VARGATEF ® SLIDE KIT A short overview of VARGATEF ® in advanced adenocarcinoma of the lung Nintedanib is approved in the European union (EU) under the.

VARGATEF® SLIDE KITA 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.

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

2

1. Reck M, et al. Lancet Oncol 2014;15:143-155. 2. VARGATEF® SmPC 2015. 3. Hilberg F, et al. Cancer Res 2008;68:4774-4782.

1.8MILLION

1.6MILLION

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

• Approximately 68% of patients are diagnosed at stage III or IV2

• One-year survival from lung cancer is strongly relatedto stage at diagnosis2

3

Unknown Stage I Stage II Stage III Stage IV0%

10%

20%

30%

40%

50%

60%

70%

80%

NEW LUNG CANCER CASES ANNUALLY*

LUNG CANCER DEATHS ANNUALLY*

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 http://globocan.iarc.fr/old/FactSheets/cancers/lung-new.asp. Accessed15 Sep 2015. 3. Cancer Research UK. Lung cancer survival statistics. Available at http://www.cancerresearchuk.org/cancer-info/cancerstats/types/lung/survival/lung-cancer-survival-statistics#stage. Accessed 14 April 2015.

19.4%

Lung cancer is a heterogeneous disease

Adenocarcinoma is the most common form of lung cancer1,2

4

• 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

83.4%

13.3%

Small cell lung cancer (SCLC)

Other (3.4%)

NSCLC

Non-small cell lung cancer (NSCLC)

Squamous cell carcinoma

22.6%

Large cell carcinoma

2.1%

Other specified carcinomas

4.9%

Adenocarcinoma43.3%

Non-small cell carcinoma

10.5%

Carcinoma, not otherwise spec.

3.1%

1. Howlader N, et al. SEER Cancer Statistics Review, 1975–2012, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site, April 2015. Accessed 14 June 2015. 2. Richer AL, et al. Pharmacogenomics Personalized Med 2015;8:63-79.

5

In nearly a decade, there has been no significant OS improvement for patients with adenocarcinoma of the lung in the

2nd-line setting

Adenocarcinoma of the lung: Better treatment options after 1st-line failure required

No approved treatment options after 1st-line chemotherapy

• 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

1998 2000 2002 2004 2006 2008 2010 2012 2014

Pemetrexed approved by EMA for previously treated NSCLC

1. Scagliotti G, et al. Oncologist 2009;14:253-263. 2. Wojtowicz-Praga S, et al. Ann Oncol 2012;23(suppl 9):ix419 [Abstract 1277P], doi:10.1093/annonc/mds365/mds366. 3. De Marinis F, et al. Oncologist 2008;13(suppl 1):14-20. 4. De Marinis F, et al. Eur J Cancer 2011;47(suppl 3):S258-271.

• 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 therapy 9,10

Nintedanib: Mechanisms of action

Angiogenesis4 Inhibition of angiogenesis2

FGFR, VEGFR, and PDGFR regulate growth of new blood vessels

FGFR VEGFR PDGFR

New blood vessels provide nutrients for growth & spread of tumour

Tumour is deprivedof nutrients requiredfor growth andspread

Nintedanib targets FGFR, VEGFR, and PDGFR to inhibit growth of new blood vessels

Nintedanib

FGFR VEGFR PDGFR

6

Triple angiokinase inhibitor that blocks angiogenesis

Anti-fibrotic and anti-inflammatory activity

1. VARGATEF® SmPC 2015. 2. Hilberg F, et al. Cancer Res 2008;68:4774-4782. 3. Rashdan S, Hanna N. Expert Opin Pharmacother 2014;15:729-739. 4. Ellis LM, Hicklin DJ.et al. Nat Rev Cancer 2008;8:579-591. 5. Wollin L, et al. Eur Respir J 2015;45:1434–1445. 6. Chaudhary NI, et al. Eur Respir J 2007;29:976–985. 7. Huang J, et al. Ann Rheum Dis 2015 Apr 9. pii: annrheumdis-2014-207109. 8. Öhlund D, et al. J Exp Med 2014;211:1503–1523. 9. Cenik B, et al. Mol Cancer Ther 2013;12:992–1001. 10. Cao H, et al. Pathol Res Pract 2015;211:557–569.

