the story of bibf1120 – nintedanib – vargatef...1 the story of bibf1120 – nintedanib –...

1

The Story ofBIBF1120 – Nintedanib – Vargatef®

To be told by Rolf Kaiser & Claudia-Nanette Gann

2

The Story Started in 1971

Folkman J. New Eng J Med 1971;285:1182–1186.

3

Allows tumour cells to escape into the circulation, leading to metastases2,3

Promotes and sustains tumour growth2,3

Supplies the tumour with oxygen and nutrients1

1. Bergers G, et al. Nat Rev Cancer. 2003;3:401-410. 2. Folkman J. N Engl J Med. 1995;333:1757-1763.3. Ellis LM, et al. Nat Rev Cancer. 2008;8:579-591.

What Role Does Angiogenesis Play in Cancer?

4

Tumour Angiogenesis Is a Complex Process

VEGF = vascular endothelial growth factor; FGF = fibroblast growth factor; PDGF = platelet-derived growth factor.

5

BI Accepts the Challenge

6

… but it was still a long way to go

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

PHASE II

Thendiscovery of BIBF 1120;

Patent in2000

EMAsubmission

in 2013and CUPstarted

EMA approval in 2014

Other indications to follow

PHASE IIIPHASE I

Discovery of BIBF

1000

7

Once upon a time …

Thendiscovery of BIBF 1120;

Patent in2000

Discovery of BIBF

1000

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

STOP

8

BIBF 1120 – Triple Angiokinase Inhibition

Triple angiokinaseprofile

VEGFR1 / 2 / 3

PDGFRα / β

FGFR1 / 2 / 3

IC50 [nM] 34 / 21 / 13 59 / 65 69 / 37 / 108

IGF1R, InsR EGFR, HER2, CDK1, CDK2, CDK4

IC50 [nM] >1000, <10,000 >50,000

Additionallytargeted kinases

Flt-3 Ret Src, Lck, Lyn

IC50 [nM] 26 35 156 / 16 / 195

Hilberg F, et al. Cancer Res. 2008;68:4774-4782.

9

Nintedanib and Its Mode of Action

BIBF 1120

BIBF 1120BIBF 1120


10

Nintedanib Metabolisation Via the Esterase/UGT1A1 Pathway

UGT1A1,7,8,10

m1m/z 526.2454

m2m/z 702.2775

BIBF 1202 BIBF 1202-G

m0m/z 540.2611

BIBF 1120

Esterase


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

11

Next steps

PHASE IIPHASE I

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

12

Nintedanib Phase I

• Recommended dose1–5

– 200 mg orally twice daily in combination with chemotherapy• Safety6

– Generally well tolerated– Reversible liver enzyme elevations – Gastrointestinal side effects mostly mild and manageable

• First efficacy signals in Phase I7,8

– Monotherapy One CR and four PRs (CRC and RCC) Disease stabilisation in ≈30%

– Combination therapy Indicating additive effect of BIBF 1120

1. du Bois A. Ann Oncol. 2010;21:370-375; 2. Doebele RC, et al. Ann Oncol. 2012;23:2094-2102; 3. Ellis PM, et al. Clin Cancer Res. 2010;16:2881-2889; 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;16:311-319; 7. Lee C-P, et al. J Clin Oncol. 2006;24(S18). Abstract 3015; 8. Boehringer Ingelheim. Date on file.

13

Nintedanib: Phase II (1199.10)A double-blind, dose-ranging, randomised study in patients with advanced NSCLC

Primary end points: PFS; ORR

Continuous daily treatment

Randomisation, n=73

2 ×250 mgn=36

2 ×150 mgn=37

2 ×150 mg 2 ×100 mg

DLT DLT

Patients with:• NSCLC stage IIIb/IV• Recurrent disease after previous platinum-based therapy

Phase II Data in NSCLC Study Design

Reck M, et al. Ann Oncol. 2011;22:1374-1381.

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All Patientsn=73

ECOG PS 0–1n=56

Median PFS 6.9 weeks 11.6 weeks

Median OS 21.9 weeks 37.7 weeks

Disease stabilisation rate 46% 59%One confirmed PR @ 250 mg

Phase II Results in NSCLC Leading to Start of Phase III Trials LUME-Lung 1 & 2

• 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;22:1374-1381.

