The Story of BIBF1120 Nintedanib Vargatef. To be told by Rolf Kaiser & Claudia-Nanette Gann

Transcription

1 1 The Story of BIBF1120 Nintedanib Vargatef To be told by Rolf Kaiser & Claudia-Nanette Gann

2 The Story Started in Folkman J. New Eng J Med 1971;285:

3 What Role Does Angiogenesis Play in Cancer? 3 Supplies the tumour with oxygen and nutrients 1 Promotes and sustains tumour growth 2,3 Allows tumour cells to escape into the circulation, leading to metastases 2,3 1. Bergers G, et al. Nat Rev Cancer. 2003;3: Folkman J. N Engl J Med. 1995;333: Ellis LM, et al. Nat Rev Cancer. 2008;8:

4 Tumour Angiogenesis Is a Complex Process 4 VEGF = vascular endothelial growth factor; FGF = fibroblast growth factor; PDGF = platelet-derived growth factor.

5 BI Accepts the Challenge 5

6 but it was still a long way to go Discovery of BIBF 1000 Then discovery of BIBF 1120; Patent in 2000 PHASE I PHASE II PHASE III EMA submission in 2013 and CUP started EMA approval in 2014 Other indications to follow

7 Once upon a time Discovery of BIBF 1000 Then discovery of BIBF 1120; Patent in 2000 STOP

8 BIBF 1120 Triple Angiokinase Inhibition 8 Triple angiokinase profile IC 50 [nm] VEGFR 1 / 2 / 3 34 / 21 / 13 PDGFR α / β FGFR 1 / 2 / 3 59 / / 37 / 108 Additionally targeted kinases Flt-3 Ret Src, Lck, Lyn IC 50 [nm] / 16 / 195 IC 50 [nm] IGF1R, InsR >1000, <10,000 EGFR, HER2, CDK1, CDK2, CDK4 >50,000 Hilberg F, et al. Cancer Res. 2008;68:

9 Nintedanib and Its Mode of Action 9 BIBF 1120 BIBF 1120 BIBF 1120 Hilberg F, et al. Cancer Res. 2008;68:

10 Nintedanib Metabolisation Via the Esterase/UGT1A1 Pathway 10 m0 m/z m1 m/z m2 m/z Esterase UGT1A1,7,8,10 BIBF 1120 BIBF 1202 BIBF 1202-G Nintedanib can be administered in patients with renal impairment without the need for dose adjustment Nintedanib shows no evidence of CYP 450 interaction, thus it is unlikely to cause drug drug interactions based on CYP metabolism Nintedanib is a substrate of P-gp, hence co-administration of Nintedanib with P-gp inducers or inhibitors has to be carefully considered Hilberg F, et al. Cancer Res. 2008;68:

11 Next steps PHASE I PHASE II

12 Nintedanib Phase I 12 Recommended dose mg orally twice daily in combination with chemotherapy Safety 6 Generally well tolerated Reversible liver enzyme elevations Gastrointestinal side effects mostly mild and manageable First efficacy signals in Phase I 7,8 Monotherapy One CR and four PRs (CRC and RCC) Disease stabilisation in 30% Combination therapy Indicating additive effect of BIBF du Bois A. Ann Oncol. 2010;21: ; 2. Doebele RC, et al. Ann Oncol. 2012;23: ; 3. Ellis PM, et al. Clin Cancer Res. 2010;16: ; 4. Raymond E, et al. Eur J Cancer. 2007;5:S108; 5. Prenen H, et al. J Clin Oncol. 2010;28(suppl). Abstract e14054; 6. Mross K, et al. Clin Cancer Res. 2010;16: ; 7. Lee C-P, et al. J Clin Oncol. 2006;24(S18). Abstract 3015; 8. Boehringer Ingelheim. Date on file.

13 Phase II Data in NSCLC Study Design 13 Nintedanib: Phase II ( ) A double-blind, dose-ranging, randomised study in patients with advanced NSCLC Patients with: NSCLC stage IIIb/IV Recurrent disease after previous platinum-based therapy Randomisation, n= mg n=36 DLT mg n=37 DLT mg mg Continuous daily treatment Primary end points: PFS; ORR Reck M, et al. Ann Oncol. 2011;22:

