1. VARGATEF® Slide Kit
A short overview of VARGATEF® in advanced adenocarcinoma of the lung
Nintedanib is approved in the European union (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. Registration conditions differ internationally, please refer to locally approved prescribing information. Nintedanib is not approved in other oncology indications.

2. What is VARGATEF®?
VARGATEF® (nintedanib) is a new treatment for advanced adenocarcinoma of the lung*
VARGATEF® is a triple angiokinase inhihitor, which blocks angiogenesis1,2
VARGATEF® targets 3 of the key growth factor receptors involved in angiogenesis and tumour growth2,3
VEGFR (Vascular endothelial growth factor receptor)
PDGFR (Platelet-derived growth factor receptor)
FGFR (Fibroblast growth factor receptor)
*VARGATEF® is indicated 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 1st-line chemotherapy.2
1. Reck M, et al. Lancet Oncol 2014;15: VARGATEF® SmPC Hilberg F, et al. Cancer Res 2008;68:

3. Lung cancer is common and has a poor prognosis
Lung cancer is responsible for the greatest number of cancer deaths worldwide1
Lung cancer is often diagnosed at a late stage, resulting in a poor prognosis
1.8MILLION
Approximately 68% of patients are diagnosed at stage III or IV2
One-year survival from lung cancer is strongly related to stage at diagnosis2
NEW LUNG CANCER
CASES ANNUALLY*
1.6MILLION
LUNG CANCER DEATHS ANNUALLY*
19.4%
OF ALL CANCER DEATHS ANNUALLY*
*Figures for 2012
1. Torre LA, et al. CA Cancer J Clin 2015;65:87-108; 2. GLOBOCAN Cancer Fact Sheets: Lung Cancers. Available at Accessed 15 Sep Cancer Research UK. Lung cancer survival statistics. Available at Accessed 14 April 2015.

4. Lung cancer is a heterogeneous disease
Adenocarcinoma is the most common form of lung cancer1,2
Other (3.4%)
Small cell lung cancer (SCLC)
Targeted therapy is available for lung cancer patients who carry actionable mutations (e.g. EGFR-mutations, ALK rearrangements)2
However, over 75% of lung tumours do not carry a mutation that can be effectively targeted2
13.3%
83.4%
NSCLC
Non-small cell lung cancer (NSCLC)
Adenocarcinoma 43.3%
Squamous cell carcinoma
22.6%
Non-small cell carcinoma
10.5%
Other specified carcinomas
4.9%
Carcinoma, not otherwise spec.
3.1%
Large cell carcinoma
2.1%
1. Howlader N, et al. SEER Cancer Statistics Review, 1975–2012, National Cancer Institute. Bethesda, MD, based on November 2014 SEER data submission, posted to the SEER web site, April Accessed 14 June Richer AL, et al. Pharmacogenomics Personalized Med 2015;8:63-79.

5. Adenocarcinoma of the lung: Better treatment options after 1st-line failure required
Current treatment options after 1st-line chemotherapy are limited
Median OS is <1 year with docetaxel, pemetrexed, or erlotinib1,2
Major unmet clinical need for more effective and well-tolerated treatment options after 1st-line chemotherapy1
EU approvals3,4
Docetaxel approved by EMA for previously treated NSCLC
Erlotinib approved by EMA for previously treated NSCLC
No approved
treatment options after 1st-line chemotherapy
In nearly a decade, there has been no significant OS improvement for patients with adenocarcinoma of the lung in the 2nd-line setting
1998
2000
2002
2004
2006
2008
2010
2012
2014
Pemetrexed approved by EMA for previously treated NSCLC
1. Scagliotti G, et al. Oncologist 2009;14: Wojtowicz-Praga S, et al. Ann Oncol 2012;23(suppl 9):ix419 [Abstract 1277P], doi: /annonc/mds365/mds De Marinis F, et al. Oncologist 2008;13(suppl 1): De Marinis F, et al. Eur J Cancer 2011;47(suppl 3):S

