenograft
Calu-6 xenograft
1,000
Control 125 mg/kg, q7d
T/C
900
Pemetrexed ip
64%
Control
T/C
1,800
800
Nintedanib, 50 mg/kg, qd
41%
Nintedanib, 25 mg/kg, qd, po
60%
Nintedanib + pemetrexed
24%
1,600
Docetaxel, 7.5 mg/kg q7d, iv
69%
700
1,400
Nintedanib + docetaxel
24%
600
1,200
Tumour volume (mm³)
500
Tumour volume (mm³)
1,000
400
800
600
300
400
200
200
100 13 15 17 19 21 23 25 27 29 31 33 35 5 10 15 20 25 30
Days
Days
Suboptimal doses of nintedanib combined with docetaxel in an NCI-H460 xenograft model of NSCLC substantially reduced tumour volume (T/C: 60% for nintedanib monotherapy, 69% for docetaxel monotherapy and 24% for nintedanib plus docetaxel).
Similarly, a combination of nintedanib with pemetrexed in a Calu-6 NSCLC xenograft model reduced tumour volume (T/C: 64% for pemetrexed monotherapy, 41% for nintedanib monotherapy and 24% for nintedanib plus pemetrexed).
These preclinical data indicate that a possible additive effect of nintedanib with docetaxel or pemetrexed in NSCLC is worth investigating in the clinic.
Hilberg F, Brandstetter I. Efficacy of BIBF 1120, a potent triple angiokinase inhibitor, in models of human non-small cell lung cancer is augmented by chemotherapy. Journal of Thoracic Oncology 2007;2(Supplement 4):S380.
ip, Intraperitoneal; iv, intravenous; po, per os (oral administration); qd, four times daily; q7d, once weekly; T/C, treatment versus control. This information is from an international website which is intended for healthcare professionals not located in the United States of America (US) and the United Kingdom (UK).
1. Hilberg F, Brandstetter I. J Thorac Oncol 2007;2(Suppl. 4):Abstract C7-03 and poster.