14 Phase II Results in NSCLC Leading to Start of Phase III Trials LUME-Lung 1 & 2 14 All Patients n=73 ECOG PS 0 1 n=56 Median PFS 6.9 weeks 11.6 weeks Median OS 21.9 weeks 37.7 weeks Disease stabilisation rate 46% 59% One confirmed 250 mg Continuous treatment with nintedanib was well tolerated with no difference in efficacy between treatment arms Nintedanib is active in patients with recurrent NSCLC PFS and objective response rate with single-agent treatment in advanced disease warrants further exploration Reck M, et al. Ann Oncol. 2011;22:

15 Crucial step forward PHASE III

16 LUME-Lung 1: Randomised Controlled Phase III Study 16 Stage IIIB/IV* or recurrent NSCLC patients after first-line chemotherapy (all histologies) R A N D O M I S E N=1314 1:1 Nintedanib 200 mg BID po, Days docetaxel 75 mg/m 2 IV, Day 1, 21-day cycles (n=655) Placebo BID po, Days 2 21, + docetaxel 75 mg/m 2 IV, Day 1, 21-day cycles (n=659) Number of docetaxel cycles not restricted Monotherapy allowed after 4 cycles of combination therapy PD PD Stratification: ECOG PS (0 vs. 1) Prior bevacizumab (yes vs. no) Histology (squamous vs. non-squamous) Brain metastases (yes vs. no) Regions: Europe/Asia/South Africa Accrual: 23 Dec 2008 to 09 Feb 2011 *UICC/AJCC=Union Internationale Contre le Cancer/American Joint Committee on Cancers (6th or 7th edition). BID = twice daily; po = by mouth; IV = intravenous; NSCLC = non-small cell lung cancer; PD = progressive disease; PFS = progression-free survival; OS = overall survival; ITT = intent-to-treat; ECOG PS = Eastern Cooperative Oncology Group performance status. Reck M, et al. Lancet Oncol. 2014;15:

17 LUME-Lung 1 Statistical Methodology 17 Primary endpoint Independently assessed PFS ITT/all histologies Significant finding OS Adenocarcinoma Time since start of first-line therapy <9 mo Key secondary endpoint An exploratory analysis of LUME-Lung 2 data showed evidence for enhanced survival benefit in early progressing adenocarcinoma tumours 1,2 To confirm this finding in LUME-Lung 1, a pre-specified stepwise testing was incorporated in the secondary endpoint OS analysis. This stepwise approach was applied to control the type I error rate 3 Significant finding OS All adenocarcinoma Significant finding OS ITT/all histologies OS = overall survival; PFS = progression-free survival; ITT = intention-to-treat. 1. Hanna N, et al. J Clin Oncol. 2013;31(suppl; Abstract 8034); 2. Kaiser R, et al. Eur J Cancer. 2013;49(Suppl 2):Abstract 3479, Poster P ; 3. Reck M, et al. Lancet Oncol. 2014;15:

18 Demographics and Baseline Characteristics Were Balanced Between the Treatment Arms 18 All Patients (N=1314) Nintedanib + docetaxel (n=655) Placebo + docetaxel (n=659) Patients (%) ECOG PS = Eastern Cooperative Oncology Group performance status. Reck M, et al. Lancet Oncol. 2014;15:

19 LUME-Lung 1 Met Its Primary Endpoint with Significant Improvement in Progression-Free Survival in All Patients 19 Primary Endpoint PFS by Independent Central Review, All Patients Probability of PFS (%) Median PFS (months) Nintedanib + docetaxel Placebo + docetaxel HR = 0.79 (95% CI: ); P= No. at risk Nintedanib Placebo Time (months) CI = confidence interval; HR = hazard ratio; PFS = progression-free survival. Reck M, et al. Lancet Oncol. 2014;15:

20 Consistent Progression-Free Survival Benefit Regardless of Histology 20 PFS by Histology, Independent Central Review 100 Adenocarcinoma 100 Squamous cell carcinoma Probability of PFS (%) Median PFS (months) Nintedanib + docetaxel Placebo + docetaxel HR = 0.77 (95% CI: ); P= Probability of PFS (%) Median PFS (months) Nintedanib + docetaxel Placebo + docetaxel (95% CI: ); P= Time (months) Time (months) No. at risk Nintedanib Placebo CI = confidence interval; HR = hazard ratio; PFS = progression-free survival. Reck M, et al. Lancet Oncol. 2014;15: ; Reck M, et al. J Clin Oncol. 2013;31(Suppl.):Abstract LBA8011 and oral presentation. No. at risk Nintedanib Placebo

21 Overall Survival in Patients with Adenocarcinoma Who Progressed in <9 Months After Start of First-Line Therapy 21 Key Secondary Endpoint, Pre-specified Hierarchical Analysis 100 Nintedanib + docetaxel Placebo + docetaxel Probability of survival (%) % Median OS (months) YEAR SURVIVAL HR = 0.75 (95% CI: ); P= % Time (months) 20.7% 10.4% 2-YEAR SURVIVAL No. at risk Nintedanib Placebo CR = complete response; HR = hazard ratio; OS = overall survival. Reck M, et al. Lancet Oncol. 2014;15: ; Boehringer Ingelheim data on file.

