new tki in lung cancer

NEW TKI IN LUNG CANCER

R6 洪逸平Supervisor 顏厥全醫師

Some slide revised from Boehringer Ingelheim Afatinib Launch Meeting

KRAS

EGFR

ALKPIK3CABRAFMET

HER2MEK

ROS1RET

Unknown35%

Vandetanib?XL184? Sunitinib?

Actionable targets in lung adenocarcinomas

Unknown75%

1999 2005–2013

EGFR

2004

Unknown60%

SelumetinibTrametinib

GefitinibErlotinibAfatinibDacomitinibCO1686, AZD9291

Crizotinib, LDK378, CH5424802, AP26113

NRAS

Crizotinib

Selumetinib?

Afatinib?Dacomitinib?

MetMab?Dabrafenib, vemurafenibregorafenib, MEK inhibitors

MK2206?BKM120?

RETROS1

MEKHER2

MET BRAF PIK3CAALK

KRAS

EGFR

ALKPIK3CABRAFMET

HER2MEK

ROS1RET

Unknown35%

Vandetanib?XL184? Sunitinib?

Actionable targets in lung adenocarcinomas

Unknown75%

1999 2005–2013

EGFR

2004

Unknown60%

SelumetinibTrametinib

GefitinibErlotinibAfatinibDacomitinibCO1686, AZD9291

Crizotinib, LDK378, CH5424802, AP26113

NRAS

Crizotinib

Selumetinib?

Afatinib?Dacomitinib?

MetMab?Dabrafenib, vemurafenibregorafenib, MEK inhibitors

MK2206?BKM120?

RETROS1

MEKHER2

MET BRAF PIK3CAALK

HSP90 client oncoproteinAUY922, IPI504, ganetespib

PD1/PD-L1 expression Lambrolizumab, nivolumab, MPDL3280A, BMS936559

AntiangiogenesisBevacizumab, nintedanib*,motesanib

*Nintedanib is an investigational compound and is not yet approved. Its safety and efficacy have not yet been fully established.

Austin Hospital surgical series: TxN0 only

Main mutations and survival in N0 patients

你相信有平行世界嗎？那些年，我們一起追的女孩九把刀

EGFR mutation + EGFR mutation –

EGFR TKI Chemotherapy

Conversations in Oncology 2009 – Vienna

Tony Mok, Vienna, 2009.

Conversations in Oncology in Asia – 2013, Taipei

EGFR mut Alk-EML4 HER-2 K-ras ROS1--

RET-- B-Raf ??

Conversations in Oncology in Asia – 2013, Taipei

Chemotherapy

Antiangiogenesis

HSP90 inhibitors

PD1/PD-L1 antibodies

cMET/HGF inhibition

IGF/IGFR inhibition

IPASS: Progression-free survival in EGFR mutation positive and negative patients

Mok TS, et al. N Engl J Med 2009;361:947–57.

Gefitinib (n=91)

0 4 8 12 16 20 240.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty P

FS

0 4 8 12 16 20 240.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty o

f PFS

Months Months

Carboplatin/paclitaxel (n=129)

Gefitinib (n=132) Carboplatin/paclitaxel (n=85)

EGFR mutation-positiveHR: 0.48 p<0.001

EGFR mutation-negativeHR: 2.85 p<0.001

Treatment by subgroup interaction test, p<0.0001Qualitative interaction!!!

At risk:Gefitinib 132 108 71 31 11 3 0 C/P 129 103 37 7 2 1 0

91 21 4 2 1 0 0 85 58 14 1 0 0 0

USA (456)2–14%

(15–25%)

Brazil (2017)30%

Spain (2105)17%

France (1227)14%

Italy (860)

5% (10%)

India (2527)25–40%

(36%)

China (1068)24–39% (41–50%)

Korea (513)20–36% (38–48%)

Australia (83)

7% (14%)

Japan (1498)26–40% (41–49%)

Taiwan (267)34%

(56–62%)

Hong Kong (161)(47%)

Vietnam (120)(64%)

Thailand (403)(54%)

The Philippines (65)

(52%)

Qatar (25)

(32%)

EGFR mutations in NSCLC geographical map

Key: Country (N=) % mutation NSCLC (% mutation in adenocarcinoma). Parikh PM, Puri T. Ind J Cancer 2013.

Developing a targeted agent that irreversibly blocks signalling from the ErbB Family receptors

...from the bench to the clinic

Afatinib: An ErbB Family Blocker

AfatinibErlotinib and gefitinib

Afatinib

• Oral, small molecule TKI• Covalently binds to and is highly specific for EGFR,

HER2, ErbB4 (ErbB family)• Retains activity in erlotinib/gefitinib-resistant models

Molecular potency and selectivity (IC50)EGFR (nM) 0.5HER2 (nM) 14ErbB4 (nM) 1HGFR (nM) >10,000VEGFR2 (nM) >100,000

Molecular potency and selectivity (IC50)EGFR L858R

EGFR L858R/T790M

Afatinib 0.4 10

Gefitinib 0.8 1013

Erlotinib 1 1520

Li D, et al. Oncogene 2008;27:4702–4711.