15

Crucial step forward

PHASE III

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

16

LUME-Lung 1: Randomised Controlled Phase III Study

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 AfricaAccrual: 23 Dec 2008 to 09 Feb 2011

Nintedanib 200 mg BID po, Days 2–21+ docetaxel 75 mg/m2 IV, Day 1,

21-day cycles (n=655)

Placebo BID po, Days 2–21,+ docetaxel 75 mg/m2 IV, Day 1,

21-day cycles (n=659)

N=1314

RANDOMISE

1:1

PD

PD

Number of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy

Stage IIIB/IV*or recurrent

NSCLC patients after first-line chemotherapy

(all histologies)

*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;15:143-155.

17

LUME-Lung 1 Statistical Methodology

Primary endpoint Key secondary endpoint

Independently assessed PFS

ITT/all histologiesOS

Adenocarcinoma Time since start of

first-line therapy <9 mo

OSAll adenocarcinoma

OSITT/all histologies

Significant finding

Significant finding

• An exploratory analysis of LUME-Lung 2 data showed evidence for enhanced survival benefit in early progressing adenocarcinoma tumours1,2

• 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 rate3

Significant finding

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 P388.2013; 3. Reck M, et al. Lancet Oncol. 2014;15:143-55.

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Demographics and Baseline Characteristics Were Balanced Between the Treatment Arms

18

73 7075

71

8290

6

97

4

4942

9

7368

7671

81

92

6

98

4

51

42

7

0

10

20

30

40

50

60

70

80

90

100

Patie

nts

(%)

Nintedanib + docetaxel (n=655)Placebo + docetaxel (n=659)

All Patients (N=1314)

ECOG PS = Eastern Cooperative Oncology Group performance status.Reck M, et al. Lancet Oncol. 2014;15:143-155.

19

Primary Endpoint PFS by Independent Central Review, All Patients

LUME-Lung 1 Met Its Primary Endpoint with Significant Improvement in Progression-Free Survival in All Patients

CI = confidence interval; HR = hazard ratio; PFS = progression-free survival.Reck M, et al. Lancet Oncol. 2014;15:143-155.

565 295 155 57 19 4 3 1 0569 250 116 43 21 2 1 0 0

NintedanibPlacebo

No. at risk

100

80

60

40

20Prob

abili

ty o

f PFS

(%)

0

Time (months)

02 4 6 8 10 12 14 16 18

Nintedanib+ docetaxel

Placebo + docetaxel

Median PFS (months) 3.4 2.7

HR = 0.79 (95% CI: 0.68–0.92); P=0.0019

20

Consistent Progression-Free Survival BenefitRegardless of Histology

CI = confidence interval; HR = hazard ratio; PFS = progression-free survival.Reck M, et al. Lancet Oncol. 2014;15:143-155; Reck M, et al. J Clin Oncol.2013;31(Suppl.):Abstract LBA8011 and oral presentation.

PFS by Histology, Independent Central Review

Nintedanib + docetaxel

Placebo + docetaxel


HR = 0.77 (95% CI: 0.62–0.96); P=0.0193


Placebo + docetaxel


0.77 (95% CI: 0.62–0.96); P=0.0200

Adenocarcinoma100

80

60

40

20Prob

abili

ty o

f PFS

(%)

0

Time (months)

0

2 4 6 8 10 12 14 16

NintedanibPlacebo

No. at risk277 150 86 32 13 1 1 0285 129 70 28 12 1 1 0

NintedanibPlacebo

No. at risk

Squamous cell carcinoma100

80

60

40

20Prob

abili

ty o

f PFS

(%)

0

Time (months)

0

2 4 6 8 10 12 14 16

240 122 59 22 5 3 2 1247 101 36 13 8 1 0 0

00

21

Overall Survival in Patients with Adenocarcinoma Who Progressed in <9 Months After Start of First-Line Therapy

CR = complete response; HR = hazard ratio; OS = overall survival.Reck M, et al. Lancet Oncol. 2014;15:143-155; Boehringer Ingelheim data on file.

Key Secondary Endpoint, Pre-specified Hierarchical Analysis

206 167 119 92 73 51 35 16 9199 154 91 62 42 25 17 12 5

NintedanibPlacebo

No. at risk31

100

80

60

40

20Prob

abili

ty o

f sur

viva

l (%

)

0

Time (months)

0

4 8 12 16 20 24 28 32 36


Placebo + docetaxel

Median OS (months) 10.9 7.9

HR = 0.75 (95% CI: 0.60–0.92); P=0.0073

46.8%

34.3% 20.7%

1-YEAR SURVIVAL

2-YEAR SURVIVAL

10.4%

22

Significant Improvement in Median Overall Survival in Patients With Adenocarcinoma

CI = confidence interval; HR = hazard ratio; OS = overall survival.Reck M, et al. Lancet Oncol. 2014;15:143-155.