22 Significant Improvement in Median Overall Survival in Patients With Adenocarcinoma 22 Key Secondary Endpoint, Pre-specified Hierarchical Analysis 100 Nintedanib + docetaxel Placebo + docetaxel Probability of survival (%) No. at risk Nintedanib Placebo % Median OS (months) YEAR SURVIVAL HR 0.83 (95% CI: ); P= % Time (months) 19.1% 2-YEAR SURVIVAL 25.7% CI = confidence interval; HR = hazard ratio; OS = overall survival. Reck M, et al. Lancet Oncol. 2014;15:

23 No Significant Difference in Overall Survival in All Patients 23 Key Secondary Endpoint, Pre-specified Hierarchical Analysis 100 Probability of survival (%) Nintedanib + docetaxel Placebo + docetaxel Median OS (months) HR = 0.94 (95% CI: ); P= Time (months) No. at risk Nintedanib Placebo CI = confidence interval; HR = hazard ratio; OS = overall survival. Reck M, et al. Lancet Oncol. 2014;15:

24 Consistent Overall Survival Benefit Across Most Subgroups of Patients with Adenocarcinoma Histology 24 OS in Subgroups, Patients with Adenocarcinoma Characteristic Overall Sex Female Male Age class <65 years 65 years Ethnic origin Asian Non-Asian Smoking status Current smoker/ex-smoker Never-smoker ECOG PS 0 1 Brain metastases No Yes Prior bevacizumab No Yes Time since start of first-line <9 months 9 months Best response to first-line CR/PR/SD PD Favours nintedanib HR (95% CI) Favours placebo CI = confidence interval; CR = complete response; ECOG PS = Eastern Cooperative Oncology Group performance status; HR = hazard ratio; PD = progressive disease; PR = partial response; SD = stable disease Reck M, et al. Lancet Oncol. 2014;15:

25 Overall Survival in Patients with Adenocarcinoma and No Response to First-Line Chemotherapy Adenocarcinoma and PD as Best Response to First-Line Chemotherapy No. at risk Probability of survival (%) Nintedanib Placebo % Time (months) Nintedanib + docetaxel Placebo + docetaxel Median OS (months) % 1-YEAR SURVIVAL HR = 0.62 (95% CI: ); P= % 5.3% 2-YEAR SURVIVAL CR = complete response; HR = hazard ratio; OS = overall survival; PD = progressive disease. K Mellemgaard A, et al. Eur J Cancer. 2013;49(suppl 2):Abstract 3409 and oral presentation.

26 Inverse Relationship Between Hazard Ratio for Overall Survival and Time Since Start of First-Line Therapy 26 Final OS Analysis in Patients with Adenocarcinoma HR (95% CI) Time since start of first-line therapy (months) The shorter the time from start of first-line chemotherapy to randomisation, the better the treatment effect from nintedanib CR = complete response; HR = hazard ratio; OS = overall survival. Kaiser R, et al. Eur J Cancer. 2013;49(suppl 2):Abstract 3479 and poster P388.

27 Extending survival in early progressing patients 27 Reck M, et al. Lancet Oncol. 2014;15:

28 Consistent Trend Towards Survival Benefit Regardless of Prior Treatment in Patients With Adenocarcinoma 28 Overall Survival by Prior First-line Chemotherapy Prior taxane treatment Prior pemetrexed treatment Prior bevacizumab treatment 100 Nintedanib + docetaxel Placebo + docetaxel 100 Nintedanib + docetaxel Placebo + docetaxel 100 Nintedanib + docetaxel Placebo + docetaxel Probability of survival (%) Median OS (months) HR = 0.75 (95% CI: ) Median OS (months) HR = 0.79 (95% CI: ) Median OS (months) HR = 0.61 (95% CI: ) No. at risk Time (months) Time (months) Time (months) Nintedanib Placebo CR = complete response; HR = hazard ratio; OS = overall survival. Krzakowski M, et al. Ann Oncol. 2014;25(suppl 4):iv158. Abstract 471P and poster; Mellemgaard A, et al. Ann Oncol. 2014;25(suppl 4): iv157. Abstract 473P and poster; Boehringer Ingelheim data on file.