ErbB-dependent tumours

Over-expression

Gen

e am

plifi

catio

n EGFR HER2

ErbB3 ErbB4

Mutation

Chromosomal polysomy

NSCLCBreastHead and neck GastricOesophagealPancreaticBiliaryEndometrialOvarianGlioblastomaMelanoma

Metastatic/ recurrent

Locally advancedadjuvant

HNSCC

EGFRmutation positive

Head-to-head trials

Erlotinib/gefitinibpretreated

NSCLC/adenocarcinoma NSCLC / SCC

LUX-Lung 1 LUX-Lung 2 LUX-Lung 7

LUX-Lung 4 LUX-Lung 3


LUX-Lung 8 LUX-HN 1 LUX-HN 2

LUX-HN 3 LUX-HN 4

LUX trial programme

Yang JC, Taipei, August 2013.

Continued EGFR inhibition

Afatinib in NSCLC: Key trials

Improve outcomes in EGFR M+ 1st/2nd line

Improve outcomes in (EGFR M+) 3rd/4th line

Squamous cell NSCLC

Irreversible vs. reversible EGFR blockade

Improve on monotherapy effect in EGFR M+ 3rd/4th lineAfa + Cet

LL5

LL1 & 4

LL2, 3 & 6

LL7 & 8

LL8

EGFR-TKI pretreated

EGFR-TKI naïve

LUX-LungProgramme

LUX-Lung 1: Post erlotinib/gefitinib – third/fourth line

Miller V, et al. Lancet Oncol 2012;13:528–538.

Stage IIIB/IV adenocarcinoma of the lungProgressed after one or two lines of chemotherapy

(including one platinum-based regimen) and ≥12 weeks of treatment with erlotinib or gefitinib

ECOG PS 0–2

Randomization 2:1 (double blind)

Primary endpoint: OSSecondary endpoints: PFS, ORR, QoL (LC13/C30), safety

Oral placebo once daily + BSC

Oral afatinib 50 mg once daily + BSC

LUX-Lung 1: OS and PFS

Updated OS analysis (February 2012) PFS (independent review)Afatinib

n=390Placebon=195

Median OS (months) 10.9 11.7

HR 1.01 p=0.54


Afatinib n=390

Placebo

n=195

Median PFS (months) 3.3 1.1

HR 0.38 p<0.0001

LUX-Lung 1: OS and subsequent systemic treatment


Estim

ated

sur

viva

l pr

obab

ility

(%)

100

80

60

40

20

0

Time since randomization (months)0 3 6 9 12 15 18 21 24

100

80

60

40

20

0

Time since randomization (months)0 3 6 9 12 15 18 21 24

Afatinib=5.8 monthsPlacebo=4.6 monthsHR=0.66; p=0.027

Patients with no subsequent therapy (n=191)

Patients with ≥1 subsequent therapy (n=394)

Afatinib=12.7 monthsPlacebo=14.4 monthsHR=1.09; p=0.535

Estim

ated

sur

viva

l pr

obab

ility

(%)

LUX-Lung 1: PFS and likelihood of EGFR mutation

Afatinib=4.4 months Placebo=1.0 months

Afatinib=2.8 months Placebo=1.8 months

Estim

ated

PFS

pro

babi

lity

(%)

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.0

Time since randomization (months)0 3 6 9 12 15

134 6 2 1 0 0257 111 49 10 7 3

Number at riskPlaceboAfatinib

Time since randomization (months)0 3 6 9 12 15

61 9 2 1 0 0133 41 16 6 2 0

Number at riskPlaceboAfatinib

Estim

ated

PFS

pro

babi

lity

(%)

Boehringer Ingelheim. Data on file.

YESHigh (>80%) likelihood of mutant EGFR

NOLower (<30%) likelihood of mutant EGFR

CR or PR to prior EGFR-TKI or ≥48 weeks duration of prior EGFR-TKI

LUX-Lung 1: Key learnings

• Afatinib significantly improved PFS compared to placebo

– Post erlotinib/gefitinib failure

• EGFR mutation-positive patients do better– Predictive for afatinib efficacy– Prognostic (longer OS in the trial population)

• Impact of subsequent therapy on OS – Was OS an appropriate endpoint for this setting?

LUX-Lung 4: Phase I/II single arm in Japan

• Population and results: Similar to LUX-Lung 1

Japanese NSCLC patients Failure of conventional treatment or no therapy of proven efficacy

ECOG PS 0 or 1Progressed after one or two lines of chemotherapy (including one platinum-based regimen)

and ≥12 weeks of treatment with erlotinib or gefitinib (Phase II)

ORR=8.2%Median PFS 4.4 months Median OS 19 months

Results (Phase II, n=62)

Afatinib N=90 in Phase I/II; MTD: 50 mg/day

Murakami H, et al. Cancer Chemother Pharmacol 2012;69:891–899; Katakami N, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].