322 263 203 163 131 96 72 46 25336 269 184 139 101 73 55 33 15

NintedanibPlacebo

No. at risk107


Placebo + docetaxel


HR 0.83 (95% CI: 0.70–0.99); P=0.0359

100

80

60

40

20Prob

abili

ty o

f sur

viva

l (%

)

0

Time (months)

0

4 8 12 16 20 24 28 32 36

52.7%

44.7%25.7%

1-YEAR SURVIVAL

2-YEAR SURVIVAL

19.1%

23

No Significant Difference in Overall Survival in All Patients


CI = confidence interval; HR = hazard ratio; OS = overall survival.Reck M, et al. Lancet Oncol. 2014;15:143-155.

655 516 374 271 200 147 106 67 34659 511 344 250 162 120 91 58 28

NintedanibPlacebo

No. at risk1413


Placebo + docetaxel


HR = 0.94 (95% CI: 0.83–1.05); P=0.2720

100

80

60

40

20Prob

abili

ty o

f sur

viva

l (%

)

0

Time (months)

0

4 8 12 16 20 24 28 32 36

24

Consistent Overall Survival Benefit Across Most Subgroups of Patients with Adenocarcinoma Histology

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 diseaseReck M, et al. Lancet Oncol. 2014;15:143-155.

OS in Subgroups, Patients with Adenocarcinoma

HR (95% CI)

CharacteristicOverallSex Female

MaleAge class <65 years

≥65 yearsEthnic origin Asian

Non-AsianSmoking status Current smoker/ex-smoker

Never-smokerECOG PS 0

1Brain metastases No

YesPrior bevacizumab No

YesTime since start of first-line <9 months

≥9 monthsBest response to first-line CR/PR/SD

PD

Favours nintedanib Favours placebo

0.4 0.5 1.0 2.0 2.5

25

Overall Survival in Patients with Adenocarcinoma and No Response to First-Line Chemotherapy

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.

Adenocarcinoma and PD as Best Response to First-Line Chemotherapy100

80

60

40

20Prob

abili

ty o

f sur

viva

l (%

)

0

Time (months)

0

4 8 12 16 20 24 28 32 36

53 44 27 22 18 13 10 7 464 51 24 14 11 7 3 2 2

NintedanibPlacebo

No. at risk21


Placebo + docetaxel


HR = 0.62 (95% CI: 0.41–0.94); P=0.0246

43.0%

24.6%21.5%

1-YEAR SURVIVAL

2-YEAR SURVIVAL

5.3%

26

Inverse Relationship Between Hazard Ratio for Overall Survival and Time Since Start of First-Line Therapy

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.

Final OS Analysis in Patients with Adenocarcinoma

4.000

2.000

1.000

0.500

HR

(95%

CI)

0

Time since start of first-line therapy (months)

0.250

5 10 15 20 25

27

Extending survival in early progressing patients

Reck M, et al. Lancet Oncol. 2014;15:143-155

28

Consistent Trend Towards Survival Benefit Regardless of Prior Treatment in Patients With Adenocarcinoma

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.

Overall Survival by Prior First-line Chemotherapy

NintedanibPlacebo

No. at risk

Prob

abili

ty o

f sur

viva

l (%

)

Prior taxane treatment100

80

60

40

20

0

Time (months)

04 8 12 16 20 24 3628 32

77 66 55 44 34 28 23 41665 53 40 30 21 16 11 18

82

Prior pemetrexed treatment100

80

60

40

20

0

Time (months)

04 8 12 16 20 24 3628 32

61 48 37 30 24 17 14 0762 65 49 31 25 18 13 112

25

Prior bevacizumab treatment100

80

60

40

20

0

Time (months)

04 8 12 16 20 24 3628 32

24 20 15 14 11 8 7 2621 15 12 7 6 4 4 02

41


Placebo + docetaxel


HR = 0.75 (95% CI: 0.51–1.11)


Placebo + docetaxel


HR = 0.79 (95% CI: 0.53–1.18)


Placebo + docetaxel


HR = 0.61 (95% CI: 0.31–1.20)

29

Significant Improvement in Disease Control Rate

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;15:143-155.

Independent Central Review at the Time of Final OS Analysis

n (%)

Adenocarcinoma All patientsNintedanib +

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 0 0 1 (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<0.0001 1.68; P<0.0001

Progressive Disease 87 (27.0) 147 (43.8) 200 (30.5) 298 (45.2)

30

Nintedanib + Docetaxel Safety Profile: All Grades Adverse Events

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;15:143-155. Suppl; Boehringer Ingelheim data on file.

