until tumour progression until tumour progression

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Adenocarcinoma of the lung Stage IIIb/IV EGFR mutation (Del19 and/or L858R) in the tumour tissue No prior treatment for advanced/metastatic disease ECOG PS 0-1 1:1 randomisation N=319 gefitinib 250 mg once daily until tumour progression afatinib 40 mg oral once daily until tumour progression LUX-Lung 7 is a randomised, open-label, phase IIb trial of afatinib versus gefitinib as a first-line treatment of patients with EGFR M+ advanced adenocarcinoma of the lung. X Lung 7 Clinical Trial Median follow-up: 27.4 months

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Secondary endpoints included LUX Lung 7 Study Endpoints Primary endpoints Progression-free survival (PFS) by independent review Time to treatment failure (TTF): the time from randomisation to discontinuation for any reason, allowing continuation of treatment if physicians consider patients to be receiving clinical benefit Overall survival (OS) Secondary endpoints included Objective response rate (ORR) Time to and duration of response Duration of disease control Tumour shrinkage Health related quality of life (HRQoL), as reported by EQ-5D patient questionnaires

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Page 1: until tumour progression until tumour progression

• Adenocarcinoma of the lung • Stage IIIb/IV • EGFR mutation (Del19 and/or

L858R) in the tumour tissue • No prior treatment for

advanced/metastatic disease• ECOG PS 0-1

1:1 randomisation

N=319

gefitinib 250 mg once daily

until tumour progression

afatinib

40 mg oral once dailyuntil tumour progression

LUX-Lung 7 is a randomised, open-label, phase IIb trial of afatinib versus gefitinib as a first-line treatment of patients with EGFR M+ advanced adenocarcinoma of the lung.

LUX Lung 7 Clinical Trial

Median follow-up: 27.4 months

Page 2: until tumour progression until tumour progression

• Progression-free survival (PFS) by independent review

• Time to treatment failure (TTF): the time from randomisation to discontinuation for any reason, allowing continuation of treatment if physicians consider patients to be receiving clinical benefit

• Overall survival (OS)

• Objective response rate (ORR)

• Time to and duration of response

• Duration of disease control

• Tumour shrinkage

• Health related quality of life (HRQoL), as reported by EQ-5D patient questionnaires

Primary endpoints

Secondary endpoints included

LUX Lung 7 Study Endpoints

Page 3: until tumour progression until tumour progression

3

Recruitment: Dec 2011-Aug 2013

Germany 14

Spain 25

France 34

Norway 3

Sweden 14

UK 7

Ireland 9

China 48

Hong Kong 6

Taiwan 22

Korea 56

Singapore 27

Australia 19

Canada 31

LUX Lung 7: 64 sites in 14 countries

Page 4: until tumour progression until tumour progression

Afatinib160, N (%)

Gefitinib159, N (%)

Total319, N (%)

Age, median yrs (min-max) 63 (30-86) 63 (32-89) 63 (30-89)

GenderFemale 91 (56.9) 106 (66.7) 197(61.8)

Male 69 (43.1) 53 (33.3) 122 (38.2)

Race Asian 94 (58.8) 88 (55.3) 182 (57.1)

Non-Asian* 66 (41.2) 71 (44.7) 137 (42.9)

Brain mets 26 (16.3) 25 (15.7) 51 (16.0)

Never smoker 106 (66.3) 106 (66.7) 212 (66.5)

Baseline ECOG 0 51 (31.9) 47 (29.6) 98 (30.7)

1 109 (68.1) 112 (70.4) 221 (69.3)

NSCLC stage IIIB 8 (5.0) 3 (1.9) 11 (3.5)

IV 152 (95.0) 156 ( 98.1) 308 (96.6)

EGFR mutationDel19# 93 (58.1) 93 (58.4) 186 (58.3)

L858R 67 (41.9) 66 (41.6) 133 (41.7)

Patient demographics and characteristics were well balancedbetween the 2 treatment arms

Page 5: until tumour progression until tumour progression

LUX-LUNG 7

Efficacy

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6

Afatinib demonstrated a 27% reduction in relative risk of death or progression compared to gefitinib

Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

• Patients twice as likely to be alive and progression free at 2 years with afatinib vs gefitinib (18% vs 8%, respectively)

Progression-free survival by independent review (primary endpoint)

Estim

ated

PFS

pro

babi

lity

0.2

0.4

0.6

0.8

1.0

0.0

Time of progression free survival (months)

0 3 6 9 18 2112 15 24 42

Hazard ratio 0.73(95% CI, 0.57-0.95)P=0.0165

Afatinib® (n=160)Gefitinib (n=159)

18%vs 8%

Median (months)

11.010.9

27 30 33 36 39

27%vs 15%

Page 7: until tumour progression until tumour progression

7

Afatinib – PFS benefit consistent across subgroups,including EGFR mutation type

Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

Total 319 0.732 (0.566, 0.947)

EGFR mutation

L858R 133 0.708 (0.475, 1.055)

Del19 186 0.764 (0.549, 1.063)

Brain métastasés

Absent 268 0.739 (0.560, 0.976)

Present 51 0.764(0.405, 1.439)

Baseline ECOG score

0 98 0.892 (0.542, 1.469)

1 221 0.705 (0.524, 0.948)

Gender

Maie 122 0.876 (0.585, 1.312)

Female 197 0.653 (0.469, 0.910)

Age group

<65 years 177 0.681 (0.479, 0.968)

>65 years 142 0.845 (0.585, 1.221)

Race

Non-Asian 137 0.717 (0.487, 1.056)

Asian 182 0.756 (0.539, 1.060)

Smoking hïstory

Never smoked 212 0.801 (0.584, 1.097)