LUX-Lung 5: Continued EGFR inhibition

Phase III trial, Part B blinded and still recruiting

PFSOS

PRO

LUX-Lung 5: PFS in Part A

Schuler M, et al. J Clin Oncol 2012;30(Suppl.):Abstract/Poster 7557.

Overall (n=1154)

mPFS: 3.3 monthsAdenoca (n=985 ): 3.3 monthsSquamous (n=91): 3.7 months

By histology

Lower (n=556): 2.8 monthsHigher (n=598): 4.2 months

By likelihood of EGFR mutation

Kim J-H, et al. J Clin Oncol 2012;30(Suppl.):Abstract/Poster 7558.Schuler M, et al. J Clin Oncol 2012;30(Suppl.):Abstract/Poster 7557.

LUX-Lung 2: Phase II in EGFR M+ first/second line

Yang CH, et al. Lancet Oncol 2012;13:539–548.

Adenocarcinoma of the lung Stage IIIB/IVEGFR mutation

Chemotherapy naïve or progressive disease following first-line chemotherapy

EGFR-TKI naïveECOG PS 0–2

Primary endpoint: ORRSecondary endpoints: PFS, OS

Oral afatinib; starting dose 50 mg/day or 40 mg/day

LUX-Lung 2: PFS, ORR, tumour shrinkage, OS

First line Second line

Treated 61 68

ORR (%) 65.6 57.4

DCR (%) 86.9 77.9

OS (month) NA 23.3

Yang CH, et al. Lancet Oncol 2012;13:539–548; Boehringer Ingelheim. Data on file.

• Comparable activity in first-/second-line treatment of EGFR mutation-positive NSCLC

Median PFS (months) Independent / Investigator

First line (n=61)Second line (n=68)

12 / 15.68 / 10.5

Prog

ress

ion

free

surv

ival

(%)

0

40

20

60

80

100

LUX-Lung 3 and 6: First-line EGFR M+ NSCLC

Yang CH, et al. J Clin Oncol 2012;30(Suppl.):Abstract/Oral presentation LBA7500; Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print];Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract/Poster 8016.

Stage IIIB(wet)/IV NSCLC adenocarcinomaEGFR mutation positive tumour (central test)

ECOG PS 0‒1

Randomization 2:1

Primary endpoint: PFS (independent review) Secondary endpoints: ORR, DCR, OS, PRO

Cisplatin + pemetrexed (LL3)Cisplatin + gemcitabine (LL6)

up to 6 cycles

Afatinib 40 mgonce daily continuously

LUX-LUNG 3

LUX-Lung 3: Study design

*EGFR29: 19 deletions in exon 19, three insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I; †Dose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10 mg decrements in case of related Grade 3 or prolonged Grade 2 AE; ‡Tumour assessments: every 6 weeks until Week 48 and every 12 weeks thereafter until progression/start of new therapy; §Patient-reported outcomes: Q-5D, EORTC QLQ-C30 and QLQ-LC13 at randomization and every 3 weeks until progression or new anti-cancer therapy. Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].

Randomization 2:1 Stratified by:

EGFR mutation (Del19/L858R/other) Race (Asian/non-Asian)

Cisplatin + pemetrexed 75 mg/m2 + 500 mg/m2 i.v.

every 21 days, up to 6 cycles

Primary endpoint: PFS (RECIST 1.1, independent review)‡

Secondary endpoints: ORR, DCR, DoR, tumour shrinkage, OS, PRO§, safety, PK

Stage IIIB (wet)/IV lung adenocarcinoma (AJCC version 6)

EGFR mutation in tumour(central lab testing; Therascreen EGFR29* RGQ PCR)

Afatinib 40 mg/day†

ASIAHong Kong

JapanKorea

Malaysia Philippines

Taiwan Thailand

LUX-Lung 3: The largest global trial in the EGFR mutation-positive NSCLC population

NORTH AMERICAUSA

Canada

SOUTH AMERICA Argentina, Brazil,

Chile, Peru

EUROPEAustria, Belgium, France, Germany,

Hungary, Ireland, Italy, Romania, Russia, Ukraine, UK

Australia

345 patients from 133 sites in 25 countries

LUX-Lung 3: Patient demographics/characteristics

Afatinib (n=230)

Cis/pem (n=115)

Total (n=345)

Gender, n (%) Male 83 (36) 38 (33) 121 (35)

Female 147 (64) 77 (67) 224 (65)

Age, years, median (range) 62 (28–86) 61 (31–83) 61 (28–86)

Race, n (%) Caucasian 61 (27) 30 (26) 91 (26)

Eastern Asian 165 (72) 83 (72) 248 (72)

Other 4 (1) 2 (2) 6 (2)

Smoking status, n (%) Never smoked 155 (67) 81 (70) 236 (68)

Ex-smoker 70 (30) 32 (28) 102 (30)

Current smoker 5 (2) 2 (2) 7 (2)

Stage (AJCC 6.0), n (%) IIIB (wet) 20 (9) 17 (15) 37 (11)

IV 210 (91) 98 (85) 308 (89)

ECOG PS, n (%) 0 92 (40) 41 (36) 133 (39)

1 138 (60) 73 (64) 211 (61)

2 0 1 (1) 1 (<1)

EGFR mutation, n (%) Del19 113 (49) 57 (49) 170 (49)

L858R 91 (40) 47 (41) 138 (40)

Other 26 (11) 11 (10) 37 (11)

Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].

