1 sitemap storyflow title slideoverview slide13.6 months pfssymptom controlqol os across 7 trials3...

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Title slide Overview slide 13.6 months PFS Symptom control QoL

OS across 7 trials 3 months OS > 12 month OS Summary slide

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Title slide Overview slide 13.6 months PFS Symptom control QoL

OS across 7 trials 3 months OS > 12 month OS Summary slide

PFS comparison

Subsequent therapy OS Forest Plot Del 19 OS Forest Plot L858R PFS Forest Plot L858R

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GIOTRIF® (afatinib) as monotherapy is indicated for the treatment of Epidermal Growth Factor Receptor (EGFR) TKI- naïve adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation(s).* Secondary endpoint, primary endpoint was PFS; combined post-hoc analysis of common EGFR mutations (del19/L858R) vs chemotherapy (LUX-lung 3 vs pemetrexed/cisplatin and LUX-Lung 6 vs gemcitabine/cisplatin).EGFR M+=epidermal growth factor receptor mutation positive; NSCLC=non-small cell lung cancer; OS=overall survival.1.Yang JC et al. ASCO oral presentation and abstract. J Clin Oncol 32:5s, 2014 (suppl; abstr 8004^).

GIOTRIF® - First targeted therapy to show significant first-line OS benefit in EGFR M+ NSCLC*1

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GIOTRIF® – First approved irreversible ErbB Family Blocker1

* vs pemetrexed/cisplatin in prespecified subgroup of patients with common mutations (del19/L858R); ** Secondary endpoint, primary endpoint was PFS; combined post-hoc analysis of common EGFR mutations (del19/L858R) vs chemotherapy (LUX-lung 3 vs pemetrexed/cisplatin and LUX-Lung 6 vs gemcitabine/cisplatin). † vs pemetrexed/cisplatin.PFS=progression-free survival; QoL=quality of life.1.Solca F et al. J Pharmacol Exp Ther. 2012;343(2):342-350.2.Sequist LV et al. J Clin Oncol. 2013;31(27):3327-3334.3.Yang JC et al. ASCO oral presentation and abstract. J Clin Oncol 32:5s, 2014 (suppl; abstr 8004^).4.Yang JC et al. J Clin Oncol. 2013;31(27):3342-3350.

Clinically meaningfulSymptom

Improvement†4

Significant Overall Survival

benefit**3

Significantlybetter QoL†4

13.6 months PFS(del19/L858R)*2

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GIOTRIF® – First approved irreversible ErbB Family Blocker1

Clinically meaningfulSymptom Improvement

vs. pemetrexed/cisplatin†4

Significant Overall Survival benefit

vs. pemetrexed/cisplatin or gemcitabine/cisplatin **3

Significantly better QoLvs. pemetrexed/cisplatin†4

13.6 months PFSvs. pemetrexed/cisplatin(del19/L858R)*2


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Del9/L858R mutationsLUX-Lung 3 prespecified subgroup analysis

GIOTRIF® – Superior first-line PFS vs pemetrexed/cispatin in common mutations (del19/L858R)1

PFS=progression-free survival.1.Sequist LV et al. J Clin Oncol. 2013;31(27):3327-3334.

PF

S r

ate

(%)

0.2

0.4

0.6

0.8

1.0

0.0

Time (months)

0 3 6 9 18 2112 15 24 27

Hazard ratio 0.47(95% CI, 0.34-0.65)

P<0.001

GIOTRIF® (n=204)Pemetrexed/cisplatin (n=104)

13.6months

• ~90% of patients in LUX-Lung 3 had common mutations (del19/L858R)

6.9months

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GIOTRIF® – Longer PFS than reversible TKIs when indirectly compared

The data presented above come from separate studies with different designs and therefore results cannot be directly compared.* Common EGFR mutations (Del19/L858R); † Prespecified subgroup analysis (89% of patients); ‡ Common and uncommon muatations; PFS=progression-free survival; TKI=tyrosine kinase inhibitor.1.Sequist LV et al. J Clin Oncol. 2013;31(27):3327-3334.2.Rosell R et al. Lancet Oncol. 2012;13(3):239-46. 3.Mok TS et al. New Engl J Med 2009;361:947-957.

