click on the links below to view additional content...phase iii trial of afatinib versus erlotinib...

Phase III trial of afatinib versus erlotinib in patients with squamous cell carcinoma of the lung (LUX-Lung 8): EGFR molecular aberrations and survival outcomes Glenwood D. Goss, Enriqueta Felip, Manuel Cobo, Shun Lu, Konstantinos Syrigos, Wei Li, Caicun Zhou, Keunchil Park, Flavio Solca, Nicole Krämer, Vikram K. Chand, Jean-Charles Soria, for the LUX-Lung 8 Investigators Poster #3084 presented at the European Cancer Congress (ECC) 2015

Second-line afatinib versus erlotinib in patients with advanced squamous cell carcinoma of the lung: patient-reported outcome data from the global LUX-Lung 8 Phase III trial Sanjay Popat, Enriqueta Felip, Manuel Cobo, Andrea Fulop, Charles Dayen, José Manuel Trigo, Richard Gregg, Corelius F. Waller, James Gordon, Robert Lorence, Bushi Wang, Vikram K. Chand, Vera Hirsh for the LUX-Lung 8 Investigators Poster #3085 presented at the European Cancer Congress (ECC) 2015

Click on the links below to view additional content

Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial Jean-Charles Soria, Enriqueta Felip, Manuel Cobo, Shun Lu, Konstantinos Syrigos, Ki Hyeong Lee, Erdem Göker, Vassilis Georgoulias, Wei Li, Dolores Isla, Salih Z. Guclu, Alessandro Morabito, Young J. Min, Andrea Ardizzoni, Shirish M. Gadgeel, Bushi Wang, Vikram K. Chand, Glenwood D. Goss, for the LUX-Lung 8 Investigators Lancet Oncol 2015 Aug;16(8):897–907

Debating EGFR inhibitors for squamous cell lung cancer patients video

Afatinib versus erlotinib as second-line therapy of patients with advanced squamous cell carcinoma of the lung following platinum-based chemotherapy Overall survival analysis from LUX-Lung 8 global Phase III trial Jean-Charles Soria, Enriqueta Felip, Manuel Cobo, Shun Lu, Konstantinos N. Syrigos, Ki Hyeong Lee, Erdem Göker, Vassilis Georgoulias, K.Wei Li, Dolores Isla, Salih Z. Guclu, Alessandro Morabito, Young J. Min, Andrea Ardizzoni, Shirish M. Gadgeel, Bushi Wang, Vikram K. Chand, Glenwood D. Goss for the LUX-Lung 8 Investigators Oral presentation #8002 presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2015

Tumor genetic analysis from LUX-Lung 8: a Phase III trial of afatinib versus erlotinib in squamous cell carcinoma of the lung Jean-Charles Soria, Enriqueta Felip, Manuel Cobo, Shun Lu, Vassilis Georgoulias, Andrea Ardizzoni, Shirish Gadgeel, Neil Gibson, Carina Ittrich, Vikram K. Chand, Glenwood D. Goss Oral presentation #1401 presented at the World Congress of Lung Cancer (WCLC) 2015

Afatinib mechanism of action video

https://www.youtube.com/watch?v=2Zw3gx9gFak

http://we.tl/RKUNGwLgYy

http://www.elsevier-reprints.de/dwl/LancetOncol-2015-Soria-46561.pdf

Phase III trial of afatinib versus erlotinib in

patients with squamous cell carcinoma

of the lung (LUX-Lung 8): EGFR molecular

aberrations and survival outcomes Glenwood D. Goss,1 Enriqueta Felip,2 Manuel Cobo,3 Shun Lu,4 Konstantinos Syrigos,5

Wei Li,6 Caicun Zhou,7 Keunchil Park,8 Flavio Solca,9 Nicole Krämer,10

Vikram K. Chand,11 Jean-Charles Soria12 for the LUX-Lung 8 Investigators

1Division of Medical Oncology, University of Ottawa, Ottawa, Canada; 2Vall d’Hebron University Hospital, Barcelona, Spain;

3Hospital Carlos Haya, Malaga, Spain; 4Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,

Shanghai, China; 5Athens School of Medicine, Athens, Greece; 6First Hospital Affiliated to Jilin University, Jilin, China; 7Tongji University Medical School Cancer Institute, Shanghai, China; 8Samsung Medical Center, Sungkyunkwan University

School of Medicine, Seoul, South Korea; 9Boehringer Ingelheim GmbH, Vienna, Austria; 10Staburo GmbH, Munich, Germany

on behalf of Boehringer Ingelheim Pharma GmBH & Co. KG, Biberach, Germany; 11Boehringer Ingelheim Pharmaceuticals, Inc.,

Ridgefield, CT, USA; 12Gustave Roussy Cancer Campus and University Paris-Sud, Paris, France

• SCC of the lung has a high burden of somatic mutations/genomic alterations1

• Overexpression/derangements of EGFR,2,3 HER2,4,5 HER45 and/or

dysregulation of their downstream pathways are implicated in the pathogenesis

of SCC of the lung, providing rationale for ErbB inhibitors in this setting of major

unmet medical need

• The LUX-Lung 8 trial investigated second-line afatinib, an irreversible ErbB

family blocker, versus erlotinib, a reversible EGFR TKI, in patients with SCC of

the lung

• Primary analysis of LUX-Lung 8, conducted while recruitment was ongoing,

showed significantly better PFS with afatinib than erlotinib

• Here we report primary analysis of OS after 632 deaths, updated PFS (at time of

OS analysis) and exploratory tumour genetic analysis using FoundationOne™

NGS of select tumour samples

Introduction

1. Ugocsai K, et al. Anticancer Res 2005;25:3061‒6; 2. Lawrence MS, et al. Nature

2013;499:214‒8; 3. Lopez-Malpartida AV, et al. Lung Cancer 2009;65:25‒33;

4. Hirsch FR, et al. J Clin Oncol 2003;21:3798‒807;

5. Heinmoller P, et al. Clin Cancer Res 2003;9:5238‒43

NGS, next-generation sequencing; OS, overall survival;

PFS, progression-free survival; SCC, squamous cell carcinoma;

TKI, tyrosine kinase inhibitor

Goss GD, et al. Abstract #3084 presented at the European Cancer

Congress (ECC), Vienna, Austria, 25–29 September 2015

• LUX-Lung 8 was a global, 1:1 randomised, open-label, Phase III study

– Primary endpoint: PFS by central independent radiology review RECIST v1.1

– Key secondary endpoint: OS (only to be tested if PFS was statistically

significant)

– Other secondary endpoints: ORR, DCR, tumour shrinkage and safety

Methods

DCR, disease control rate; ORR, objective response rate;

RECIST v1.1, Response Evaluation Criteria in Solid Tumours version 1.1



Study design

QD, once daily

Stage IIIB/IV squamous NSCLC

second-line treatment (N=795)

Primary endpoint: PFS (independent review)

Key secondary endpoint: OS

Tumour and blood sample for exploratory biomarker analysis

required at study entry

Afatinib 40 mg QD Erlotinib 150 mg QD



• Analysis of archival tumour tissue was performed using the FoundationOne™

NGS platform, which offered detailed somatic genetic analysis of ~300

cancer-related genes including all ErbB family mutations and amplifications

• The following genes were assessed

– EGFR (kinase and non-kinase domains) and genes that frequently have SVs

or CNAs in patients with SCC

– Gene families: ErbB receptor and FGF ligand and receptor

• NGS analyses investigated the potential of tumour genetic alterations as

predictive biomarkers of PFS and OS

Tumour genetic analysis

CNAs, copy number alterations; FGF, fibroblast growth factor;

SVs, short variants



Primary PFS (n=669) and selection for tumour

genetic analysis

CI, confidence interval; HR, hazard ratio

Afatinib Erlotinib

Median, months

(95% CI)

2.4

(2.0–2.9)

1.9

(1.9–2.1)