Median follow-up: 16.4 months; 221 independently reviewed PFS events. At the time of data cut-off for primary analysis of PFS, 45 (20%) patients in the afatinib arm and three (3%) patients in the chemotherapy arm were known to be alive and progression-free.Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].

Primary endpoint: Afatinib improved PFS versus chemotherapy

Number at riskAfatinib 230 180 151 120 77 50 31 10 3 0Cis/Pem 115 72 41 21 11 7 3 2 0 0

Progression-free survival (months)

Afatinib

n=230Cis/pem

n=115

PFS event, n (%) 152 (66) 69 (60)

Median PFS (months) 11.1 6.9Hazard ratio (95% CI) 0.58 (0.43–0.78)

p=0.0004

Prog

ress

ion-

free

sur

viva

l (pr

obab

ility

)

1.0

0.8

0.6

0.4

0.2

0.00 3 6 9 12 15 18 21 24 27

47%

22%

Independent review – all randomized patients

Factors Number of patients

Hazard ratio(95% confidence interval)

Total 345 0.58 (0.43–0.78)Gender Male Female

121224

0.61 (0.37–1.01)0.54 (0.38–0.78)

Age at baseline: <65 vs. ≥65 years <65 years ≥65 years

211134

0.53 (0.36–0.76)0.64 (0.39–1.03)

Race stratification factor Non-Asian Asian

96249

0.68 (0.39–1.19)0.54 (0.38–0.76)

EGFR mutation category Del19/L858R (common) Del19 L858R

308170138

0.47 (0.34–0.65)0.28 (0.18–0.44)0.73 (0.46–1.17)

Baseline ECOG score 0 1

133211

0.50 (0.31–0.82)0.63 (0.43–0.91)

Smoking history Never smoked <15 packet years + stop >1 year Other current/ex-smoker

2363079

0.47 (0.33–0.67)0.50 (0.19–1.34)1.04 (0.54–1.98)

1/16 5/8 6 1/4

LUX-Lung 3: PFS subgroup analysis

Favours afatinib Favours cis/pem



LUX-Lung 3: Updated OS analysis

Boehringer Ingelheim International GmbH; July 2013. Available online: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf [Last accessed 24/07/13]

Afatinib (n=230)

Cis/pem (n=115)

Overall survival*

Number of Deaths, N (%) 116 (50.4%) 59 (51.2%)

Median Overall Survival (months) 28.1 28.2

95% CI (24.6, 33.0) (20.7, 33.2)

HR (95% CI) 0.91 (0.66, 1.25)

Stratified Log-Rank Test P-value* 0.55

*At the time of cutoff, only 98 (28%) had died. Hence, OS data are considered preliminary. Median OS has not yet been reached for any group.

Prog

ress

ion-

free

sur

viva

l (pr

obab

ility

)

1.0

0.8

0.6

0.4

0.2

0.0

Number at riskAfatinib 204 169 143 115 75 49 30 10 3 0Cis/Pem 104 62 35 17 9 6 2 2 0 0

Progression-free survival (months)0 3 6 9 12 15 18 21 24 27

Afatinib

n=204Cis/pem

n=104

PFS event, n (%) 130 (64) 61 (59)

Median PFS (months) 13.6 6.9Hazard ratio (95% CI) 0.47 (0.34–0.65)

p<0.0001

Afatinib improved PFS versus chemotherapy in patients with common mutations (Del19/L858R)

51%

21%

Independent review – patients with Del19/L858R (n=308)


Afatinib improved rates of response versus chemotherapy

Independent InvestigatorCE/ 通用格式

CE/ 通用格式

CE/ 通用格式

CE/ 通用格式CE/ 通用格式

CE/ 通用格式

CE/ 通用格式

AfatinibCis/pem

All patients Common mutations (Del19/L858R)


CE/ 通用格式

CE/ 通用格式


CE/ 通用格式

CE/ 通用格式

AfatinibCis/pem

Median duration of response: 11.1 vs. 5.5 months (all patients; independent review)

p<0.001 p<0.001 p<0.0001 p<0.0001

Patie

nts,

%


Patie

nts,

%

*Grouped term; †No Grade 5 events for the presented AEs.Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].