Med

ian

PF

S (

mon

ths)

Series10

2

4

6

8

10

12

14

LUX-Lung 31 EURTAC2 IPASS3

Cisplatin + Pemetrexed

Erlotinib Cisplatin/carboplatin + gemcitabine/

docetaxel

GIOTRIF® Gefitinib Carboplatin + Paclitaxel

13.6*†

6.9*†

5.2*

9.5‡

6.3‡

9.7*

PFS in first-line phase III registration trials in NSCLC

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GIOTRIF® – Delayed time to deterioration of clinically relevant symptoms1

TTD=time to deterioration.EORTC=European Organisation for Research and Treatment of Cancer.1.Yang JC et al. J Clin Oncol. 2013;31(27):3342-3350.

LUX-Lung 3: TTD of symptoms (EORTC QoL QLQ-C30 and QLQ LC-13)

Se-ries1

0 2 4 6 8 10 12 14 16

Cough

Dyspnoea

Pain

Median TTD (months)

p=0.007

p=0.015

p=0.19

8.0

2.9

3.1

10.3 months

4.2 months

Median not reached

GIOTRIF® (n=230)

Cis/Pem (n=115)

>97% questionnaire

completion

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GIOTRIF® –Significantly improved QoL vs pemetrexed/cisplatin1

Qo=quality of life.EORTC=European Organisation for Research and Treatment of Cancer.1. Yang JC et al. J Clin Oncol. 2013;31(27):3342-3350.

Global health status/QoL

Physical functioning

Role functioning

Cognitive functioning

Emotional functioning

Social functioning

Favours GIOTRIF® Favours pem/cis Significant difference favouring GIOTRIF®

Differences in mean scores (95% confidence intervals)

-10 -5 0 5

>97% questionnaire

completion

LUX-Lung 3: EORTC QLQ-C30 questionnaire scores longitudinal analysis

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No first-line OS benefit demonstrated with reversible EGFR TKIs

N/A=not applicable; NS=not significant; OS=overall survival; TKI=tyrosine kinase inhibitor.1.TARCEVA® (erlotinib) prescribing information, 2013.2.Fukuoka et al. J Clin Oncol. 2011;29:2866-74.3.Wu et al. J Thorac Oncol. 2013;8:suppl 2 (P1.11-021)4.Zhou et al. J Clin Oncol 30, 2012 (suppl; abstr 7520).5.Inoue et al. Ann Oncol. 2013;24:54-59.6.Yoshioka H, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8117).7.Han et al. J Clin Oncol. 2012;30:1122-8.

Trial Reversible EGFR TKI Registration trial Hazard ratio

Overall survival p value

EURTAC1 Erlotinib Yes 0.93 NS

IPASS2 Gefitinib Yes 1.0 NS

ENSURE3 Erlotinib No N/A NS

OPTIMAL4 Erlotinib No 1.04 NS

NEJ0025 Gefitinib No 0.89 NS

WJTOG34056 Gefitinib No 1.25 NS

FIRST-SIGNAL7 Gefitinib No 1.04 NS

First-line phase III trials with reversible EGFR TKIs

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Del19/L858R mutationsPost-hoc combined analysis (LUX-Lung 3 & 6)

GIOTRIF® – Significantly increased first-line OS vs chemotherapy*1

* Secondary endpoint, primary endpoint was PFS; combined post-hoc analysis of common EGFR mutations (Del19/L858R) vs chemotherapy (LUX-lung 3 vs pemetrexed/cisplatin and LUX-Lung 6 vs gemcitabine/cisplatin). ITT=intent to treat; OS=overall survival.1.Yang JC et al. ASCO oral presentation and abstract. J Clin Oncol 32:5s, 2014 (suppl; abstr 8004^).