HR (95% CI) 0.82 (0.68–1.00)

p value 0.0427

Estim

ate

d P

FS

pro

ba

bili

ty

Time (months)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

0.4

0.8

1.0

0.6

0.2

0

Group 2 (control):

patients with little or no

benefit from

afatinib/erlotinib

Group 1:

patients

benefiting from

afatinib/erlotinib

0

• Patients were retrospectively selected for NGS analyses based on PFS criteria with an enrichment of

patients with long PFS (>2 months)



Demographics and baseline characteristics

*Percentages may not total 100 due to rounding; †<1% were ECOG PS 2; ‡<15 pack years and stopped >1 year before diagnosis; §<1% were

Stage IIIA; ¶<1% were undifferentiated (considered to be of squamous histology); **Considered to be of squamous histology; ‡‡<1% had PD

CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; PR, partial response; SD, stable disease

Afatinib* Erlotinib* Total

Number randomised 398 397 795

ECOG PS,† % 0 32 34 33

1 68 66 67

Male, % 84 83 84

Race (for stratification), % Non-East Asian 78 78 78

East Asian 22 22 22

Median age, years 65 64 64

Smoking history, % Never smoker 7 5 6

Ex-smoker‡ 3 3 3

Smoker 91 92 92

Median time since diagnosis, years 0.8 0.7 0.7

Clinical stage,§ % IIIB 12 12 12

IV 88 87 87

Histology,¶ % SCC 96 96 96

Mixed type** 4 4 4

Prior chemotherapy, % Platinum-doublet 100 100 100

Best response to first-line chemotherapy, ‡‡ %

CR/PR 47 47 47

SD 41 42 41

Unknown 12 11 11



• After a median follow-up of 18.4 months, OS was significantly improved with

afatinib versus erlotinib (median 7.9 vs 6.8 months; HR=0.81; 95% CI:

0.69–0.95; p=0.0077)

– The effect of afatinib on OS was consistent across subgroups (Figure 4)

• At the time of primary OS analysis, PFS was found to be significantly improved

with afatinib versus erlotinib (median 2.6 vs 1.9 months; HR=0.81, 95% CI:

0.69–0.96; p=0.0103)

Key study outcomes



OS for the 795 patients in LUX-Lung 8

Patients were censored after 632 deaths (as specified in the protocol)

3 6 9 12 15 30 18 21 24 27

Time (months)

0.2

0.4

0.6

0.8

1.0

0

Estim

ate

d O

S p

rob

abili

ty

0

36.4%

28.2% 22.0%

14.4%

Afatinib Erlotinib

Median, months

(95% CI)

7.9

(7.2–8.7)

6.8

(5.9–7.8)

HR (95% CI) 0.81 (0.69–0.95)

p value 0.0077



OS subgroup analysis

Factors Patients HR (95% CI)

Overall 795 0.81 (0.69–0.95)

Age

<65 years 399 0.68 (0.55–0.85)

≥65 years 396 0.95 (0.76–1.19)

Gender

Male 666 0.82 (0.69–0.97)

Female 129 0.77 (0.51–1.14)

Race

Non-East Asian 623 0.87 (0.73–1.03)

East Asian 172 0.62 (0.44–0.88)

ECOG at baseline

0 260 0.76 (0.58–1.01)

1 531 0.80 (0.66–0.97)

Smoking history

Never smoker 44 0.77 (0.37–1.57)

Light ex-smoker 23 0.43 (0.16–1.12)

Current and other ex-smoker 728 0.81 (0.69–0.96)

Histology

Squamous 763 0.82 (0.70–0.96)

Mixed 32 0.55 (0.26–1.17)

Best response to first-line

chemotherapy

CR/PR 371 0.91 (0.72–1.15)

SD 328 0.71 (0.56–0.90)

Unknown 89 0.72 (0.44–1.17)

1/16

Favours afatinib Favours erlotinib

1/4 1 4 16



ORR and DCR, independent review

*Odds ratio: 1.56, 95% CI: 1.18–2.06; p=0.002 †Odds ratio: 2.06, 95% CI: 0.98–4.32; p=0.055

7.3

3.7

0

2

4

6

8

10

12

Median duration of response

Tim

e (

mo

nth

s)

50.5

5.5

39.5

2.8

0

10

20

30

40

50

60

DCR ORR

Afatinib

Erlotinib

*

†

Pe

rce

nt



• The frequency of AEs was similar with afatinib and erlotinib

– Overall: n=390 (99.5%) with afatinib and n=385 (97.5%) with erlotinib; grade

≥3: n=224 (57.1%) with afatinib and n=227 (57.5%) with erlotinib

• AEs were consistent with the mechanistic profile of each drug; there was a

higher incidence of drug-related grade ≥3 diarrhoea and stomatitis with afatinib

and a higher incidence of grade ≥3 rash/acne with erlotinib

Safety

AEs, adverse events



Patient disposition; tumour genetic analysis

*Samples enriched for those with PFS >2 months †e.g., poor quality samples, shipment restrictions, etc.

Unable to

perform

tumour genetic

analysis†

n=195

Afatinib n=130 Erlotinib n=108

PFS >2 months

n=86

PFS ≤2 months

n=44

PFS >2 months

n=58

PFS ≤2 months

n=50

Able to perform tumour genetic analysis n=238

(PFS >2 months: n=144; PFS ≤2 months: n=94)*

Clinically selected for tumour genetic analysis

N=433

• Biomarker analyses were performed on samples from 238 (~30%) patients



EGFR genomic aberrations

†Tumour genetic analysis subset

Afatinib

6% (8/130)

Erlotinib

6% (6/108)

SV

mutations

Afatinib

7% (9/130)

Erlotinib

6% (6/108)

CNAs

Objective response

Censored

Median PFS afatinib†

Median PFS erlotinib†

CNA=51

CNA=86

CNA=66

CNA=28 * CNA=22

CNA=19 * CNA=8 * CNA=7 *

CNA=22

CNA=39

CNA=33

CNA=16 * CNA=10

CNA=7

CNA=6 *

0 2 4 6 8 10 12 14 16 18

PFS (months)

0 2 4 6 8 10 12 14 16 18

G532D

R255Q

L861Q

E687V

A127T

E967V

E114K

R1052K

Q1021*

W1157C

L858R

T273I

I664F

PFS (months)

Su

bje

cts

R377K Patient censored at Day 1

*

*

*

*

*

Previously described

mutations

*

• The frequency of EGFR genomic aberrations was low



Genetic alterations and OS/PFS

*Data after 632 deaths were not censored (unlike that for primary OS analysis), hence the slight difference in HR †Tumour genetic analysis subset, n=238

Subgroup

Aberration

present (%) OS HR (95% CI) PFS HR (95% CI)

LL8

LL8 subset†

0.82 (0.71–0.96)*

0.73 (0.56–0.96)

0.81 (0.69–0.96)

0.65 (0.48–0.87)

TP53 No (12.2)

Yes (87.8)

0.54 (0.24–1.24)

0.74 (0.55–0.99)

0.57 (0.24–1.37)

0.64 (0.47–0.89)

EGFR No (94.1)

Yes (5.9)

0.72 (0.54–0.95)

1.04 (0.33–3.25)

0.65 (0.48–0.88)

0.52 (0.13–2.01)

LRP1B No (60.5)

Yes (39.5)

0.74 (0.52–1.05)

0.73 (0.47–1.13)

0.56 (0.38–0.84)

0.77 (0.49–1.23)

MLL2 No (67.2)

Yes (32.8)

0.68 (0.49–0.96)

0.83 (0.52–1.32)

0.63 (0.44–0.90)

0.64 (0.38–1.08)

CDKN2A No (71.4)

Yes (28.6)

0.75 (0.54–1.03)

0.68 (0.40–1.14)

0.62 (0.44–0.89)

0.65 (0.37–1.13)

FAT3 No (72.3)

Yes (27.7)