<15 pack years + stopped >1 year before 40 1.094 (0.559, 2.140)

Other current or ex-smokers 67 0.477 (0.270, 0.845)

Factors Hazard ratio (95% Cl)Number of patients

Favours afatinib Favours gefitinib1/4 1 4 161/16

Progression-free survival by independent review (primary endpoint) prespecified subgroups

Page 8: until tumour progression until tumour progression

8

Patients remained on treatment significantly longer with afatinib than with gefitinib

TTF is the time from randomisation to discontinuation for any reason, allowing continuation of treatment if physicians consider patients to be receiving clinical benefit

Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

• 27% significant reduction in relative risk of treatment failure vs gefitinib (P=0.0073)

• Overall survival data not yet mature

Estim

ated

pro

babi

lity

of b

eing

free

of

trea

tmen

t fai

lure

0.2

0.4

0.6

0.8

1.0

0.0

Time to treatment failure (months)

0 3 6 9 18 2112 15 24 42

Hazard ratio 0.73(95% CI, 0.58-0.92)P=0.0073

Afatinib® (n=160)Gefitinib (n=159)

Median (months)

13.711.5

27 30 33 36 39

Time to treatment failure (primary endpoint)

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9

Afatinib demonstrated significantly improved response rates vsgefitinib

• Improved objective response and disease control rates vs gefitinib (ORR: 70% vs 56%, P=0.0083; DCR: 91.3% vs 87.4%)

• Longer duration of response vs gefitinib (10.1 vs 8.4 months, respectively)

Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

Objective response by independent review (secondary endpoint)

P=0.0083

0%

20%

40%

60%

80%70%

56%

Obj

ectiv

e re

spon

se ra

te (%

)

Afatinib Gefitinib

Page 10: until tumour progression until tumour progression

Greater tumour shrinkage in all mutations with afatinib versus gefitinib

Based on maximum percentage decrease from baseline in the sum of target lesion diameters.Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

All mutationsTumour shrinkage by independent review (secondary endpoint)

-100

-80

-60

-40

-20

0

20

40

Max

imum

dec

reas

e fr

om b

asel

ine

(%)

Afatinib

Gefitinib

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Greater tumour shrinkage in Del19 mutation patients with afatinib versus gefitinib

Based on maximum percentage decrease from baseline in the sum of target lesion diameters.Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

Del19 mutationsTumour shrinkage by independent review (secondary endpoint)

-100

-80

-60

-40

-20

0

20

40

Max

imum

dec

reas

e fr

om b

asel

ine

(%)

-100

-80

-60

-40

-20

0

20

40

Max

imum

dec

reas

e fr

om b

asel

ine

(%)

Afatinib Gefitinib

≥20% increase

≥0 - <20% increase

>0 - <30% decrease

≥30 - <50% decrease

≥50% decrease

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12

Greater tumour shrinkage in L858R mutation patients with afatinib versus gefitinib

Based on maximum percentage decrease from baseline in the sum of target lesion diameters.Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

L858R mutationsTumour shrinkage by independent review (secondary endpoint)

-100

-80

-60

-40

-20

0

20

40

Max

imum

dec

reas

e fr

om b

asel

ine

(%)

Afatinib Gefitinib

≥20% increase

≥0 - <20% increase

>0 - <30% decrease

≥30 - <50% decrease

≥50% decrease

-100

-80

-60

-40

-20

0

20

40

Max

imum

dec

reas

e fr

om b

asel

ine

(%)

Page 13: until tumour progression until tumour progression

LUX-LUNG 7

Adverse events

13

Page 14: until tumour progression until tumour progression

14

• Equally low rates of AE-related discontinuation (6.3% vs 6.3%) with differing causes; skin-related, diarrhoea and fatigue for GIOTRIF®, liver enzyme elevation and ILD for gefitinib

• The most common AEs were predictable and generally manageable through supportivecare and dose reduction

Pattern of AEs consistent with the known profiles ofboth agents

AE=adverse event; ILD=interstitial lung disease.Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

AE-related discontinuation

0%

5%

10%

15%

Obj

ectiv

e re

spon

se ra

te (%

)

Afatinib Gefitinib

6.3% 6.3%

Page 15: until tumour progression until tumour progression

15

Pattern of AEs consistent with the known profiles ofboth agents

ALT=alanine aminotransferase; AST=aspartate transaminase; ILD=interstitial lung disease.Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.

*Preferred terms of AEs.4 cases of ILD with gefitinib, 3 of them ≥ grade 3, no case of ILD with GIOTRIFR. 1 case of grade 4 diarrhoea with GIOTRIF®,1 case of grade 4 ALT with gefitinib.

Related Aes occuringin >10% patients, n(%)

Afatinib Gefitinib

All Grades Grade 3 All Grades Grade 3

Diarrhoea 144 (90.0) 19 (11.9) 97 (61.0) 2 (1.3)

Rash/Acne* 142 (88.8) 15 (9.4) 129 (81.1) 5 (3.1)

Stomatitis* 103 (64.4) 7 (4.4) 38 (23.9)

Paronychia* 89 (55.6) 3 (1.9) 27 (17.0) 1 (0.6)

Dry skin 52 (32.5) 59 (37.1)

Pruritus 37 (23.1) 36 (22.6)

Fatigue* 33 (20.6) 9 (5.6) 23 (14.5)

Decreased appetite 26 (16.3) 1 (0.6) 19 (11.9)

Nausea 26 (16.3) 2 (1.3) 22 (13.8)

Alopecia 17 (10.6) 24 (15.1)

Vomiting 17 (10.6) 6 (3.8) 1 (0.6)

ALT increase 15 (9.4) 38 (23.9) 12 (7.5)

AST increase 10 (6.3) 33 (20.8) 4 (2.5)