Est

imat

ed O

S p

roba

bilit

y

0.2

0.4

0.6

0.8

1.0

0.0

Time of overall survival (months)

27.3months

Hazard ratio 0.81(95% CI, 0.66-0.99)

P=0.0374

GIOTRIF® (n=419)Chemotherapy (n=212)

24.3months

0 3 6 9 18 21 30 36 39 4512 15 24 27 33 42 48 51

+3monthsmedian OS

• The proportion of patients who received subsequent therapies was balanced in both arms

• OS in ITT population (N=345) was 28.16 and 28.22 months for GIOTRIF® vs pemetrexed/cisplatin, respectively (HR 0.88, 95% CI, 0.66-1.17;P=0.3850)

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GIOTRIF® – balanced subsequent therapy validates OS outcome1

TKI = tyrosine kinase inhibitor.1. Yang JC et al. ASCO oral presentation and abstract. J Clin Oncol 32:5s, 2014 (suppl; abstr 8004^).

Subsequent therapy in LUX-Lung 3 and 6

• The proportion of patients who received subsequent therapies was balanced in both arms

Trial

(% patients) with subsequent therapy

GIOTRIF® Pem/cis or gem/cis

LUX-Lung 3 71% chemo 75% EGFR TKI

LUX-Lung 6 59% chemo 56% EGFR TKI

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Del19 mutationsLUX-Lung 3 overall survival

GIOTRIF® – Pronounced OS benefit in del19 (exon 19) patients1

Est

imat

ed O

S p

roba

bilit

y

0.2

0.4

0.6

0.8

1.0

0.0


0 3 6 9 18 21 30 36 39 4512 15 24 27 33 42 48 51

33.3months

Hazard ratio 0.54(95% CI, 0.36-0.79)

P=0.0015


21.1months

OS=overall survival.1. Yang JC et al. ASCO oral presentation and abstract. J Clin Oncol 32:5s, 2014 (suppl; abstr 8004^).

• Over 1 year extended survival with GIOTRIF® vs pem/cis in del19 (exon 19) patients (P=0.0015)

• Over 1 year extended survival also demonstrated in LUX-Lung 6

>12months increase

median OS

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GIOTRIF® – First targeted therapy to offer del19 (exon 19) patients a significant OS benefit1-6

OS=overall survival; HR=hazard ratio.1.Yang JC et al. ASCO oral presentation and abstract. J Clin Oncol 32:5s, 2014 (suppl; abstr 8004^).2.Mok et al. N Engl J Med. 2009;361:947-57.3.Yang et al. Eur J of Cancer. 2011 (suppl1;S633).4.Rosell et al. Lancet Oncol. 2012;13:239-46.5.TARCEVA® (erlotinib) prescribing information

• ~50% of patients in LUX-Lung 3 and 6 had del19 mutations

Favours targeted therapy Favours chemotherapy

1/4 1 4 16

GIOTRIF®

EURTAC4,5Erlotinib 0.94 (0.57 – 1.54)

IPASS2,3Gefitinib 0.79 (0.54 – 1.15)

LUX-Lung 61 0.64 (0.44 – 0.94)

LUX-Lung 31 0.54 (0.36 – 0.79)

HR (95% CI)

OS in registration trials in del19 (exon 19) patients

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No OS benefit yet demonstrated by targeted therapies in L858R (exon 21) patients1-6

OS=overall survival; HR=hazard ratio.1.Yang JC et al. ASCO oral presentation and abstract. J Clin Oncol 32:5s, 2014 (suppl; abstr 8004^).2.Mok et al. N Engl J Med. 2009;361:947-57.3.Fukuoka et al. J Clin Oncol. 2011;29:2866-74.4.Yang et al. Eur J of Cancer. 2011 (suppl1;S633).5.Rosell et al. Lancet Oncol. 2012;13:239-46.6.TARCEVA® (erlotinib) prescribing information

• ~40% of patients in LUX-Lung 3 and 6 had L858R mutations


GIOTRIF®

EURTAC5,6Erlotinib

IPASS2-4Gefitinib

LUX-Lung 61

LUX-Lung 31

HR (95% CI)