6. Nintedanib: Mechanisms of action
Triple angiokinase inhibitor that blocks angiogenesis
Nintedanib targets three growth factor receptor families crucially involved in angiogenesis:1-3 VEGFR, PDGFR and FGFR. Targeting these multiple receptors may be required for effective blockage of angiogenesis, so that the tumour does not find an alternative route to grow and spread3
Nintedanib has also shown consistent anti-fibrotic and anti-inflammatory activity in animal models, and anti-fibrotic effect in primary human lung fibroblasts5-7
Aberrant tumour stroma (TAFs) support cancer initiation, growth, invasion and metastasis as well as stemness and resistance to therapies.8 Nintedanib may interfere selectively with the accumulation of TAFs in lung adenocarcinoma
Nintedanib does not induce EMT, a predictor of poor prognosis and associated with resistance to therapy9,10
Angiogenesis4
Inhibition of angiogenesis2
FGFR, VEGFR, and PDGFR regulate growth of new blood vessels
Nintedanib targets FGFR, VEGFR, and PDGFR to inhibit growth of new blood vessels
New blood vessels provide nutrients for growth & spread of tumour
Tumour is deprived
of nutrients required
for growth and
spread
FGFR
VEGFR
PDGFR
FGFR
VEGFR
PDGFR
Nintedanib
Anti-fibrotic and anti-inflammatory activity
1. VARGATEF® SmPC Hilberg F, et al. Cancer Res 2008;68: Rashdan S, Hanna N. Expert Opin Pharmacother 2014;15: Ellis LM, Hicklin DJ.et al. Nat Rev Cancer 2008;8: Wollin L, et al. Eur Respir J 2015;45:1434– Chaudhary NI, et al. Eur Respir J 2007;29:976– Huang J, et al. Ann Rheum Dis 2015 Apr 9. pii: annrheumdis Öhlund D, et al. J Exp Med 2014;211:1503– Cenik B, et al. Mol Cancer Ther 2013;12:992– Cao H, et al. Pathol Res Pract 2015;211:557–569.

7. The pivotal LUME-Lung 1 trial: A multinational, randomised, controlled, phase III trial1
Stage IIIB/IV or recurrent NSCLC patients (all histologies) †
2nd-line Setting
Randomisation (n=1314)
Nintedanib 200mg BID PO, D 2-21
+ docetaxel 75 mg/m2 IV, D1
21-day cycles (n=655)
Placebo 200mg BID PO, D 2-21
+ docetaxel 75 mg/m2 IV, D1
21-day cycles (n=659)
Progressive disease or unacceptable adverse events
Progressive disease or unacceptable adverse events
Primary endpoint: PFS measured by independent central review (modified RECIST criteria)
Key secondary endpoint: OS, pre-specified stepwise analysis
Other secondary endpoints: Safety, objective response, disease control, health-related quality of life
† Biomarker testing was not performed in LUME-Lung 1.
1. Reck M, et al. Lancet Oncol 2014;15:

8. Progression-free survival (%)
LUME-Lung 1: Significantly improved progression-free survival in patients with advanced NSCLC1
Primary endpoint: PFS1
Intention-to-treat population (all histologies)
Nintedanib plus docetaxel significantly improved PFS vs placebo plus docetaxel*
Median PFS was 3.4 months vs 2.7 months, respectively* (HR: 0.79 [95% CI ]; P=0.0019)
Primary endpoint met
Median 3.4
months
Hazard Ratio 0.79
(95% CI )
P=0.0019
Progression-free survival (%)
Median
2.7
months
Time (months)
Patients (n)
Nintedanib
Placebo
565
569
295
250
155
116 57 43 19 21 4 2 3 1 1
*Intention-to-treat (ITT)-population; all histologies.
1. Reck M, et al. Lancet Oncol 2014;15:

9. LUME-Lung 1: Significantly improved overall survival in patients with adenocarcinoma1
Key secondary endpoint: OS1
Adenocarcinoma subpopulation*
In patients with adenocarcinoma, nintedanib plus docetaxel significantly improved OS vs placebo plus docetaxel
Median OS was months vs months, respectively* (HR: 0.83 [95% CI ]; P=0.0359)
More than a quarter of patients with adenocarcinoma lived longer than 2 years
Median 12.6
months
Hazard Ratio 0.83
(95% CI )
P=0.0359
Overall survival (%)
Median
10.3
months
Time (months)
Patients (n)
Nintedanib
Placebo
322
336
263
269
203
184
163
139
131
101 96 73 72 55 46 33 25 15 10 7
*Pre-specified analysis of the adenocarcinoma subpopulation.
1. Reck M, et al. Lancet Oncol 2014;15:

10. LUME-Lung 1: Significantly improved overall survival in early progressors with adenocarcinoma
Secondary endpoint: OS1
Patients with adenocarcinoma & early progression after 1st-line chemotherapy*
In patients with early progression after 1st- line chemotherapy,‡ nintedanib plus docetaxel significantly improved OS vs placebo plus docetaxel
Median OS was months vs months, respectively* (HR: 0.75 [95% CI ]; P=0.0073)
Median 10.9
months
Hazard Ratio 0.75
(95% CI )
P=0.0073
Overall survival (%)
Median
7.9
months
Time (months)
Patients (n)
Nintedanib
Placebo
206
199
167
154
119 91 92 62 73 42 51 25 35 17 16 12 9 5 3 1
*Prespecified analysis of population of patients with adenocarcinoma histology and ‡time since initiation of 1st-line chemotherapy <9 months.
1. Reck M, et al. Lancet Oncol 2014;15:

11. AEs reported in ≥10% of adenocarcinoma patients1
LUME-Lung 1 safety: Generally manageable adverse events (AEs) with nintedanib + docetaxel1
AEs reported in ≥10% of adenocarcinoma patients1
Patients on nintedanib + docetaxel:
comparable discontinuation rate due to AEs vs placebo + docetaxel (20.9% vs 17.7%, respectively)1
0.9% discontinued due to diarrhoea vs 0.3% on placebo + docetaxel2
8.1% were dose- reduced due to diarrhoea vs 3.3% on placebo + docetaxel2
no increase in docetaxel side effects2**
Adenocarcinoma
patients with an AE
Nintedanib + docetaxel (n=320)
Placebo + docetaxel (n=333)
All grades (%)
Grade ≥3 (%)
Patients with AEs
96.3
75.9
94.3
68.5
Diarrhoea
43.4
6.3
24.6
3.6
Neutrophil count decreased
40.9
36.3
40.5
34.8
ALT increased
37.8
11.6
9.3
0.9
Fatigue
30.9
4.7
29.4
4.2
AST increased
30.3
4.1
7.2
0.6
Nausea
28.4
17.7
WBC decreased
27.8
19.7
28.2
18.3
Decreased appetite
23.4
1.3
15.6
1.5
Vomiting
19.4
12.3
Alopecia
17.5
0.3
20.4
0.0
Dyspnoea
16.9
6.0
Neutropenia
13.8
11.9
15.3
13.5
Cough
13.1
18.9
Pyrexia
12.2
14.1
Stomatitis
11.3
7.8
Haemoglobin decreased
10.9
2.1
Constipation
6.9
11.7
*AEs were classified according to Common Terminology Criteria for Adverse Events version 3.0. **Febrile neutropenia slightly raised.
1. Reck M, et al. Lancet Oncol 2014;15: [Supplementary appendix]. 2. Data on file.

12. Considerations on nintedanib dosing adjustment algorithm for diarrhoea, nausea, vomiting* and other non-haematological or haematological reactions1
Grade 1, or grade 2 if this lasts for 7 days or less
Diarrhoea ≥ grade 2 for more than 7 consecutive days despite antidiarrhoeal treatment
Vomiting ≥ grade 2
Other non-haematological or haematological adverse reactions of ≥ grade 3 or
and/or
Diarrhoea ≥ grade 3 despite anti-diarrhoeal treatment
Nausea ≥ grade 3 despite anti-emetic treatment
No dose-adjustment or interruption
Interrupt treatment and allow recovery to grade 1 or baseline
*Supportive care for nausea and vomiting may include medicinal products with anti-emetic properties and adequate hydration.1
Then, reduce dose from 200 mg twice daily to 150 mg twice daily If a 2nd dose reduction is considered necessary, reduce dose from 150 mg twice daily to 100 mg twice daily
1. VARGATEF® SmPC 2015.

13. Elevation of AST and/or ALT values to > 5 x ULN
Considerations on nintedanib dosing adjustment algorithm for liver enzyme elevations and bilirubin1
Elevation of AST and/or ALT values to > 2.5 x ULN in conjunction with total bilirubin elevation to ≥ 1.5 x ULN
Elevation of AST and/or ALT values to > 3 x ULN in conjunction with an increase of total bilirubin to ≥ 2 x ULN and ALKP < 2 x ULN or
Elevation of AST and/or ALT values to > 5 x ULN
Interrupt treatment and allow recovery of transaminase values to ≤ 2.5 x ULN in conjunction with bilirubin to normal
Unless there is an alternative cause established, VARGATEF® should be permanently discontinued
Treatment continuation:
Reduce dose from 200 mg twice daily to 150 mg twice daily
If a 2nd dose reduction is considered necessary, reduce dose from 150 mg twice daily to 100 mg twice daily
1. VARGATEF® SmPC 2015.