LUX-Lung 3: Most frequent related adverse events

Afatinib (n=229)

Cis/pem (n=111)

All Gr† (%) Gr 3 (%) Gr 4 (%) All Gr† (%) Gr 3 (%) Gr 4 (%)

Diarrhoea 218 (95.2) 33 (14.4)

0 17 (15.3) 0 0

Rash/acne* 204 (89.1) 37 (16.2)

0 7 (6.3) 0 0

Stomatitis/mucositis* 165 (72.1) 19 (8.3) 1 (0.4) 17 (15.3) 1 (0.9) 0

Paronychia 130 (56.8) 26 (11.4)

0 0 0 0

Dry skin 67 (29.3) 1 (0.4) 0 2 (1.8) 0 0

Nausea 41 (17.9) 2 (0.9) 0 73 (65.8) 4 (3.6) 0

Decreased appetite 47 (20.5) 7 (3.1) 0 59 (53.2) 3 (2.7) 0

Fatigue* 40 (17.5) 3 (1.3) 0 52 (46.8) 14 (12.6) 0

Vomiting 39 (17.0) 7 (3.1) 0 47 (42.3) 3 (2.7) 0

Neutropenia 2 (0.9) 1 (0.4) 0 35 (31.5) 17 (15.3) 3 (2.7)

Anaemia 7 (3.1) 1 (0.4) 0 31 (27.9) 5 (4.5) 2 (1.8)

>20% difference between treatment arms

NE, not estimated.Yang J.C-H, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].

Afatinib delayed the worsening of lung cancer-related symptoms

Pain

Cough Dyspnoea

Yang J.C-H, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].

Quality of life: EORTC QoL C-30

10 5 0 –5

Global health status/QoL

Overall health

Quality of life

Physical functioning

Role functioning

Emotional functioning

Cognitive functioning

Social functioning

Treatment difference3.28

3.52

3.13

4.83

4.50

0.85

3.24

1.18

Favours afatinib Favours cis/pem

Difference in mean scores over time (longitudinal analysis)

LUX-LUNG 3:ASIAN PATIENTS

Primary endpoint: PFS – Asian patients Independent review

PFS

(pro

babi

lity)

1.0

0.8

0.6

0.4

0.2

0.0

PFS (months)0 3 6 9 12 15 18 21 24 27

PFS (months)

PFS

(pro

babi

lity)

1.0

0.8

0.6

0.4

0.2

0.00 3 6 9 12 15 18 21 24 27

Number at riskAfatinib 166 137 113 91 60 40 26 8 3Cis/pem 83 50 30 16 8 5 2 1 0

Number at riskAfatinib 149 130 108 87 58 39 25 8 3Cis/pem 75 43 26 13 6 4 1 1 0

Afatinib

n=166

Cis/pem

n=83

PFS event, n (%) 112 (68) 50 (60)


HR (95% CI) 0.54 (0.38–0.76)p=0.0003

Afatinib

n=149

Cis/pem

n=75

PFS event, n (%) 98 (66) 44 (59)


HR (95% CI) 0.44 (0.30–0.63)p<0.0001

All Asian patients Asian patients with Del19/L858R

49%

22%

52%

20%

Mok T, et al. 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.

LUX-Lung 3: Objective response


CE/ 通用格式

CE/ 通用格式


CE/ 通用格式

CE/ 通用格式

AfatinibAll patients

Median duration of response: 11.1 vs. 5.5 months

(independent review)

p<0.0001 p<0.0001

Patie

nts,

%


CE/ 通用格式

CE/ 通用格式

62.7

20.5

AfatinibAsian patients

p<0.0001 p<0.0001

Median duration of response:11.2 vs. 4.2 months

(independent review)

74.7

43.4

Mok T, et al. 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.

Patie

nts,

%

Afatinib Asian (n=165) Non-Asian (n=64)All Gr† (%) Gr 3 (%) Gr 4 (%) All Gr† (%) Gr 3 (%) Gr 4 (%)

Diarrhea 96 16 0 94 11 0

Rash/acne* 91 17 0 84 14 0

Stomatitis/mucositis* 85 9 0 39 6 1.6

Paronychia 65 14 0 36 5 0

Dry skin 33 0.6 0 19 0 0

Decreased appetite 26 4 0 6 1.6 0

Pruritus 21 0 0 14 1.6 0

LUX-Lung 3: Most frequent related AEs – Asian patients

Cis/pem Asian (n=80) Non-Asian (n=31)All Gr† (%) Gr 3 (%) Gr 4 (%) All Gr† (%) Gr 3 (%) Gr 4 (%)

Nausea 66 4 0 65 3 0

Decreased appetite 64 4 0 26 0 0Vomiting 48 4 0 29 0 0Fatigue* 45 9 0 52 23 0Neutropenia 34 15 4 26 16 0Anemia 30 5 1.3 23 3 3Leukopenia 24 11 0 7 0 0Constipation 21 0 0 13 0 0

*Grouped term; †No Grade 5 events for the presented AEs. Mok T, et al. 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.

LUX-LUNG 3: SUMMARY

LUX-Lung 3: Summary

• LUX-Lung 3 is the largest* global prospective trial in EGFR mutation-positive lung cancer and the first using cisplatin and pemetrexed as the comparator

• LUX-Lung 3 met its primary endpoint with median PFS (independent review):

– Overall population: 11.1 vs. 6.9 months – Common mutations: 13.6 vs. 6.9 months – Consistent efficacy in all relevant subgroups

• Afatinib significantly improved rates of response versus chemotherapy

• Efficacy findings from the Asian subgroup are in line with those from the overall trial population

*n=345. Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print]; Mok T, et al. Presented at the 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.