OS in registration trials in L858R (exon 21) patients

1.30 (0.80 – 2.11)

1.22 (0.81 – 1.83)

1.44 (0.90 – 2.30)

0.99 (0.56 – 1.76)

1/4 1 4 16

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GIOTRIF® – Superior PFS vs chemotherapy in L858R (exon 21) patients

OS=overall survival, HR=hazard ratio.1.Sequist LV et al. J Clin Oncol. 2013;31(27):3327-3334.2.Wu YL et al. Lancet Oncol. 2014;15(2):213-22.3.Mok et al. N Engl J Med. 2009;361:947-57.4.Fukuoka et al. J Clin Oncol. 2011;29:2866-74.5.Rosell et al. Lancet Oncol. 2012;13:239-46.


GIOTRIF®

EURTAC5

Investigator reviewErlotinib

IPASS3,4

Investigator reviewGefitinib

LUX-Lung 62

Independent review

LUX-Lung 31

Investigator review

HR (95% CI)

PFS in registration trials in L858R (exon 21) patients

0.60 (0.39 – 0.93)

0.32 ( 0.19 – 0.52)

0.55 (0.35 – 0.87)

0.55 ( 0.29 – 1.02)

1/4 1 4 16

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Clinically meaningfulSymptom

Improvement†4

Significant Overall Survival

benefit**3

Significantlybetter QoL†4

13.6 months PFS(del19/L858R)*2

GIOTRIF® – Longer, better life for your patients*1,2


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Back-up

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Majority of patients in LUX-Lung 3 had del19 (exon 19) mutations

• Del19 (exon 19) and L858R (exon 21) mutations represent approximately 90% of EGFR mutations in NSCLC— Del19 mutations consist of in-frame deletions of amino acids 747-750

— L858R mutations are exon 21 point mutations

49%Del19 (exon 19)

40%L858R (exon 21)

11%uncommon

1. Sequist LV et al. J Clin Oncol. 2013;31(27):3327-3334.

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All EGFR mutationsLUX-Lung 3 PFS by independent review

GIOTRIF® - superior first-line PFS vs pemetrexed/cisplatin1

PFS=progression-free survival.1. Sequist LV et al. J Clin Oncol. 2013;31(27):3327-3334.

PF

S r

ate

(%)

0.2

0.4

0.6

0.8

1.0

0.0

11.1months

Hazard ratio 0.58(95% CI, 0.43-0.78)

P<0.001


6.9months

Time (months)

0 3 6 9 18 2112 15 24 27

At the time of primary analysis, a total of 45 (20%) patients treated with GIOTRIF® and 3 (3%) patients treated with chemotherapy were known to be alive and progression-free and are censored in the above graph. The primary PFS analysis was conducted after a total of 221 PFS events; it included 152 patients (66.1%) in the GIOTRIF® arm

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All EGFR mutationsLUX-Lung 6 PFS by independent review

GIOTRIF® - superior first-line PFS vs gemcitabine/cisplatin1

PFS=progression-free survival.1.Wu YL et al. Lancet Oncol. 2014;15(2):213-22.

PF

S r

ate

(%)

0.2

0.4

0.6

0.8

1.0

0.0

11.0months

Hazard ratio 0.28(95% CI, 0.20-0.39)

P<0.0001


5.6months

Time (months)

0 3 6 9 18 2112 15 24 27

22

GIOTRIF® – Delayed time to deterioration of clinically relevant symptoms1

TTD=time to deterioration.EORTC=European Organisation for Research and Treatment of Cancer.1. Yang JC et al. J Clin Oncol. 2013;31(27):3342-3350.