0.69 (0.50–0.96)

0.75 (0.44–1.27)

0.58 (0.41–0.83)

0.76 (0.44–1.33)

EGFR No (93.7)

Yes (6.3)

0.76 (0.57–1.01)

0.42 (0.12–1.43)

0.66 (0.48–0.89)

0.67 (0.17–2.68)

SOX2 No (56.3)

Yes (43.7)

0.78 (0.54–1.11)

0.70 (0.46–1.07)

0.74 (0.50–1.09)

0.54 (0.34–0.86)

KLHL6 No (59.7)

Yes (40.3)

0.76 (0.54–1.08)

0.72 (0.46–1.12)

0.73 (0.50–1.07)

0.54 (0.33–0.88)

PIK3CA No (63.0)

Yes (37.0)

0.72 (0.51–1.02)

0.78 (0.50–1.23)

0.66 (0.45–0.95)

0.64 (0.39–1.07)

MAP3K13 No (67.2)

Yes (32.8)

0.80 (0.57–1.11)

0.66 (0.40–1.08)

0.74 (0.52–1.06)

0.49 (0.28–0.86)

BCL6 No (68.9)

Yes (31.1)

0.74 (0.54–1.03)

0.79 (0.47–1.32)

0.71 (0.50–1.01)

0.53 (0.30–0.93)

FGF12 No (71.4)

Yes (28.6)

0.76 (0.55–1.04)

0.77 (0.45–1.32)

0.69 (0.49–0.97)

0.57 (0.31–1.05)

ERBB No (71.0)

Yes (29.0)

0.74 (0.54–1.03)

0.70 (0.42–1.16)

0.68 (0.48–0.97)

0.51 (0.28–0.92)

FGF No (41.2)

Yes (58.8)

0.69 (0.45–1.06)

0.76 (0.53–1.08)

0.81 (0.51–1.28)

0.52 (0.35–0.76)


0.5 0 1.5 2.0 1.0 2.5

SV

s

CN

As

Pre

defined fam

ilies:

any

aberr

ation


0.5 0 1.5 2.0 2.5 1.0

• There was no observed predictive association between genetic alterations and OS or PFS



• In LUX-Lung 8, OS was significantly improved with afatinib versus erlotinib in

patients with SCC of the lung

• PFS and DCR were also significantly better with afatinib than erlotinib

• Current analysis was unable to identify a marker for afatinib’s PFS and OS

superiority over erlotinib observed in LUX-Lung 8

– Specified tumour genetic alterations, including EGFR SV mutations and CNAs

do not appear to be predictive of either PFS or OS benefit

– Genetic analyses are limited in their ability to detect functional aberrations

(e.g., hypermethylation, phosphorylation), which may be the possible key to

differential efficacy

• Assessment of EGFR immunohistochemistry and blood-based markers, and

further bioinformatics analysis of NGS is ongoing

Conclusions



Second-line afatinib versus erlotinib in patients

with advanced squamous cell carcinoma of the

lung: patient-reported outcome data from the

global LUX-Lung 8 Phase III trial Sanjay Popat,1 Enriqueta Felip,2 Manuel Cobo,3 Andrea Fulop,4 Charles Dayen,5

José Manuel Trigo,6 Richard Gregg,7 Cornelius F. Waller,8 James Gordon,9

Robert Lorence,10 Bushi Wang,10 Vikram K. Chand,10 Vera Hirsh11

for the LUX-Lung 8 Investigators

1Royal Marsden National Health Service Foundation Trust, London, UK; 2Vall d’Hebron University Hospital, Barcelona, Spain;

3Hospital Carlos Haya, Málaga, Spain; 4National Koranyi Institute, Budapest, Hungary; 5Saint-Quentin Medical Center, Saint-Quentin,

France; 6Virgen de la Victoria University Hospital, Málaga, Spain; 7Cancer Centre of Southeastern Ontario at Kingston General

Hospital, Ontario, Canada; 8Medizinische Universitätsklinik Freiburg, Freiburg, Germany; 9Boehringer Ingelheim GmbH, Ingelheim,

Germany; 10Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 11McGill University Health Centre, Royal Victoria

Hospital, Montreal, Canada

• QoL and symptom control are important components of cancer care1 and

consideration of these aspects of patients’ experience of their condition is

important when choosing the most appropriate treatment options

• LUX-Lung 8, a prospective, randomised, Phase III global trial, compared afatinib

and erlotinib in patients with SCC of the lung following failure of first-line

platinum-based chemotherapy2

• Here, we report prespecified analyses of PROs from all randomised patients and

a small substudy capturing the time course and severity of diarrhoea utilising

patient diaries

Introduction

SCC, squamous cell carcinoma; PROs, patient-reported outcomes;

QoL, quality of life

1. Peppercorn JM, et al. J Clin Oncol 2011;29:755–60

2. Soria J-C, et al. Lancet Oncol 2015;16:897–907

Popat S, et al. Abstract #3085 presented at the European Cancer


• LUX-Lung 8 was an open-label, global, 1:1 randomised study

• Primary endpoint: PFS by central independent radiology review (Response

Evaluation Criteria in Solid Tumours version 1.1)

• Key secondary endpoint: OS

• Other secondary endpoints: ORR, DCR, tumour shrinkage, PROs and safety

Methods

DCR, disease control rate; ORR, objective response rate; OS, overall survival;

PFS, progression-free survival



Study design

ECOG PS, Eastern Cooperative Oncology

Group performance status; PD, progressive disease;

QD, once daily; TTD, time to deterioration

1:1

Stage IIIB/IV squamous

NSCLC

Second-line treatment

setting (PD after

≥4 cycles of a first-line

platinum-doublet)

ECOG PS 0–1

Adequate organ

function

Afatinib

40 mg QD

Erlotinib

150 mg QD Patient-reported

outcomes

Primary endpoint:

PFS

Key secondary

endpoint: OS

Secondary endpoints:

ORR, DCR, tumour

shrinkage and

EORTC QLQ-C30 and QLQ-LC13 completed

once every cycle and at end of treatment

Status change, TTD and change in scores over

time assessed for prespecified symptoms:

cough, dyspnoea, pain



• PROs were assessed using the EORTC QLQ-C30 and QLQ-LC131,2

• PROs were assessed at the first visit of each treatment course, and at the end of

treatment. Scores were converted to a 0–100 scale and analysed in line with

EORTC scoring algorithms. A change from baseline of at least 10 points was

required for improvement or deterioration

• Prespecified symptoms relevant to lung cancer are considered here; specifically

cough, dyspnoea and pain, alongside GHS/QoL

Diarrhoea substudy

• Patient-based diaries were used to capture detailed incidence and severity of

diarrhoea in selected centres at which patients already randomised in the trial

agreed to participate

Assessment of patient-reported outcomes

EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer

core quality of life questionnaire;

QLQ-LC13, EORTC lung cancer-specific module; GHS, global health status;

1. Aaronson NK, et al. J Natl Cancer Inst 1993;5:365–76

2. Bergman B, et al. Eur J Cancer 1994;30A:635–42



• A total of 795 patients were randomised: 398 in the afatinib arm and 397 in the

erlotinib arm

• Baseline characteristics were generally well balanced between the two arms1

• Afatinib improved OS compared to erlotinib (median 7.9 vs 6.8 months;

HR=0.81; 95% CI: 0.69–0.95; p=0.0077)

• In addition PFS, DCR and ORR were also improved

– PFS afatinib: median 2.6 months; erlotinib: median 1.9 months (HR=0.81;

95% CI: 0.69–0.96; p=0.010)

– DCR afatinib: 50.5%; erlotinib: 39.5% (p=0.002)

– ORR afatinib: 5.5%; erlotinib: 2.8% (p=0.055)

Results

CI, confidence interval; HR, hazard ratio 1. Soria J-C, et al. Lancet Oncol 2015;16:897–907



OS for the 795 patients in LUX-Lung 8

Time (months)