LUX-Lung 3: Summary (continued)

• First-line afatinib significantly prolonged PFS, with associated delay in worsening of lung cancer-related symptoms and improvement in quality of life

• Safety profile of afatinib consistent with previous studies

– Overall population: Diarrhoea and rash were the most frequent AEs; manageable with low treatment discontinuation rate

– Asian patients: Diarrhoea and rash were the most frequent AEs; no treatment discontinuations for rash and only one Asian patient discontinued for diarrhoea

Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print]; Mok T, et al. Presented at the 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.

LUX-LUNG 6

LUX-Lung 6: Study design

*Central lab testing; Therascreen EGFR29 RGQ PCR detecting 19 deletions in exon 19, three insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I; †Dose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10 mg decrements in case of related Grade 3 or prolonged Grade 2 AE; ‡Tumour assessments: every 6 weeks until Week 48 and every 12 weeks thereafter until progression/start of new therapy; §Patient-reported outcomes: EQ-5D, EORTC QLQ-C30 and QLQ-LC13 at randomization and every 3 weeks until progression or new anti-cancer therapy.Wu Y-L, et al. J Clin Oncol 2013; 31 (suppl): Abstract 8016 and poster.

Randomization 2:1 Stratified by:

EGFR mutation (Del19/L858R/other)

Gemcitabine + cisplatin1000 mg/m2 D1, D8 + 75 mg/m2

i.v. q21 days, up to 6 cycles

Primary endpoint: PFS (RECIST 1.1, independent review)‡

Secondary endpoints: ORR, DCR, DoR, tumour shrinkage, OS, PRO§, safety

Asian patients (China, South Korea, Thailand)Stage IIIB (wet)/IV lung adenocarcinoma

EGFR mutation in tumour(central lab testing; Therascreen EGFR29* RGQ PCR)

Afatinib 40 mg/day†

LUX-Lung 6: Patient disposition

Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8016 and poster.

910 screened

471 EGFR mutation (+)

364 randomized

107 did not meet eligibility criteria or did not enter

242 assigned to afatinib•3 did not receive treatment

57 (24%)on treatment

PFS event at data cut-off •169 (70%) by investigator

assessment•157 (65%) by independent

assessment

122 assigned to cisplatin + pemetrexed•9 did not receive treatment

0 on treatment

PFS event at data cut-off•78 (64%) by investigator

assessment•64 (53%) by independent

assessment

182 (76%) stopped treatment 113 (100%) stopped or completed treatment

LUX-Lung 6: Patient demographics/characteristics

Afatinib (n=242)

Gem/cis (n=122)

Total(n=364)

Gender, n (%) Male 87 (36) 39 (32) 126 (35)Female 155 (64) 83 (68) 238 (65)

Age, years, median (range) 58 (29–79) 58 (27–76) 58 (27–79)Smoking status, n (%) Never smoked 181 (75) 99 (81) 280 (77)

Ex-smoker 44 (18) 13 (11) 57 (16)Current smoker

17 (7) 10 (8) 27 (7)

Stage (AJCC 6.0), n (%) IIIB (wet) 16 (7) 6 (5) 22 (6)IV 226 (93) 116 (95) 342 (94)

ECOG PS, n (%) 0 48 (20) 41 (34) 89 (24)1 194 (80) 81 (66) 275 (76)

EGFR mutation, n (%) Del19 124 (51) 62 (51) 186 (51)L858R 92 (38) 46 (38) 138 (38)Other 26 (11) 14 (12) 40 (11)


Primary endpoint: Afatinib improved PFS versus chemotherapy



LUX-Lung 6: PFS subgroup analysisIndependent review – all randomized patients

Factors Number of patients

Hazard ratio(95% confidence interval)

Total 364 0.28 (0.20–0.39)Gender Male Female

126238

0.36 (0.21–0.63)0.24 (0.16–0.35)

Age at baseline <65 years ≥65 years

27886

0.30 (0.21–0.43)0.16 (0.07–0.40)

EGFR mutation category Del19/L858R (common) Del19 L858R Other (uncommon)

32418613840

0.25 (0.18–0.35)0.20 (0.13–0.33)0.32 (0.19–0.52)0.55 (0.22–1.43)

Baseline ECOG PS 0 1

89275

0.22 (0.12–0.41)0.29 (0.20–0.43)

Smoking history Never smoked <15 pack–years + stop >1 year Other current/ex-smoker

2801272

0.24 (0.16–0.34)0.39 (0.07–2.41)0.46 (0.22–1.00)

Favours afatinib Favours gem/cis 1/16 5/8 6 1/4


LUX-Lung 6: Best overall tumour response Randomized patients

Response

Independentreview

Investigatorreview

Afatinib (n=242)