29 Significant Improvement in Disease Control Rate 29 Independent Central Review at the Time of Final OS Analysis Adenocarcinoma All patients n (%) Nintedanib + docetaxel (n=322) Placebo + docetaxel (n=336) Nintedanib + docetaxel (n=655) Placebo + docetaxel (n=659) Objective Response 15 (4.7) 12 (3.6) 29 (4.4) 22 (3.3) Complete Response (CR) (0.2) Partial Response (PR) 15 (4.7) 12 (3.6) 29 (4.4) 21 (3.2) Stable Disease (SD) 179 (55.6) 136 (40.5) 325 (49.6) 250 (37.9) Disease Control Rate (CR + PR + SD) 194 (60.2) 148 (44.0) 354 (54.0) 272 (41.3) Odds ratio 1.93; P< ; P< Progressive Disease 87 (27.0) 147 (43.8) 200 (30.5) 298 (45.2) Response rates are according to modified Response Evaluation Criteria in Solid Tumors version 1.0. CR = complete response; HR = hazard ratio; OR = odds ratio; OS = overall survival; PR = partial response; SD = stable disease. Reck M, et al. Lancet Oncol. 2014;15:

30 Nintedanib + Docetaxel Safety Profile: All Grades Adverse Events 30 All Grade AEs in 10% of Patients with Adenocarcinoma Nintedanib + docetaxel Placebo + docetaxel Patients (%) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. *Group term. Highlighted events are AEs for which the frequency for nintedanib was >20% greater than with placebo. AEs = adverse events; ALT = alanine aminotransferase; AST = aspartate aminotransferase; WBC = white blood cell. Reck M, et al. Lancet Oncol. 2014;15: Suppl; Boehringer Ingelheim data on file.

31 The Majority of Grade 3 AEs Occurred at Similar Rates Between Treatment Arms 31 Grade 3 AEs in Patients with Adenocarcinoma* Nintedanib + docetaxel Placebo + docetaxel Patients (%) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. *Reported as AEs of all grades occurring in at least 10% of the patients in either treatment arm. Highlighted events are AEs for which the frequency for nintedanib was greater than twice the frequency with placebo. AEs = adverse events; ALT = alanine aminotransferase; AST = aspartate aminotransferase; WBC = white blood cell. Reck M, et al. Lancet Oncol. 2014;15: Suppl; Boehringer Ingelheim data on file.

32 The Most Commonly Reported Adverse Events Were Gastrointestinal Events and Liver Enzyme Elevations 32 Gastrointestinal (GI) events Diarrhoea, nausea and vomiting Manageable with supportive treatment and dose modification Liver enzyme evaluation (ALT/AST) Reversible upon dose modification in the majority of patients Neutropenia Dose modification of docetaxel according to label AEs = adverse events; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GI = gastrointestinal. Reck M, et al. Lancet Oncol. 2014;15:

33 Adverse Events Commonly Associated with VEGF/VEGFR Inhibitors 33 Adverse Events of Special Interest in Patients with Adenocarcinoma All grades (%) Grade 3 (%) Bleeding Bleeding Bleeding Bleeding Patients (%) GI Perforation GI Perforation Thromboembolism Thromboembolism VTE ATE VTE ATE Hypertension Hypertension Patients (%) GI Perforation GI Perforation Thromboembolism Thromboembolism VTE ATE VTE ATE Hypertension Hypertension Nintedanib + docetaxel Placebo + docetaxel ATE = arterial thromboembolism; GI = gastrointestinal; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor; VTE = venous thromboembolism Reck M, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8100 and poster); Boehringer Ingelheim data on file.

34 Addition of Nintedanib to Docetaxel Did Not Further Compromise Patient s Self-Reported Quality of Life 34 EORTC QLQ-C30 and QLQ-LC13 Prespecified Symptoms of Interest P value Cough (QLQ-LC13) NS Dyspnoea (QLQ-LC13) NS Dyspnoea at rest NS Dyspnoea after walking NS Dyspnoea after climbing stairs NS Short of breath (QLQ-C30) NS Pain (QLQ-C30) NS Have pain Pain affecting daily activities NS Pain in chest (QLQ-LC13) Pain in arm and shoulder (QLQ-LC13) Pain in other parts (QLQ-LC13) NS Global health status/qol NS Favours nintedanib Difference in mean score Favours placebo EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire-core 30; EORTC QLQ-LC13; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire and Lung Cancer-13; NS = non-significant; QoL = Quality-of-life. Novello S, et al. Eur J Cancer. 2014:DOI: /j.ejca