1.0

0.8

0.6

0.4

0.2

0

Estim

ate

d O

S p

rob

ab

ility

0 3 6 9 12 15 18 21 24 27 30

Afatinib Erlotinib

Median (months)

(95% CI)

7.9

(7.2–8.7)

6.8

(5.9–7.8)

HR (95% Cl) 0.81 (0.69–0.95)

p value 0.008



• Baseline symptom scores were low for cough, dyspnoea and pain

• Completion rates for the EORTC questionnaire were high throughout treatment

(afatinib range: 77.3–99.0%; erlotinib range: 68.7–99.0%)

Patient-reported outcomes



Status change

OR, odds ratio afatinib versus erlotinib

• The proportions of patients reporting improved global health status/QoL and cough was significantly

higher with afatinib than erlotinib. Improvement in pain was similar across both treatment arms

• While a higher proportion of patients reported improvements in dyspnoea with afatinib versus

erlotinib, the difference was not statistically significant, however the benefit observed was greatest for

the item ‘dyspnoea walked’ (34.6% vs 26.5%; p=0.022)

OR=1.41

p=0.029

OR=1.33

p=0.061

OR=1.05

p=0.775

OR=1.40

p=0.041

339 341 n 339 340 343 342 339 339

43.4

51.3

40.2

35.7 35.2

44.1

39.2

28.3

0

10

20

30

40

50

60

Cough Dyspnoea Pain GHS/QoL

Afatinib

Erlotinib

Pa

tie

nts

im

pro

ve

d (

%)



TTD of cough

Time of coughing (months)

Estim

ate

d p

rob

ab

ility

Afatinib Erlotinib

Median (months) 4.5 3.7

HR (95% Cl) 0.89 (0.72–1.09)

p value 0.256

1.0

0.8

0.6

0.4

0.2

0 0 3 6 9 12 15 18 21 24 27

• There was a trend towards delayed TTD of cough with afatinib versus erlotinib



TTD of dyspnoea

Time of dyspnoea (months)

0 3 6 9 12 15 18 21 24 27

Estim

ate

d p

rob

ab

ility

Afatinib Erlotinib


HR (95% Cl) 0.79 (0.66–0.94)

p value 0.008

1.0

0.8

0.6

0.4

0.2

0

• Afatinib significantly delayed TTD of dyspnoea compared to erlotinib

• TTD was consistent across subcategories of dyspnoea



TTD of pain

Time of pain (months)

0 3 6 9 12 15 18 21 24 27

Estim

ate

d p

rob

ab

ility

Afatinib Erlotinib


HR (95% Cl) 0.99 (0.82–1.18)

p value 0.869

1.0

0.8

0.6

0.4

0.2

0

• TTD of pain was similar across both treatment arms

• TTD was consistent across subcategories of pain



Difference in mean scores over time

Q, question

Number

of patients

Adjusted mean

difference

Cough (Q1 from QLQ-LC13) 604 –3.5

Dyspnoea (Q3–Q5 from QLQ-LC13) 603 –3.5

Pain (Q9, Q19 from QLQ-C30) 609 –2.7

GHS/QoL (Q29–Q30 from QLQ-C30) 602 –1.6

–20 –10 0 10 20


• Changes in mean scores over time significantly favoured afatinib compared with erlotinib for cough

(p=0.0091), dyspnoea (p=0.0024) and pain (p=0.0384)

• There were no significant differences between afatinib and erlotinib for changes in global health

status/QoL over time but, with the exception of social functioning, changes in functional scales over

time significantly favoured afatinib



• 63 patients consented to provide a detailed diary (36 in the afatinib arm and

27 in the erlotinib arm)

• The overall incidence of all grade diarrhoea in the substudy patients was similar

to that reported in the overall trial population (86.1% with afatinib and 51.8% with

erlotinib)

• Seven of 36 patients (19.4%) in the afatinib arm reported grade ≥3 diarrhoea

• Median duration of grade ≥3 diarrhoea with afatinib was 3 days

• No patient discontinued study treatment due to diarrhoea

Diarrhoea substudy



• In LUX-Lung 8, the significant improvement in OS and PFS achieved with

afatinib compared to erlotinib in second-line treatment of SCC was

complemented by improvements in PROs

• Improvements in several PRO parameters that included global health status/QoL

and key lung cancer-associated symptoms were observed across three key

analyses

• These analyses confirm the clinical meaningfulness of the improvements

observed for PFS, OS and tumour response with afatinib compared with erlotinib

in LUX-Lung 8

• In the substudy, diarrhoea was manageable and rates were consistent with prior

experience

• With better efficacy and PROs over erlotinib and a manageable adverse event

profile, afatinib should be considered the tyrosine kinase inhibitor of choice for

second-line treatment of SCC of the lung

Conclusions



Tumor genetic analysis from

LUX-Lung 8: a Phase III trial of

afatinib versus erlotinib in

squamous cell carcinoma of the lung

J.-C. Soria, E. Felip, M. Cobo, S. Lu, V. Georgoulias, A. Ardizzoni,

S. Gadgeel, N. Gibson, C. Ittrich, V. K. Chand, G.D. Goss

Presenting author: Glenwood D. Goss

• Jean-Charles Soria has received personal fees for advisory boards from Boehringer Ingelheim and

Roche

• Enriqueta Felip has received consulting fees from Eli Lilly, Pfizer, Roche and Boehringer Ingelheim,

and fees for speaker’s bureaus from AstraZeneca and Novartis

• Shun Lu has received consulting fees from Boehringer Ingelheim

• Shirish Gadgeel has received fees for advisory board participation from Boehringer Ingelheim

• Neil Gibson, Carina Ittrich and Vikram K. Chand are employees of Boehringer Ingelheim

• Glenwood Goss has received honoraria from AstraZeneca, Roche, Bristol-Myers Squibb and Pfizer

• All other authors have nothing to disclose

Disclosures

Squamous NSCLC: genetically complex malignancy

• High burden of somatic mutations/genomic alterations1

1. Lawrence MS, et al. Nature 2013;499:214‒8; 2. Lopez-Malpartida AV, et al. Lung Cancer 2009;65:25‒33; 3. Hirsch FR, et al. J Clin Oncol 2003;21:3798‒807;

4. Heinmoller P, et al. Clin Cancer Res 2003;9:5238‒43; 5. Ugocsai K, et al. Anticancer Res 2005;25:3061‒6; 6. Cancer Genome Atlas Research Network. Nature 2012;489:519‒25

• Overexpression/derangements of EGFR,2,3 HER2,4,5 HER45 and/or dysregulation of

their downstream pathways implicated in pathogenesis

• LUX-Lung 8 data demonstrate clinical activity of afatinib in squamous NSCLC

Squamous

NSCLC

So

ma

tic m

uta

tio

n

frequ

ency (

/Mb

)

LUX-Lung 8: study design and tissue collection

*Dose escalation to 50mg and dose reduction to 30 or 20mg permitted; †Dose reduction to 100 or 50mg permitted ‡Assessment of SVs, CNAs, REAR; §Baseline samples

CNAs, copy number alterations; IHC, immunohistochemistry; OS, overall survival;

PFS, progression-free survival; QD, once daily; REAR, gene rearrangements; SVs, short variants

Stage IIIB/IV squamous NSCLC

second-line treatment (N=795)

Primary endpoint: PFS (independent review)

Key secondary endpoint: OS

Tumor and blood sample for exploratory

biomarker analysis required at study entry:

742 tumor samples available

Tissue Analysis Status Samples

analyzed

Archival

tumor

tissue

FoundationOne®

tumor genetic

analysis‡

Initial

analysis

complete

n=238

EGFR IHC Ongoing n=67

(China)

Blood Veristrat® Ongoing n=696§

• Aim: identify predictive marker(s) for patients benefitting on afatinib/erlotinib