Gem/cis (n=122)

Afatinib (n=242)

Gem/cis (n=122)

Objective response (CR+PR), %

66.9 23.0 74.4 31.1

Median duration of response (months) (95% CI)

9.7 (8.3, 12.5)

4.3 (2.8, 5.8)

12.4 (11.2, 12.9)

4.0(2.8, 4.9)

Disease control (CR+PR+SD), %

92.6 76.2 93.0 75.4

Median duration of disease control (months) (95% CI)

11.1 (9.7, 13.8)

5.7 (5.5, 6.9)

13.8 (12.5, 14.9)

6.4 (5.5, 6.9)


*36% of gemcitabine/cisplatin patients had dose delay of ≥6 days; †2% discontinued afatinib due to rash, no discontinuations for diarrhoea; ‡Related deaths: sudden death (afatinib) and cardiac failure (gemcitabine/cisplatin).Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8016 and poster.

LUX-Lung 6: Summary of adverse events

Afatinib n=239

Gem/cis n=113

Median treatment duration (days) 398 89

Drug-related AEs (%) 98.7 99.1

Drug-related AEs Grade ≥3 (%) 36.0 60.2

Drug-related AEs leading to dose reduction (%) 32.2 26.5*

Drug-related AEs leading to discontinuation (%) 5.9† 39.8

Drug-related SAEs (%) 5.4 7.0

Related AEs leading to death‡ (%) 0.4 0.9

*Grouped term. Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8016 and poster.

LUX-Lung 6: Most frequent related adverse events

Afatinib (n=239) Gem/cis (n=113)

All grade (%) Grade 3 (%) Grade 4 (%) All grade (%) Grade 3 (%) Grade 4 (%)Diarrhoea 88.3 5.4 0 10.6 0 0

Rash/acne* 80.8 14.2 0.4 8.8 0 0

Stomatitis/mucositis* 51.9 5.4 0 5.3 0 0

Paronychia 32.6 0 0 0 0 0

ALT increase 20.1 1.7 0 15.9 1.8 0.9

Vomiting 9.6 0.8 0 80.5 15.9 3.5

Nausea 7.5 0 0 75.2 7.1 0.9

Neutropenia 2.1 0.4 0 54.0 17.7 8.8

Leukopenia 3.3 0.4 0 51.3 13.3 1.8

Decreased appetite 10.0 1.3 0 40.7 1.8 0

Fatigue* 10.0 0.4 0 36.3 0.9 0

Anaemia 5.4 0.4 0 27.4 7.1 1.8

Neutrophil count decreased 0.8 0 0 25.7 7.1 2.7

WBC decreased 0.8 0 0 23.9 6.2 0

NE, not estimated.Geater SL, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8061 and poster.

Afatinib delayed the worsening of lung cancer-related symptoms

Pain

Cough Dyspnoea

LUX-Lung 6: Summary and conclusions

• In EGFR mutation-positive Asian patients, afatinib significantly prolonged PFS compared with gemcitabine/cisplatin

– Median PFS of 11.0 vs. 5.6 months (HR=0.28; p<0.0001) (independent review)

• PFS benefit was observed across all prespecified subgroups

• Treatment with afatinib was associated with significant improvements in ORR, DCR, symptom control and quality of life compared with chemotherapy

• Safety profile was as expected in both treatment arms• Afatinib had a more favourable safety profile compared with

chemotherapy• LUX-Lung 6 is the largest prospective first-line trial in EGFR

mutation-positive lung cancer patients

OVERALL SUMMARY

Afatinib PFS benefit consistent across both trialsIndependent review – all randomized patients

LUX-Lung 3, n=345 (afatinib vs.

pem/cis )

LUX-Lung 6, n=364(afatinib vs. gem/cis)

Median PFS 11.1 vs. 6.9 11.0 vs. 5.6

HR for PFS 0.58 0.28

12-month PFS 47% vs. 22% 47% vs. 2%


Afatinib for the treatment of EGFR mutation-positive NSCLC

• Afatinib significantly prolonged PFS compared with cisplatin/pemetrexed in EGFR mutation-positive patients (LUX-Lung 3)

• Afatinib significantly prolonged PFS compared with gemcitabine/cisplatin in EGFR mutation-positive Asian patients (LUX-Lung 6)

• The results of LUX-Lung 3 and LUX-Lung 6 support the strategy of genotype-directed therapy with afatinib in previously untreated patients with EGFR mutation-positive NSCLC

LUX-Lung 7 and LUX-Lung 8: Irreversible versus reversible EGFR blockade

Recruiting…

LUX-Lung 7: http://clinicaltrials.gov/ct2/show/NCT01466660?term=1200.123&rank=1;LUX-Lung 8: http://clinicaltrials.gov/ct2/show/NCT01523587?term=1200.125&rank=1;Goss G, et al. Ann Oncol 2012;23(9):ix174, 509TiP.

