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.

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

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 http://globocan.iarc.fr/old/FactSheets/cancers/lung-new.asp. Accessed 15 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.

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, 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.

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;14:253-263. 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: 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 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.

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;15:143-155.

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 0.68- 0.92]; P=0.0019) Primary endpoint met Median 3.4 months Hazard Ratio 0.79 (95% CI 0.68-0.92) 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;15:143-155.

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 12.6 months vs 10.3 months, respectively* (HR: 0.83 [95% CI 0.70-0.99]; 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 0.70-0.99) 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;15:143-155.

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 10.9 months vs 7.9 months, respectively* (HR: 0.75 [95% CI 0.60- 0.92]; P=0.0073) Median 10.9 months Hazard Ratio 0.75 (95% CI 0.60-0.92) 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;15:143-155.

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

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.

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.

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 0.71-1.05)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;51:317-326.

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 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.

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;14:253-263. 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.