Afatinib 40mg* QD Erlotinib 150mg† QD

LUX-Lung 8: results and selection for

tumor genetic analysis

*Data cutoff for primary PFS analysis (Oct 7 2013) †Data cutoff for primary OS analysis (March 2 2015); patients were censored after 632 deaths (as specified in the protocol)


PFS: primary endpoint*

Estim

ate

d P

FS

pro

ba

bili

ty

0

Time (months)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

0.4

0.8

1.0

0.6

0.2

0

Afatinib

(n=335)

Erlotinib

(n=334)

Median, months

HR (95% CI)

p value

2.4 1.9

0.82 (0.68–1.00)

0.0427

OS: key secondary endpoint†

3 6 9 12 15 30 18 21 24 27 0

Time (months)

Estim

ate

d O

S p

rob

ab

ility

Afatinib

(n=398)

Erlotinib

(n=397)

Median, months

HR (95% CI)

p value

7.9 6.8

0.81 (0.69–0.95)

0.0077

0.4

0.8

1.0

0.6

0.2

0

LUX-Lung 8: results and selection for

tumor genetic analysis

*Data cutoff for primary PFS analysis (Oct 7 2013) †Data cutoff for primary OS analysis (March 2 2015); patients were censored after 632 deaths (as specified in the protocol)


Primary PFS analysis*

Estim

ate

d P

FS

pro

ba

bili

ty

0

Time (months)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

0.4

0.8

1.0

0.6

0.2

0

Group 1: Patients

benefiting from

afatinib/erlotinib

Group 2 (control): Patients with little

or no benefit from afatinib/erlotinib

Methods

• FoundationOne® NGS platform

– Detailed somatic genetic analysis* of 300 genes including all ErbB family

mutations and amplifications

– Aim: to identify predictive marker(s) for patients benefitting on afatinib/erlotinib

• Genes assessed

– EGFR (kinase and non-kinase domains)

– Gene families: ErbB receptor; FGF ligand and receptor

– Any genes that had SVs and/or CNAs in ≥5 patients/treatment arm

– Explored as potential markers of PFS and OS

*SVs, CNAs, REAR

NGS, next-generation sequencing; FGF, fibroblast growth factor

Afatinib n=130 Erlotinib n=108

PFS >2 months

n=86 PFS ≤2 months

n=44

Disposition

PFS >2 months

n=58 PFS ≤2 months

n=50

Unable to perform tumor

genetic analysis† n=195

Clinically selected for tumor genetic analysis*

N=433

*Samples enriched for those with PFS >2 months †Poor quality specimen, export restrictions, etc.

Able to perform tumor genetic analysis n=238

Group 1: PFS >2 months, n=144; Group 2: PFS ≤2 months, n=94

LUX-Lung 8

Overall population (n=795) Genetic analysis subset (n=238)

Mean age (SD) 64.1 (8.7) 64.5 (8.3)

Gender, %

Female

Male

16.2

83.8

10.9

89.1

Race, %

Non-eastern Asian

Eastern Asian

78.4

21.6

80.7

19.3

ECOG, %

0

1

2

32.7

66.8

0.5

36.1

63.0

0.8

Smoking history, %

Never smoker

Light ex-smoker*

Current or other ex-smoker

5.5

2.9

91.6

4.2

3.4

92.4

Best response to first-line chemotherapy, %

CR/PR

Stable disease

PD

Unknown

46.7

41.3

0.9

11.2

45.8

42.9

0.0

11.3

Clinical characteristics

*<15 pack-years and stopped >1 year before diagnosis

CR, complete response; ECOG, Eastern Cooperative Oncology Group; PD, progressive disease; PR, partial response; SD, standard deviation

Tumor genetic alterations

LUX-Lung 8 (n=238) vs TCGA (n=187)

TCGA, The Cancer Genome Atlas project

TP53

LRP1B

0

Alle

le fre

qu

ency (

LU

X-L

un

g 8

) %

0

20

40

60

80

100

10 20 30

10

30

50

70

90

40 50 60 70 80 90 100

Allele frequency (TCGA) %

m=1

Gene, % LL8 subset*

(n=238)

Group 1†

PFS >2 months (n=144)

Group 2†

PFS ≤2 months (n=94)

TP53 87.8 89.6 85.1

LRP1B 39.5 38.2 41.5

MLL2 32.8 31.2 35.1

CDKN2A 28.6 27.8 29.8

FAT3 27.7 26.4 29.8

ErbB family 21.0 24.3 16.0

EGFR 5.9 6.9 4.3

HER 2/3/4 5.0/6.3/5.5 4.9/8.3/6.9 5.3/3.2/3.2

SOX2 43.7 49.3 35.1

KLHL6 40.3 46.5 30.9

PIK3CA 37.0 42.4 28.7

MAP3K13 32.8 36.1 27.7

BCL6 31.1 34.0 26.6

FGF12 28.6 30.6 25.5

ErbB family 10.1 9.7 10.6

EGFR 6.3 7.6 4.3

HER 2 3.8 2.1 6.4

ErbB 29.0 31.9 24.5

FGF 58.8 56.3 62.8

LUX-Lung 8: most frequent

tumor genetic abnormalities

*Tumor genetic analysis subset †Any differences between Groups 1 and 2 should be interpreted with caution due to low numbers. A Fisher’s exact test found no significant differences between the groups

SVs

Predefined

families:

any aberration

CNAs

Subgroup Aberration present (%) HR (95% CI)†

LL8

LL8 subset* (n=238)

0.81 (0.69–0.96)

0.65 (0.48–0.87)

EGFR No (94.1)

Yes (5.9)

0.65 (0.48–0.88)

0.52 (0.13–2.01)

TP53 No (12.2)

Yes (87.8)

0.57 (0.24–1.37)

0.64 (0.47–0.89)

LRP1B No (60.5)

Yes (39.5)

0.56 (0.38–0.84)

0.77 (0.49–1.23)

MLL2 No (67.2)

Yes (32.8)

0.63 (0.44–0.90)

0.64 (0.38–1.08)

CDKN2A No (71.4)

Yes (28.6)

0.62 (0.44–0.89)

0.65 (0.37–1.13)

FAT3 No (72.3)

Yes (27.7)

0.58 (0.41–0.83)

0.76 (0.44–1.33)

EGFR No (93.7)

Yes (6.3)

0.66 (0.48–0.89)

0.67 (0.17–2.68)

SOX2 No (56.3)

Yes (43.7)

0.74 (0.50–1.09)

0.54 (0.34–0.86)

KLHL6 No (59.7)

Yes (40.3)

0.73 (0.50–1.07)

0.54 (0.33–0.88)

PIK3CA No (63.0)

Yes (37.0)

0.66 (0.45–0.95)

0.64 (0.39–1.07)

MAP3K13 No (67.2)

Yes (32.8)

0.74 (0.52–1.06)

0.49 (0.28–0.86)

BCL6 No (68.9)

Yes (31.1)

0.71 (0.50–1.01)

0.53 (0.30–0.93)

FGF12 No (71.4)

Yes (28.6)

0.69 (0.49–0.97)

0.57 (0.31–1.05)

ERBB No (71.0)

Yes (29.0)

0.68 (0.48–0.97)

0.51 (0.28–0.92)

FGF No (41.2)

Yes (58.8)

0.81 (0.51–1.28)

0.52 (0.35–0.76)

Predictive analysis by PFS

0.5 0 1.5 2.0 2.5 1.0

*Tumor genetic analysis subset †Interaction p values between yes/no on all markers >0.05

Favors afatinib Favors erlotinib

SVs

CNAs

Predefined

families:

any aberration

Subgroup Aberration present (%) HR (95% CI)†

LL8

LL8 subset* (n=238)

0.82 (0.71–0.96)‡

0.73 (0.56–0.96)

EGFR No (94.1)

Yes (5.9)

0.72 (0.54–0.95)

1.04 (0.33–3.25)

TP53 No (12.2)

Yes (87.8)