14. Differences in mean score for cough, dyspnea, and pain1
LUME-Lung 1: The combination of nintedanib and docetaxel maintained patients’ quality of life
The efficacy benefits of nintedanib + docetaxel were achieved with no detrimental effect on patient self-reported* QoL (HR: 0.86; 95% CI )1
Differences in mean score for cough, dyspnea, and pain1
Mean difference
95% CL
P-value
Cough (QLQ-LC13)
–0.99
–3.44 to 1.46
n.s.
Dyspnea (QLQ-LV13)
–0.03
–2.00 to 1.94
Dyspnea at rest
–0.26
–1.74 to 2.25
Dyspnea after walking
–2.54 to 2.47
Dyspnea after climbing stairs
–0.63
–3.16 to 1.90
Short of breath (QLQ-C30)
–0.17
–2.27 to 2.61
Pain (QLQ-C30)
–2.13
–4.51 to 0.24
Have pain
–2.86
–5.50 to –0.23
0.0332
Pain affecting daily activities
–1.66
–4.25 to 0.93
Pain in chest (QLQ-LC13)
–2.71
–4.98 to –0.43
0.0196
Pain in arm and shoulder (QLQ-LC13)
–4.18
–6.50 to –1.85
0.0004
Pain in other parts (QLQ-LC13)
–2.23
–4.98 to 0.53
-20
-15
-10 -5 5
Favours nintedanib + docetaxel
Favours placebo + docetaxel
Difference in mean score
* Measured using standard questionnaires: EORTC QLQ-C30, EORTC QLQ-LC13, EQ-5QD and EQ-VAS.
1. Novello S, et al. Eur J Cancer 2015;51:

15. VARGATEF® plus docetaxel presents an effective and well tolerated 2nd-line treatment option in advanced NSCLC of adenocarcinoma histology
VARGATEF® (nintedanib): a triple angiokinase inhibitor with a twice daily dosing regimen
In combination with docetaxel, nintedanib extended median OS* beyond 1 year in patients with advanced adenocarcinoma‡ of the lung after 1st-line chemotherapy1
By 2.3 months vs placebo + docetaxel (HR: 0.83 [95% CI ]; P=0.0359)
By 3 months vs placebo + docetaxel in patients who progressed <9 months after starting 1st-line chemotherapy (HR: 0.75 [95% CI ]; P=0.0073)
The combination had a manageable safety profile1
Nintedanib in combination with docetaxel significantly extended OS without any additional detrimental effects on patient quality of life2
*Key secondary endpoint; ‡pre-specified subpopulation analysis.
1. Reck M, et al. Lancet Oncol 2014;15:143– Novello S, et al. Eur J Cancer 2015;51:

16. Adenocarcinoma of the lung: Better treatment options after 1st-line failure required
Current treatment options after 1st-line chemotherapy are limited
Median OS is <1 year with docetaxel, pemetrexed, or erlotinib1,2
Major unmet clinical need for more effective and well-tolerated treatment options after 1st-line chemotherapy1
EU approvals3,4
Docetaxel approved by EMA for previously treated NSCLC
Erlotinib approved by EMA for previously treated NSCLC
Nintedanib approved by EMA for distinct types of lung adenocarcinoma after first-line chemotherapy
No approved
treatment options after 1st-line chemotherapy
In nearly a decade, there has been no significant OS improvement for patients with adenocarcinoma of the lung in the second-line setting
1998
2000
2002
2004
2006
2008
2010
2012
2014
Pemetrexed approved by EMA for previously treated NSCLC
1. Scagliotti G, et al. Oncologist 2009;14: Wojtowicz-Praga S, et al. Ann Oncol 2012;23(suppl 9):ix419 [Abstract 1277P], doi: /annonc/mds365/mds De Marinis F, et al. Oncologist 2008;13(suppl 1): De Marinis F, et al. Eur J Cancer 2011;47(suppl 3):S VARGATEF® SmPC 2015.