GIOTRIF®

n=230 Pem/cis

n=5

Median TTD (months)

Not reached 8.0

Hazard ratio0.60

95% CI, 0.41-0.87P=0.007

GIOTRIF®

n=230 Pem/cisn=115

Median TTD (months) 10.3 2.9

Hazard ratio0.68

95% CI, 0.50-0.93P=0.015

GIOTRIF®

n=230 Pem/cisn=115

Median TTD (months) 4.2 3.1

Hazard ratio0.82

95% CI, 0.62-1.10P=0.19

Cough: significantly delayed TTD Dyspnoea: significantly delayed TTD Pain: trend to longer TTD

LUX-Lung 3: TTD of symptoms (EORTC QoL QLQ-C30 and QLQ LC-13)

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Del19 mutationsPrespecified LUX-Lung 3 analysis

Prespecified LUX-Lung 3 analysis, del19:Over 2.5 years OS with 1 year improvement over pem/cis1

Est

imat

ed O

S p

roba

bilit

y

0.2

0.4

0.6

0.8

1.0

0.0


0 3 6 9 18 21 30 36 39 4512 15 24 27 33 42 48 51

33.3months

Hazard ratio 0.54(95% CI, 0.36-0.79)

P=0.0015


21.1months

OS=overall survival.Yang JC et al. ASCO oral presentation and abstract. J Clin Oncol 32:5s, 2014 (suppl; abstr 8004^).

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L858R mutationsPrespecified LUX-Lung 3 analysis

Prespecified LUX-Lung 3 analysis, L858R:Over 2 years OS1

Est

imat

ed O

S p

roba

bilit

y

0.2

0.4

0.6

0.8

1.0

0.0


0 3 6 9 18 21 30 36 39 4512 15 24 27 33 42 48 51

Hazard ratio 1.30*(95% CI, 0.80-2.11)

P=0.2919


40.3months

27.6months

*HR=1.02 (0.62, 1.69), when adjusted for baseline imbalances

OS=overall survival.Yang JC et al. ASCO oral presentation and abstract. J Clin Oncol 32:5s, 2014 (suppl; abstr 8004^).

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Del19 mutationsPrespecified LUX-Lung 6 analysis

Prespecified LUX-Lung 6 analysis, del19:Over 2.5 years OS with 1 year improvement over pem/cis1

Est

imat

ed O

S p

roba

bilit

y

0.2

0.4

0.6

0.8

1.0

0.0


0 3 6 9 18 21 30 36 39 4512 15 24 27 33 42

31.4months

Hazard ratio 0.64(95% CI, 0.44-0.94)

P=0.0229


18.4months


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L858R mutationsPrespecified LUX-Lung 6 analysis

Prespecified LUX-Lung 6 analysis, L858R:Over 1.5 years OS1

Est

imat

ed O

S p

roba

bilit

y

0.2

0.4

0.6

0.8

1.0

0.0


0 3 6 9 18 21 30 36 39 4512 15 24 27 33 42

Hazard ratio 1.22(95% CI, 0.81-1.83)

P=0.3432



24.3months

19.6months

27

Over 2.5 years OS with 1 year improvement over chemotherapy**

GIOTRIF® approved for use in these patients

NCCN recommended (cat 1)

Del19 (exon 19)

GIOTRIF® Approved for use in these patients

NCCN recommended (cat 1)

L858R (exon 21)

Superior PFS*Significant improvements in symptoms and QoL*

GIOTRIF® continues to be a treatment option

for L858R patients

GIOTRIF® should bethe standard of care

for del19 patients

How do these results impact current practice?

* vs chemotherapy (LUX-Lung 3 pemetrexed/cisplatin, LUX-Lung 6 gemcitabine/cisplatin) ** Secondary endpoint, primary endpoint was PFS; combined post-hoc analysis of common EGFR mutations (del19/L858R) vs chemotherapy (LUX-lung 3 vs pemetrexed/cisplatin and LUX-Lung 6 vs gemcitabine/cisplatin). OS=overall survival; PFS=progression-free survival; QoL=quality of life; NCCN=National Comprehensive Cancer NetworkYang JC et al. ASCO oral presentation and abstract. J Clin Oncol 32:5s, 2014 (suppl; abstr 8004^).National Comprehensive Cancer Network Guidelines Version 4.2014.

All EGFR mutations

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