0.54 (0.24–1.24)

0.74 (0.55–0.99)

LRP1B No (60.5)

Yes (39.5)

0.74 (0.52–1.05)

0.73 (0.47–1.13)

MLL2 No (67.2)

Yes (32.8)

0.68 (0.49–0.96)

0.83 (0.52–1.32)

CDKN2A No (71.4)

Yes (28.6)

0.75 (0.54–1.03)

0.68 (0.40–1.14)

FAT3 No (72.3)

Yes (27.7)

0.69 (0.50–0.96)

0.75 (0.44–1.27)

EGFR No (93.7)

Yes (6.3)

0.76 (0.57–1.01)

0.42 (0.12–1.43)

SOX2 No (56.3)

Yes (43.7)

0.78 (0.54–1.11)

0.70 (0.46–1.07)

KLHL6 No (59.7)

Yes (40.3)

0.76 (0.54–1.08)

0.72 (0.46–1.12)

PIK3CA No (63.0)

Yes (37.0)

0.72 (0.51–1.02)

0.78 (0.50–1.23)

MAP3K13 No (67.2)

Yes (32.8)

0.80 (0.57–1.11)

0.66 (0.40–1.08)

BCL6 No (68.9)

Yes (31.1)

0.74 (0.54–1.03)

0.79 (0.47–1.32)

FGF12 No (71.4)

Yes (28.6)

0.76 (0.55–1.04)

0.77 (0.45–1.32)

ERBB No (71.0)

Yes (29.0)

0.74 (0.54–1.03)

0.70 (0.42–1.16)

FGF No (41.2)

Yes (58.8)

0.69 (0.45–1.06)

0.76 (0.53–1.08)

Predictive analysis by OS

0.5 0 1.5 2.0 1.0 2.5 *Tumor genetic analysis subset †Interaction p values between yes/no on all markers >0.05 ‡Data after 632 deaths were not censored (unlike that for

primary OS analysis), hence the slight difference in HR


SVs

Predefined

families:

any aberration

CNAs

LUX-Lung 8: genomic aberrations in EGFR

Afatinib

6% (8/130) Erlotinib

6% (6/108)

SVs

Afatinib

7% (9/130)

Erlotinib

6% (6/108)

CNAs

Objective response

Censored

Median PFS afatinib (subset†)

Median PFS erlotinib (subset†)

CNA=51

CNA=86

CNA=66

CNA=28 * CNA=22

CNA=19 * CNA=8 * CNA=7 *

CNA=22

CNA=39

CNA=33

CNA=16 * CNA=10

CNA=7

CNA=6 *

0 2 4 6 8 10 12 14 16 18

PFS (months) †Tumor genetic analysis subset

*

0 2 4 6 8 10 12 14 16 18

G532D

R255Q

L861Q

E687V

A127T

E967V

E114K

R1052K

Q1021*

W1157C

L858R

T273I

I664F

PFS (months)

Su

bje

cts

R377K Patient censored at day 1

*

* * *

*

Patient with SV + CNA mutations Previously described mutations

Conclusions • Squamous NSCLC has a high somatic mutation burden and complex tumor genetic alterations

• The frequency and pattern of these alterations in the LUX-Lung 8 subset are consistent with prior reports in

patients with squamous NSCLC

• Current analysis was unable to identify a marker for afatinib’s PFS and OS superiority over erlotinib

observed in LUX-Lung 8

– Specified tumor genetic alterations, including EGFR SV mutations and CNAs:

• are not predictive of benefit to afatinib treatment compared with erlotinib

• do not appear to be associated with longer PFS/OS, regardless of treatment in LUX-Lung 8

– Genetic analyses are limited in their ability to detect functional aberrations (e.g. hypermethylation,

phosphorylation), which may be the possible key to differential efficacy

• Work addressing EGFR IHC, blood-based biomarkers and further bioinformatics analysis of NGS is ongoing

Acknowledgments

• We thank all patients, families, investigators, independent DMC and staff participating in LUX-Lung 8

DMC members: Lesley Seymour (Chair), Chandra Prakash Belani, Nick Thatcher, Bruce Turmbull. Members of the LUX-Lung 8 study group: publication steering committee: Jean-Charles Soria,

Glenwood Goss, Andrea Ardizzoni, Enriquetta Felip, Shirish Gadgeel, Vassilis Georgoulias, Shun Lu, Vikram Chand. Investigators: Argentina: Luis Fein, Claudio Martin, Norma Pilnik, Eduardo

Richardet; Austria: Otto Burghuber, Wolfgang Eisterer, Martin Flicker, Roland Kropfmüller, Andrea Mohn-Staudner; Canada: Richard Gregg, Vera Hirsh, Christopher Lee; Chile: Osvaldo Aren,

Christian Lorenzo Caglevic Medina, Francisco Javier Orlandi Jorquera, Luis Alejandro Matamala Rebelledo; China: Gang Cheng, Jifeng Feng, Chengping Hu, Wei Li, Shun Lu, Shukui Qin, Jie Wang,

Li Zhang, Caicun Zhou; Denmark: Karin Holmskov Hansen, Anders Mellemgaard, Kim Wederwang; France: Nathalie Baize, Fabrice Barlesi, Anatole Cessot, François Chomy, Eric Dansin, Charles

Dayen, Didier Debieuvre, Patrick Dumont, Sylvie Friard, Sylvestre Le Moulec, Hervé Lena, Anne Madroszyk, Patrick Merle, Olivier Molinier, Isabelle Monnet, Elizabeth Quoix, Arnaud Scherpereel,

Jean-Charles Soria, Gérard Zalcman; Germany: Lars Arne Berger, Nicolas Dickgreber, Wilfried Eberhardt, Martin Faehling, Gerald Schmid-Bindert, Claus-Peter Schneider, Martin Sebastian, Monika

Serke, Cornelius Waller, Rainer Wiewrodt; Greece: Athanasios Athanasiadis, Vasilios Georgoulias, Christos Papandreou, Dimosthenis Skarlos, Konstantinos Syrigos; Hungary: Krisztina Bogos,

Andrea Fulop, Gabriella Herodek, Albert Istvan, Zsolt Kiraly, György Losonczy, Gyula Ostoros, Veronika Sarosi, Attila Somfay, Peter Szabo, Mark Zsuzsanna; India: Chanchal Goswami, Minish Jain,

Niti Raizada Narang, Rajiv Paliwal, Kumar Prabhash, Anita Ramesh, S Subramanian, Srinivasan Venkatesan; Ireland: Sinead Cuffe; Italy: Alba Brandes, Federico Cappuzzo, Libero Ciuffreda, Adolfo

Favaretto, Francesco Ferrau, Alessandro Morabito, Pasqualina Giordano, Rodolfo Passalacqua, Armando Santoro, Angela Maria Sibau, Marcello Tiseo, Enrico Vasile; Mexico: Oscar Gerardo Arrieta

Rodriguez, Ángel Gomez Villanueva, Francisco Alejo Medina Soto; The Netherlands: Joachim Aerts, Bonne Biesma, Anne-Marie Dingemans, Gerarda Herder, JM Smit, Ben van den Borne; Portugal:

Teresa Almodovar, Isabel Azevedo, Fernando Barata, Bárbara Parente, Henrique Queiroga, Encarnacao Teixeira; Singapore: Yee Hong Chia, Eng Huat Tan; South Korea: Eun Kyung Cho, Jin-

Hyoung Kang, Hoon-Gu Kim, Hoon Kyo Kim, Sang-We Kim, Jong-Seok Lee, Ki Hyeong Lee, Keunchil Park, Joo Min Young, Spain: Manuel Cobo, Javier De Castro, Enriqueta Felip, Amelia Insa,

Rosario García Campelo, Jose Luis Gonzalez Larriba, Delores Isla, Margarida Majem, Jose Manuel Trigo; Taiwan: Gee-Chen Chang, Te-Chun Hsia, Chun-Liang Lai, Chun-Ming Tsai, Chin-Chou