Nintedanib 200mg BID PO, D 2-21+ docetaxel 75 mg/m2 IV, D1

21-day cycles (n=655)

Progressive disease or unacceptable adverse events

Progressive disease or unacceptable adverse events

Randomisation (n=1314)

Stage IIIB/IV or recurrent NSCLC patients (all histologies) †2nd-line Setting

Placebo 200mg BID PO, D 2-21+ docetaxel 75 mg/m2 IV, D1

21-day cycles (n=659)

The pivotal LUME-Lung 1 trial:A multinational, randomised, controlled, phase III trial1

7

† Biomarker testing was not performed in LUME-Lung 1.1. Reck M, et al. Lancet Oncol 2014;15:143-155.

• 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

LUME-Lung 1: Significantly improved progression-free survival in patients with advanced NSCLC1

8

*Intention-to-treat (ITT)-population; all histologies.1. Reck M, et al. Lancet Oncol 2014;15:143-155.

Hazard Ratio 0.79(95% CI 0.68-0.92)P=0.0019

Median2.7

months

Median 3.4

months

Time (months)

Prog

ress

ion-

free

sur

viva

l (%

)

Patients (n)NintedanibPlacebo

565569

295250

155116

1921

42

31

10

00

5743

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 0.68-0.92]; P=0.0019)

•Primary endpoint met

Key secondary endpoint: OS1

• Adenocarcinoma subpopulation*

LUME-Lung 1: Significantly improved overall survival in patients with adenocarcinoma1

9

*Pre-specified analysis of the adenocarcinoma subpopulation. 1. Reck M, et al. Lancet Oncol 2014;15:143-155.

Median10.3

months

Median 12.6

months

Ove

rall

surv

ival

(%)

• In patients with adenocarcinoma, nintedanib plus docetaxel significantly improved OS vs placebo plus docetaxel

•Median OS was 12.6 months vs 10.3 months, respectively*(HR: 0.83 [95% CI0.70-0.99]; P=0.0359)

•More than a quarter of patients with adenocarcinoma lived longer than 2 years

Time (months)Patients (n)NintedanibPlacebo

322336

263269

203184

131101

9673

7255

4633

2515

163139

107

Hazard Ratio 0.83(95% CI 0.70-0.99)P=0.0359

LUME-Lung 1: Significantly improved overall survival in early progressors with adenocarcinoma

10

*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;15:143-155.

Median 10.9

months

Median7.9

months

Secondary endpoint: OS1

• Patients with adenocarcinoma & early progression after 1st-line chemotherapy*

Ove

rall

surv

ival

(%)

• In patients with early progression after 1st-line chemotherapy,‡ nintedanib plus docetaxel significantly improved OS vs placebo plus docetaxel

•Median OS was 10.9 months vs 7.9 months, respectively* (HR: 0.75 [95% CI 0.60-0.92]; P=0.0073)

Time (months)Patients (n)NintedanibPlacebo

206199

167154

11991

7342

5125

3517

1612

95

9262

31

Hazard Ratio 0.75(95% CI 0.60-0.92)P=0.0073

11

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**

LUME-Lung 1 safety: Generally manageable adverse events (AEs) with nintedanib + docetaxel1

AEs reported in ≥10% of adenocarcinoma patients1

Adenocarcinoma patients with an AE

Nintedanib + docetaxel (n=320) Placebo + docetaxel (n=333)

All grades (%) Grade ≥3 (%) 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 0.9 17.7 0.6