Co-primary: PFS, TTF and OS at 24 monthsSecondary: ORR, DCR, QoL at 24 months

EGFR M+ NSCLC adenocarcinomaECOG PS 0–1

First-line setting

Afatinib 40 mg/day

Gefitinib 250 mg/day

Randomization 1:1

Primary: PFSSecondary: OS, PRO

Squamous NSCLCECOG PS 0–1

Second-line setting (post chemo)

Afatinib 40 mg/day

Erlotinib150 mg/day

Randomization 1:1

LUX-Lung trial programme

Adenocarcinoma EGFR-TKI pretreatedLikely EGFR mutation

LUX Lung 5

LUX Lung 1

LUX Lung 4

Third/fourth line

AdenocarcinomaEGFR-TKI naïve

EGFR mutation positive

LUX Lung 3

LUX Lung 7

LUX Lung 2

LUX Lung 6

First/second line

First line

Squamous cellEGFR-TKI naïve

LUX Lung 8

Second line

Afatinib beyond LUX-Lung programme

• Focus on rational targeted combinations:

– Improve monotherapy effect– Delay resistance– Overcome resistance

Afatinib

Anti-EGFR antibodies

MET inhibitors

PI3K/mTOR inhibitors

HDAC inhibitors

IGF inhibitors

MEKinhibitors

...investigation continues

Afatinib + cetuximab

Afatinib 40 mg daily + cetuximab 500 mg/m2 q2w

Define MTD

ORR, PFS

EGFR M+ lung adenocarcinoma with acquired resistance to

erlotinib/gefitinib

Janjigian YY, et al. Ann Oncol 2012;23(9):ix401, 1227O.

• In a heavily pretreated population with EGFR M+ tumours: T790M+ or T790M‒

– ORR = 30% (median DOR = 8 months)– DCR = 75%– Median PFS = 4.7 months

Continuous and simultaneous EGFR inhibition

非有以御其內，其勢不止；非有以治其外，疾未易為也。明方孝儒指喻

Summary

• LUX-Lung programme is investigating afatinib in NSCLC

– Addressing different questions– Different settings– Different patient subgroups– Different combinations

• Afatinib demonstrates efficacy in EGFR mutation-positive NSCLC

– Irrespective of line of treatment– Irrespective of prior treatment with EGFR-TKIs

• Investigation continues...

First-line treatment algorithm for advancedNSCLC (2013)

EGFR mutation positiveor ALK fusion positive

Poor PSGood PS

Gefitinib, erlotinibor crizotinib

(to progression)

Molecular Clinical (PS)

Non-squamous Squamous Single-agent or combinationchemotherapy

Bevacizumab eligible

Bevacizumab ineligible

Platinum/pemetrexed (or other*) ± bevacizumab

Platinum/pemetrexed

(or other*)

Platinum doublet*

Histological

Clinical

*With docetaxel, paclitaxel, gemcitabine, vinorelbine or nab-paclitaxel.Adapted from Gandara DR, et al. Clin Lung Cancer 2009;10:392–394.

Diagnosis

(No CT)

(No TKI)

Schematic of patients with activating EGFR mutationreceiving EGFR TKI, CT and BSC in various sequences

Mok T, et al. J Clin Oncol 2013;31:1081–1088.

Asian contribution to development of afatinib in NSCLC: Re-look into history

2007 First Asian patient enrolled in Taiwan for Phase II trial, LUX-Lung 2 About 80% of patients in study were enrolled from 7 sites in Taiwan

2008 First patient enrolled in Japan for Phase II trial, LUX-Lung 4

2008 First patient enrolled in Asia for Phase III trial, LUX-Lung 1Taiwan, Korea, China, Hong Kong, Singapore and Thailand contributed 61% of randomized patients

2009 First patient enrolled in Asia for Phase III trial, LUX-Lung 3 Taiwan, Korea, Hong Kong, Malaysia, Thailand and the Philippines contributed 50% of total patients

2009 First Phase II study in EGFR wild-type patients initiated in KoreaFirst afatinib study to be led by OPU in Asia

2010 First patient enrolled into LUX-Lung 5 China, Taiwan, Korea and India contributed 45% of total patients

2010 First patient enrolled in Asian regional study, LUX-Lung 6 First afatinib Phase III study led by China OPU; China, Korea and Thailand contributed all patients

Asian contribution to development of afatinib in NSCLC: Current activities

2011 First patient enrolled in LUX-Lung 7 head-to-head comparison with gefitinib in treatment-naïve NSCLC patients with EGFR mutationFirst afatinib global study to be led from Asia OPU (BI Korea)Study completing recruitment and data analysis planned for Q1 2015

2011 NPU programme started In Asia, so far 1545 patients have received afatinib under NPUIn Taiwan alone, 837 patients have received afatinib under NPU

2012 First global Phase III trial (LUX-Lung 8) in squamous NSCLC was initiatedChina, Taiwan, Korea, India and Singapore are currently recruiting patients So far, Asian contribution is 25% of global recruitment

First positive regulatory appraisals for afatinib

Giotrif/Gilotrif (US)

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