All Grade AEs in ≥10% of Patients with Adenocarcinoma

4341

38

31 3028 28

23

19 19 18 17 1714 13 12

11 117

25

41

9

29

7

18

28

1612

17

20

16

11

1519

14

8

1412

0

10

20

30

40

50

Patie

nts

(%)


Placebo + docetaxel

31

The Majority of Grade ≥3 AEs Occurred at Similar Rates Between Treatment Arms

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;15:143-155. Suppl; Boehringer Ingelheim data on file.

Grade ≥3 AEs in Patients with Adenocarcinoma*

36.3

19.7

11.9 11.6

6.34.7 4.7 4.1 3.1

1.3 1.3 1.3 0.9 0.9 0.9 0.6 0.3 0.0

34.8

18.3

13.5

0.93.6

6.04.2

0.6 0.9 1.5 0.6 0.32.1

0.6 0.6 0.3 0.0 0.30

10

20

30

40

50

Patie

nts

(%)


Placebo + docetaxel

32

The Most Commonly Reported Adverse Events Were Gastrointestinal Events and Liver Enzyme Elevations

– 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;15:143-155.

33

Adverse Events Commonly Associated with VEGF/VEGFR Inhibitors

ATE = arterial thromboembolism; GI = gastrointestinal; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor; VTE = venous thromboembolismReck M, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8100 and poster); Boehringer Ingelheim data on file.

3.4

1.0

2.8

5.3

0.3

10.9

0.6

2.0

1.2

5.4

0.3

11.1

0 5 10 15

Hypertension

ATE

VTE

Thromboembolism

GI Perforation

Bleeding

Adverse Events of Special Interest in Patients with Adenocarcinoma

All grades (%) Grade ≥3 (%)

Patie

nts

(%)

0.3

1.0

0.9

2.5

0.3

1.3

0.3

1.0

0.6

3.3

0.3

1.5

0 5 10 15

Hypertension

ATE

VTE

Thromboembolism

GI Perforation

Bleeding

Patie

nts

(%)

Nintedanib + docetaxel Placebo + docetaxel

Bleeding

GI Perforation

Thromboembolism

VTE

ATE

Hypertension

Bleeding

GI Perforation

Thromboembolism

VTE

ATE

Hypertension

Grade ≥3 (%)

34

Addition of Nintedanib to Docetaxel Did Not Further Compromise Patient’s Self-Reported Quality of Life

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: 10.1016/j.ejca.2014.11.015.

EORTC QLQ-C30 and QLQ-LC13 Prespecified Symptoms of Interest

Difference in mean score

P valueCough (QLQ-LC13) NSDyspnoea (QLQ-LC13) NS

Dyspnoea at rest NSDyspnoea after walking NSDyspnoea after climbing stairs NS

Short of breath (QLQ-C30) NSPain (QLQ-C30) NS

Have pain 0.0332Pain affecting daily activities NS

Pain in chest (QLQ-LC13) 0.0196Pain in arm and shoulder (QLQ-LC13) 0.0004Pain in other parts (QLQ-LC13) NS

Global health status/QOL NS

Favours nintedanib

-10 -5 0 5

Favours placebo

35

Summary of LUME-Lung 1 Results

• 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: 0.68–

0.92), P=0.0019– Significant improvement in OS in patients with

adenocarcinoma Median OS 12.6 vs 10.3 months, HR=0.83 (95% CI: 0.70–

0.99), P=0.0359– 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;15:143-155; Novello S, et al. Eur J Cancer.2014:DOI: 10.1016/j.ejca.2014.11.015.

36

LUME-Lung 2 Study Design

n=713

Stratification: ECOG PS (0 vs 1)Prior bevacizumab (yes vs no)Histology (adeno vs non-adeno)Brain metastases (yes vs no)

Stage IIIB/IV or recurrent NSCLC Failed 1stline

chemotherapy Non-squamous

histology only

1:1R

BIBF 1120 200 mg twice daily p.o., D2–21, + pemetrexed 500 mg/m2 i.v., D1, in 21-day cycles

(n=353)PD

Placebo 200 mg twice daily p.o., D2–21, + pemetrexed 500 mg/m2 i.v., D1, in 21-day cycles

(n=360)PD

Hanna NH, et al. J Clin Oncol. 2013;31(Suppl.):Abstract 8034 and poster presentation.

1◦ endpoint: PFS (independent central review)2◦ endpoints: OS, PFS (investigator assessment), ORR, safety

Number of pemetrexed cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy

37

LUME-Lung 2: Progression-free Survival

*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.