WBC decreased 27.8 19.7 28.2 18.3

Decreased appetite 23.4 1.3 15.6 1.5

Vomiting 19.4 1.3 12.3 0.6

Alopecia 17.5 0.3 20.4 0.0

Dyspnoea 16.9 4.7 15.6 6.0

Neutropenia 13.8 11.9 15.3 13.5

Cough 13.1 0.9 18.9 0.6

Pyrexia 12.2 0.6 14.1 0.3

Stomatitis 11.3 1.3 7.8 0.3

Haemoglobin decreased 10.9 0.9 13.8 2.1

Constipation 6.9 0.0 11.7 0.3

*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;15:143-155 [Supplementary appendix]. 2. Data on file.

No dose-adjustment or interruption Interrupt treatment and allow recovery to grade 1 or baseline

Then, reduce dose from 200 mg twice daily to 150 mg twice dailyIf a 2nd dose reduction is considered necessary, reduce dose from 150 mg twice daily to 100 mg

twice daily

Diarrhoea ≥ grade 3 despite anti-diarrhoeal

treatment

Nausea ≥ grade 3 despite anti-emetic

treatment

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

Considerations on nintedanib dosing adjustment algorithm for diarrhoea, nausea, vomiting* and other non-haematological or haematological reactions1

12

or and/or

*Supportive care for nausea and vomiting may include

medicinal products with anti-emetic properties and adequate hydration.1

1. VARGATEF® SmPC 2015.

Interrupt treatment and allow recovery of transaminase values to ≤ 2.5 x ULN in conjunction with bilirubin to

normal

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

Elevation of AST and/or ALT values to > 5 x ULN

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

Considerations on nintedanib dosing adjustment algorithm for liver enzyme elevations and bilirubin1

13

or

Unless there is an alternative cause established, VARGATEF® should be permanently discontinued

1. VARGATEF® SmPC 2015.

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 n.s.

Dyspnea at rest –0.26 –1.74 to 2.25 n.s.

Dyspnea after walking –0.03 –2.54 to 2.47 n.s.

Dyspnea after climbing stairs –0.63 –3.16 to 1.90 n.s.

Short of breath (QLQ-C30) –0.17 –2.27 to 2.61 n.s.

Pain (QLQ-C30) –2.13 –4.51 to 0.24 n.s.

Have pain –2.86 –5.50 to –0.23 0.0332

Pain affecting daily activities –1.66 –4.25 to 0.93 n.s.

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 n.s.

-20 -15 -10 -5 0 5

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 0.71-1.05)1

14

Differences in mean score for cough, dyspnea, and pain1

Favours nintedanib + docetaxel Favours placebo + docetaxelDifference 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;51:317-326.

VARGATEF® plus docetaxel presents an effective and well tolerated 2nd-line treatment option in advanced NSCLC of adenocarcinoma histology

15

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 0.70-0.99]; 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 0.60-0.92]; 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;15:143–155. 2. Novello S, et al. Eur J Cancer 2015;51:317-326.

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

In nearly a decade, there has been no significant OS improvement for patients with adenocarcinoma of the lung in the

second-line setting

No approved treatment options after 1st-line chemotherapy

Docetaxel approved by EMA for previously treated NSCLC

Erlotinib approved by EMA for previously treated NSCLC

1998 2000 2002 2004 2006 2008 2010 2012 2014

Pemetrexed approved by EMA for previously treated NSCLC

Nintedanib approved by EMA for distinct types of lung adenocarcinoma

after first-line chemotherapy

1. Scagliotti G, et al. Oncologist 2009;14:253-263. 2. Wojtowicz-Praga S, et al. Ann Oncol 2012;23(suppl 9):ix419 [Abstract 1277P], doi:10.1093/annonc/mds365/mds366. 3. De Marinis F, et al. Oncologist 2008;13(suppl 1):14-20. 4. De Marinis F, et al. Eur J Cancer 2011;47(suppl 3):S258-271. 5. VARGATEF® SmPC 2015.