Wang, Cheng-Ta Yang, James Chin-Hsin Yang; Turkey: Isikdogan Abdurrahman, Mehmet Aliustaoglu, Hasan Coskun, Evrensel Turkkan, Erdem Göker, Salih Guclu, Murat Kiyik, Alper Sevinc; UK:

Rachael Barton, Ekaterini Boleti, Samual Chan, Sanjay Popat, Vanessa Potter, Riyaz Shah, Nicola Steele, Elizabeth Toy, Ian Woolhouse; USA: Athanassios Argiris, Maria Baggstrom, Lyudmila

Bazhenova, Deepti Behl, Nagarajan Chandrasekaran, Shirish Gadgeel, Jerome Goldschmidt, Stephen Graziano, Sucharu Prakash, Missak Haigentz, Paul Hesketh, Sujith Kalmadi, Barry Kaplan,

Farrah Khan, Waseemullah Khan, Leonard Klein, Goetz Kloecker, Ira Oliff, Gregory Otterson, John Paschold, Taral Patel, Nathan Pennell, Bilal Piperdi, Luis Raez, Mark Rarick, Edgardo Santos,

Pedro Sanz-Altamira, Deric Savior. As part of the LUX-Lung 8 biomarker sub-team: Nicole Krämer (Staburo GmbH, Munich, on behalf of Boehringer Ingelheim Pharma GmbH & Co. KG) and Flavio

Solca (Boehringer Ingelheim, Vienna, Austria)

Afatinib versus erlotinib as second-line therapy of

patients with advanced squamous cell carcinoma of the

lung following platinum-based chemotherapy

Overall survival analysis

from LUX-Lung 8

global Phase III trial

J-C. Soria, E. Felip, M. Cobo, S. Lu, K.N. Syrigos, K.H. Lee, E. Göker,

V. Georgoulias, K.W. Li, D. Isla, S.Z. Guclu, A. Morabito,

Y.J. Min, A. Ardizzoni, S.M. Gadgeel, B. Wang, V.K. Chand, G.D. Goss

for the LUX-Lung 8 Investigators

• Honoraria

– Roche, Boehringer Ingelheim

Disclosures

• SCC of the lung remains a disease with high unmet medical need

• ErbB pathway dysregulation is frequently observed in SCC1–3

• Erlotinib, a reversible EGFR TKI is an approved second-line therapy for these

patients

– Improved tolerability over docetaxel4 yet similar survival in second-line

unselected and EGFRwt NSCLC5

• Afatinib could confer additional benefit over erlotinib

– Irreversible inhibition of signaling from ErbB1(EGFR), HER2 to HER46

Background

1. Heinmoller P, et al. Clin Cancer Res 2003;9:5238‒43; 2. Ugocsai K, et al. Anticancer Res

2005;25:3061‒611; 3. Cancer Genome Atlas Research Network. Nature 2012;489:519‒25;

4. Lee CK, et al. J Natl Cancer Inst. 2013;105:595–605.;5. Li N, et al. PLoS One

2014;9(7):e102777. 6. Solca F, et al. J Pharmacol Exp Ther 2012;343:342–50 SCC, squamous cell carcinoma; TKI, tyrosine kinase inhibitor;

wt, wild type; NSCLC, non-small cell lung cancer

Study design

*Dose escalation to 50 mg and dose reduction to 30 or 20 mg permitted †Dose reduction to 100 or 50 mg permitted ‡Tumor assessment at baseline, Weeks 8, 12, 16; every 8 weeks thereafter

1. Edge S, et al. (Editor). AJCC Cancer Staging Manual. 7th ed. New

York: Springer-Verlag New York, 2010.

Key secondary

endpoint

Overall survival

Other secondary

endpoints:

ORR, DCR,

tumor shrinkage,

PRO, safety

1:1

Stratified by east Asian vs

non-east Asian

Afatinib

40 mg* QD

Erlotinib

150 mg† QD

SCC of the lung

(Stage IIIB/IV)1

Progressed after

≥4 cycles of a

first-line

platinum-doublet

ECOG PS 0–1

Adequate organ

function

Primary

endpoint

PFS by

independent

review‡

Timelines

1. Goss G, et al. Ann Oncol 2014;25(Suppl 4):iv426–iv470 (abstr 1222O)

Recruitment Follow-up

Mar 2012 Jan 2014

n=795

Mar 2015 Oct 2013

n=669

Primary OS

analysis

Updated PFS,

ORR, DCR,

PRO, safety

Primary PFS

analysis

ESMO 20141

• Primary endpoint: PFS by independent radiology review (RECIST version 1.1)

– Required ≥372 PFS events (90% power; HR=0.714*; median PFS 10 vs 14

weeks)

– Endpoint was met: PFS significantly improved favoring afatinib

• HR=0.82; 95% CI: 0.68–1.00; p=0.0427; median 2.4 vs 1.9 months1

• Key secondary endpoint: OS

– Required 632 death events (80% power to detect HR of 0.80*)

• Increase in median OS from 7.0 to 8.75 months

Statistical assumptions

*Two-sided 5% significance level 1. Goss G, et al. Ann Oncol 2014;25(Suppl 4):iv426–iv470 (abstr 1222O)

Recruitment

China

India

Korea

Singapore

Taiwan

Canada

Mexico

USA

Argentina

Chile Austria, Denmark, France,

Germany, Greece, Hungary,

Ireland, Italy, Netherlands,

Portugal, Spain, Turkey, UK

Patient disposition

Did not meet entry

criteria or did not enter

(n=182)

6 still on treatment 3 still on treatment

Assessed for eligibility (n=977)

307 died 325 died

392 treated 395 treated

Randomized (n=795)

Afatinib (n=398) Erlotinib (n=397)

Demographics and baseline characteristics

*Includes Black/African American and American Indian/Alaska Native; †Fifteen pack years and stopped >1 year before diagnosis; ‡Seventy-one (17.8%) and 85 (21.4%) patients were

current smokers, respectively; § <1% were ECOG PS 2; ¶ ≤1% were stage IIIA; ||<1% were undifferentiated (considered to be of squamous histology); **Percentages may not total 100

due to rounding

Afatinib**

n=398

Erlotinib**

n=397

Median age (years) 65 64

Male (%) 84 83

Race (%)

Asian 24 24

East Asian 22 22

White 72 73

Other* 2 3

Smoking history (%)

Never smoker 7 5

Light ex-smoker† 3 3

Current and other ex-smoker‡ 91 92

ECOG§ (%) 0/1 32/68 34/66

Clinical stage¶ (%) IIIB/IV 12/88 12/87

Histology|| (%) Squamous 96 96

Mixed 4 4


chemotherapy (%)

CR/PR 47 47

SD 41 42

Unknown 12 11

Primary analysis of OS (n=795)

Median follow-up time: 18.4 months

Afatinib

n=398

Erlotinib

n=397

Median, months

(95% CI)

7.9

(7.2–8.7)

6.8

(5.9–7.8)

HR (95% CI) 0.81 (0.69–0.95)

p value 0.0077

3 6 9 12 15 30 18 21 24 27 Time of overall survival (months)

0.2

0.4

0.6

0.8

1.0

0

Esti

mate

d O

S p

rob

ab

ilit

y

0

36.4%

28.2%

22.0%

14.4%

Afatinib

Erlotinib

No. at risk

398 316 249 170 124 82 47 28 10 4 0

397 305 210 150 94 54 30 11 4 2 0

Factors Patients HR

Overall 795 0.81 (0.69–0.95)

Age

<65 years 399 0.68 (0.55–0.85)

≥65 years 396 0.95 (0.76–1.19)

Gender

Male 666 0.82 (0.69–0.97)

Female 129 0.77 (0.51–1.14)

Race

Non-east Asian 623 0.87 (0.73–1.03)

East Asian 172 0.62 (0.44–0.88)