Central independent review after 498 events100

80

60

40

20

00 2 4 6 8 10 12 14 16 18 20 22 24 26

Estim

ated

pat

ient

s al

ive

and

prog

ress

ion-

free

(%)

Time from randomization (months)

360311 210 160 137 110 85 64 59 49 39 36 31 24 19 17 15 12 11 9 8 7 6 6 4 4 3353316 229 174 156 126 101 87 74 56 46 37 30 21 16 16 13 11 9 9 8 5 4 3 3 2 2

PlaceboBIBF 1120

Patients at risk

BIBF 1120 + pemetrexed (n=353)

239 (67.7) 259 (71.9)Events, n (%)

0.83 (0.70–0.99)

Placebo + pemetrexed (n=360)

4.4 3.6Median PFS, months

Stratified analysisHR (95% CI)*

Log-rank P value* 0.0435

37

38

LUME-Lung 2: Summary

• 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 1120 + pemetrexed:– Significant prolongation of centrally reviewed PFS– Significant increase in disease control rate

• There was no improvement in OS in BIBF 1120 + pemetrexed-treated patients

Hanna NH, et al. J Clin Oncol. 2013;31(Suppl.):Abstract 8034 and poster presentation.

39

… Getting Close

EMAsubmission

in 2013and CUPstarted

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

40

Data Package Submitted 30.09.2013

41

1199.55 - Nintedanib NPU/CUP SummaryPatient Status: 1157 Patients

41

195

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)

888

Australia (20)Hong Kong (13)India (-)South Korea (41)Malaysia (-) Philippines (-)Singapore (-)Taiwan (-)Thailand (-)

74

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 (-)

2015-10-01

*CUP = Compassionate Use Program*MNP = Medical Need Program

activated planned

not participatingdeactivated

ended

42

Our goal is reached: approval

EMA approval in 2014

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

43

Approval by EMA Received on November 21, 2014

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

Vargatef® (nintedanib) Summary of Product Characteristics. Boehringer Ingelheim.

Brussels, November 21st 2014

44

Outlook: how to continue the path

Other indications to follow

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

45

Nintedanib Biomarker NIS in Advanced Lung Adenocarcinoma BioNIS

• Initiating soon

*75 mg/m2 IV, on Day 1 of every 3-week cycle-Treatment according to label

N=300

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.

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

PD/AENintedanib 200 mg BID + Docetaxel*

100 Study Sites in Europe.

• Archived tumour samples

46

Nintedanib + Weekly Docetaxel - Phase I Study

Initiating soon

*35 mg/m2 IV, on Day 1, 8, 15 of every 4-weeks

Nintedanib +/- on days of chemotherapy

PD/AEN=24-30

Nintedanib BID + Weekly Docetaxel *

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

Primary Endpoint: MTDSecondary 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

• 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

Nintedanib adds to the

armamentarium to treat NSLC

adenocarcinoma patients

48

Nintedanib*

Number of CRC pts 28

Partial responses(RECIST)

3.5% (n=1)

Stable disease- at week 7- at week 23

78%22%

Time on treatment (median)

72 days

PFS (days)

Ref: *BJC 2014, 14, 510 Mross et al.

Before treatment After 8 weeks

DCE-MRI of a CRC patient withliver metastases treated with 250

mg bid of nintedanib

DCE-MRI=dynamic contrast-enhanced magnetic resonance imaging.

Nintedanib showed activity in refractory phase I CRC patients

49

LUME-Colon 1: Study Design

*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.

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)

Nintedanib *200 mg bid + BSC

Placebo*200 mg bid+ BSC

RANDOMISE

PDPatients with refractory CRC- After failure of standard

chemotherapy and anti-VEGF, anti-EGFR agents

- Regorafenib-naϊve patients limilted to ≤70% PD

n=382

n=382

Follow-up for OS;

survival data

collected every 90 days

Co-primary endpoints- PFS by central review- OSSecondary endpoints- Objective response by central review- Disease control by central review

N=767

50

LUME-Colon 1 – Location of Participating Sites

51

Nintedanib in Mesothelioma

Nintedanib: 200 mg bid + Pemetrexed/Cistplatin*

Placebo: 200 mg bid+ Pemetrexed/Cistplatin*

RANDOMISE

PD

*500 mg/m2 / 75 mg/m 2 iv, every 21 daysMaximum Treatment Duration 6 Cycles

Patients with unresectable

MPM that meet eligibility criteria PD

n=43

n=43

Primary endpoint: PFS

Stratification for: Histology (epitheloid vs biphasic)

N=86Ratio: 1:1

Non-PD

patients

Nintedanib

Maintenance

Non-PD

patients

Placebo

Maintenance

52

Gracias

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