35 Summary of LUME-Lung 1 Results 35 LUME-Lung 1 met its primary endpoint and demonstrated: Significant prolongation of PFS regardless of histology Median PFS 3.4 vs 2.7 months, HR=0.79 (95% CI: ), P= Significant improvement in OS in patients with adenocarcinoma Median OS 12.6 vs 10.3 months, HR=0.83 (95% CI: ), P= Manageable safety profile Commonly reported AEs included gastrointestinal events and reversible liver enzyme elevations No compromise to patients self-reported QoL HR = hazard ratio; OS = overall survival; PFS = progression-free survival; QoL = quality of life. Reck M, et al. Lancet Oncol. 2014;15: ; Novello S, et al. Eur J Cancer. 2014:DOI: /j.ejca

36 LUME-Lung 2 Study Design 36 Stage IIIB/IV or recurrent NSCLC Failed 1stline chemotherapy Non-squamous histology only n=713 R 1:1 BIBF mg twice daily p.o., D2 21, + pemetrexed 500 mg/m 2 i.v., D1, in 21-day cycles (n=353) Placebo 200 mg twice daily p.o., D2 21, + pemetrexed 500 mg/m 2 i.v., D1, in 21-day cycles (n=360) PD PD Number of pemetrexed cycles not restricted Monotherapy allowed after 4 cycles of combination therapy Stratification: ECOG PS (0 vs 1) Prior bevacizumab (yes vs no) Histology (adeno vs non-adeno) Brain metastases (yes vs no) 1 endpoint: PFS (independent central review) 2 endpoints: OS, PFS (investigator assessment), ORR, safety Hanna NH, et al. J Clin Oncol. 2013;31(Suppl.):Abstract 8034 and poster presentation.

37 LUME-Lung 2: Progression-free Survival 37 Estimated patients alive and progression-free (%) 100 Central independent review after 498 events BIBF pemetrexed (n=353) Placebo + pemetrexed (n=360) Events, n (%) 239 (67.7) 259 (71.9) Median PFS, months Stratified analysis HR (95% CI)* 0.83 ( ) Log-rank P value* Patients at risk Placebo BIBF Time from randomization (months) *Includes patients entered after June 18, 2011 (all events up to July 9, 2012). Hanna NH, et al. J Clin Oncol. 2013;31(suppl):Abstract 8034 and poster presentation.

38 LUME-Lung 2: Summary 38 The primary endpoint of LUME-Lung 2 was met even though the study was stopped prematurely Acceptable and manageable safety profile No new or unexpected safety findings Reversible liver elevations Mild-to-moderate gastrointestinal side effects Patients treated with BIBF pemetrexed: Significant prolongation of centrally reviewed PFS Significant increase in disease control rate There was no improvement in OS in BIBF pemetrexed-treated patients Hanna NH, et al. J Clin Oncol. 2013;31(Suppl.):Abstract 8034 and poster presentation.

39 Getting Close EMA submission in 2013 and CUP started

40 Data Package Submitted

41 Nintedanib NPU/CUP Summary Patient Status: 1157 Patients OPU Brazil: Brazil (-) OPU Argentina & South America: Argentina (8) Chile (-) Colombia (-) Peru (-) Venezuela (-) OPU Mexico and Central America: Costa Rica (-) Dominican Rep. (-) El Salvador (-) Guatemala (-) Honduras (-) Mexico (187) Nicaragua (-) Panamá (-) Australia (20) Hong Kong (13) India (-) South Korea (41) Malaysia (-) Philippines (-) Singapore (-) Taiwan (-) Thailand (-) Austria (19) Belgium (20) - CUP* Belgium (47) - MNP* Cyprus (-) Czech Republic (9) Denmark (11) Estonia (1) Finland (1) France (-) Germany (114) Greece (-) Ireland (3) Israel (53) Italy (63) Luxembourg (1) Norway (-) Portugal (-) Slovakia (22) Slovenia (7) Spain (324) Sweden (33) Switzerland (59) The Netherlands (8) Turkey (6) United Kingdom (87) *CUP = Compassionate Use Program *MNP = Medical Need Program 41 activated deactivated planned ended not participating

42 Our goal is reached: approval EMA approval in 2014

43 Approval by EMA Received on November 21, VARGATEF (nintedanib) 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 first-line chemotherapy Brussels, November 21 st 2014 Vargatef (nintedanib) Summary of Product Characteristics. Boehringer Ingelheim.

44 Outlook: how to continue the path Other indications to follow

45 Nintedanib Biomarker NIS in Advanced Lung Adenocarcinoma BioNIS 45 Initiating soon Inclusion Eligible for nintedanib plus docetaxel, according to label Consent to provide sample of archived tumour tissue, and one blood sample or buccal swab if collected N=300 Nintedanib 200 mg BID + Docetaxel* *75 mg/m 2 IV, on Day 1 of every 3-week cycle -Treatment according to label PD/AE Efficacy measurement: OS Study Objective: To examine whether there are genetic/genomic markers (alone or combined with clinical covariates) that can predict overall survival (OS) in patients with advanced adenocarcinoma eligible for treatment with nintedanib plus docetaxel according to the approved label. Archived tumour samples 100 Study Sites in Europe.

46 Nintedanib + Weekly Docetaxel - Phase I Study 46 Initiating soon Key inclusion criteria Stage IIIB/IV NSCLC of adenocarcinoma histology 1 prior treatment line 1 measurable target lesion ECOG PS 0 1 Key exclusion criteria Prior VEGFR inhibitors (except bevacizumab) or docetaxel Active brain metastases N=24-30 Nintedanib BID + Weekly Docetaxel * *35 mg/m 2 IV, on Day 1, 8, 15 of every 4-weeks Nintedanib +/- on days of chemotherapy PD/AE Primary Endpoint: MTD Secondary Endpoints: Safety, OR, DC, HRQoL 4 Study Sites: 2 in France, 2 in Germany.

47 Nintedanib in light of the new era of Checkpoint Inhibitors 47 Nintedanib adds to the armamentarium to treat NSLC adenocarcinoma patients Patients progressing after anti PD(L)1 treatment (either as PD or later relapse) Patients not suitable for anti PD(L)1 treatment (e.g. autoimmune disease) Patients without PD1 expression Early progressing patients with urgent need for immediate tumour stasis Nintedanib in combination with anti PD(L)1 treatment

48 Nintedanib showed activity in refractory phase I CRC patients 48 Number of CRC pts 28 Partial responses (RECIST) Nintedanib* 3.5% (n=1) DCE-MRI of a CRC patient with liver metastases treated with 250 mg bid of nintedanib Stable disease - at week 7 - at week 23 Time on treatment (median) 78% 22% 72 days PFS (days) Before treatment After 8 weeks DCE-MRI=dynamic contrast-enhanced magnetic resonance imaging. Ref: *BJC 2014, 14, 510 Mross et al.

49 LUME-Colon 1: Study Design 49 Patients with refractory CRC - After failure of standard chemotherapy and anti- VEGF, anti-egfr agents - Regorafenib-naϊve patients limilted to 70% R A N D O M I S E N=767 Nintedanib * 200 mg bid + BSC n=382 n=382 Placebo* 200 mg bid+ BSC PD PD Followup for OS; survival data collecte d every 90 days Stratification - Previous treatment with regorafenib (yes vs no) - Time from onset of metastatic disease until randomization in the trial (<24 months vs 24 months) - Region (Western Europe, North America and Australia; Asia; and rest of world) Co-primary endpoints - PFS by central review - OS Secondary endpoints - Objective response by central review - Disease control by central review *Administrated in 21 day courses until disease progression, undue toxicity, or withdrawn consent. bid = twice daily; BSC = best supported care; CRC = colorectal cancer; EGRF = epidermal growth factor receptor; OS = overall survival; PD = disease progression; PFS = progression-free survival; VEGF = vascular endothelial growth factor.

50 LUME-Colon 1 Location of Participating Sites 50

51 Nintedanib in Mesothelioma 51 Patients with unresectable MPM that meet eligibility criteria R A N D O M I S E N=86 Ratio: 1:1 Nintedanib: 200 mg bid + Pemetrexed/Cistplatin* n=43 n=43 Placebo: 200 mg bid + Pemetrexed/Cistplatin* Non-PD patients Non-PD patients Nintedanib Maintenance Placebo Maintenance PD PD *500 mg/m 2 / 75 mg/m 2 iv, every 21 days Maximum Treatment Duration 6 Cycles Primary endpoint: PFS Stratification for: Histology (epitheloid vs biphasic)

52 Gracias 52