ECOG at baseline

0 260 0.76 (0.58–1.01)

1 531 0.80 (0.66–0.97)

Smoking history

Never smoker 44 0.77 (0.37–1.57)

Light ex-smoker 23 0.43 (0.16–1.12)

Current and other ex-smoker 728 0.81 (0.69–0.96)

Histology

Squamous 763 0.82 (0.70–0.96)

Mixed 32 0.55 (0.26–1.17)


chemotherapy

CR/PR 371 0.91 (0.72–1.15)

SD 328 0.71 (0.56–0.90)

Unknown 89 0.72 (0.44–1.17)

OS subgroup analysis


1/16 1/4 1 4 16

Post-progression therapies

Afatinib

n=392

Erlotinib

n=395

Subsequent systemic treatment (%) 46.4 48.6

Chemotherapy (%) 44.9 46.8

Docetaxel 23.7 26.1

Platinum-based doublet 11.2 10.9

Gemcitabine 10.5 10.9

Vinorelbine 9.4 8.6

EGFR-targeted (%) 3.1 2.0

Erlotinib 2.3 2.0

Afatinib 0.5 0.0

Immune checkpoint inhibitor (%) 0.3 0.0

Other (%) 1.3 2.8

Data cut-off February 02 2015

PFS: independent review Updated with all randomized patients (n=795)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Esti

mate

d P

FS

pro

bab

ilit

y

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

Afatinib

n=398

Erlotinib

n=397

Median, months

(95% CI)

2.6

(2.0–2.9)

1.9

(1.9–2.1)

HR (95% CI) 0.81 (0.69–0.96)

p value 0.0103

Afatinib

No. at risk

398 139 50 30 14 10 5 2 2 0

397 99 34 17 10 2 1 1 1 0 Erlotinib

Objective response and tumor shrinkage

• Duration of response was 7.29 months for

afatinib and 3.71 months for erlotinib

Afatinib

Erlotinib Patient index sorted by maximum decrease (%)

Maxim

um

decre

ase f

rom

baselin

e S

LD

(%

)

–100

–80

–60

–40

–20

0

20

40

60

80

100 ≥20% increase (n=62)

0–<20% increase (n=90)

>0–<30% decrease (n=81)

≥30% decrease (n=22)

Patient index sorted by maximum decrease (%) –100

–80

–60

–40

–20

0

20

40

60

80

100 ≥20% increase (n=74)

0–<20% increase (n=101)

>0–<30% decrease (n=77)

≥30% decrease (n=13)

Maxim

um

decre

ase f

rom

ba

selin

e S

LD

(%

)

50.5

5.5

39.5

2.8

0%

10%

20%

30%

40%

50%

60%

Disease controlrate

Objective responserate

Afatinib

Erlotinib

p=0.055

p=0.002 60

30

50

40

10

20

0

Pe

rce

nta

ge

Disease control

rate

Objective response

rate

Number of patients HR (95% Cl)

Coughing (Q1

from QLQ-LC13) 793 0.89 (0.72–1.09)

Dyspnea (Q3–Q5

from QLQ-LC13) 793 0.79 (0.66–0.94)

Pain (Q9, Q19

from QLQ-C30) 793 0.99 (0.82–1.18)

GHS/QoL (Q29–Q30

from QLQ-C30) 793 0.93 (0.78–1.12)

Patient-reported outcomes

PRO analysis from LUX-Lung 8 reported in Gadgeel, et al; abstract #8100, poster board #425 GHS, global health status; QoL, quality of life

p=0.04

p=0.78

p=0.06

p=0.03

1/4 1/2 1 2 4

Favors

afatinib

Favors

erlotinib

Symptom improvement Time to deterioration

Patients with improvement in

symptoms (%)

28.3

39.2

44.1

35.2

35.7

40.2

51.3

43.4

0 10 20 30 40 50 60

GHS/QoL (Q29–Q30 from QLQ-C30)

Pain (Q9, Q19from QLQ-C30)

Dyspnea (Q3–Q5 from QLQ-LC13)

Coughing (Q1from QLQ-LC13)

Afatinib Erlotinib

Coughing (Q1

from QLQ-LC13)

Dyspnea (Q3–Q5

from QLQ-LC13)

Pain (Q9, Q19

from QLQ-C30)

GHS/QoL (Q29–Q30

from QLQ-C30)

Adverse events: overall summary

*Interstitial lung disease (n=2), pneumonia, respiratory failure, acute renal failure, and general physical health deterioration (one patient each) †Interstitial lung disease, pneumonitis, pneumonia, intestinal obstruction, and peritonitis (one patient each)

Events (%)

Afatinib

n=392

Erlotinib

n=395

Any AE 99.5 97.5

Drug-related AEs 93.4 81.3

AEs leading to dose reduction 26.5 14.2

AEs leading to discontinuations 20.2 17.0

CTCAE grade 3 or higher 57.1 57.4

Serious AEs 44.1 44.1

Drug-related fatal AEs 1.5* 1.3†

Drug-related AEs (>10%)

*Grouped terms

Afatinib

n=392

Erlotinib

n=395

AE category, % All Grade 3 Grade 4 All Grade 3 Grade 4

Diarrhea 70 10 1 33 2 <1

Rash/acne* 67 6 0 67 10 0

Stomatitis* 29 4 0 9 0 0

Fatigue* 15 2 0 12 2 0

Nausea 13 1 0 7 1 0

Decreased appetite 13 1 0 10 1 0

Paronychia* 11 1 0 4 <1 0

Dry skin 9 1 0 10 0 0

Pruritus 8 <1 0 12 0 0

Vomiting 8 1 0 3 1 0

Dehydration 4 1 1 1 1 0

• FoundationOne™ NGS platform used to assess 300 genes

• 238 patient samples analyzed

• EGFR aberrations infrequent and balanced between arms

– EGFRm+ n=14, not concentrated in east Asian patients

– CNA n=15

– No correlation of EGFR aberrations with PFS/OS

• Results to be presented at an upcoming congress

Ongoing tumor genomic analysis

NGS, next generation sequencing; CNA, copy number alteration

• LUX-Lung 8 is the largest Phase III trial in the second-line treatment for SCC of

the lung

• In this head to head trial, afatinib showed a significant reduction in the risk of

death and disease progression by 19% when compared to erlotinib

• Consistent advantage across all endpoints and subgroups

• Overall symptom relief and QoL measures favoring afatinib

• Pattern of AEs consistent with EGFR inhibition in both arms with similar rate of

severe, serious and fatal AEs

• Afatinib should be the TKI of choice in second-line treatment of patients with

SCC of the lung

Summary

• We thank all patients, families, investigators, independent DMC and staff

participating in LUX-Lung 8 DMC members: Lesley Seymour (Chair), Chandra Prakash Belani, Nick Thatcher, Bruce Turmbull. Members of the LUX-Lung 8 study group: publication steering

committee: Jean-Charles Soria, Glenwood Goss, Andrea Ardizzoni, Enriquetta Felip, Shirish Gadgeel, Vassilis Georgoulias, Shun Lu, Vikram Chand.

Investigators: Argentina: Luis Fein, Claudio Martin, Norma Pilnik, Eduardo Richardet; Austria: Otto Burghuber, Wolfgang Eisterer, Martin Flicker, Roland

Kropfmüller, Andrea Mohn-Staudner; Canada: Richard Gregg, Vera Hirsh, Christopher Lee; Chile: Osvaldo Aren, Christian Lorenzo Caglevic Medina, Francisco

Javier Orlandi Jorquera, Luis Alejandro Matamala Rebelledo; China: Gang Cheng, Jifeng Feng, Chengping Hu, Wei Li, Shun Lu, Shukui Qin, Jie Wang, Li Zhang,

Caicun Zhou; Denmark: Karin Holmskov Hansen, Anders Mellemgaard, Kim Wederwang; France: Nathalie Baize, Fabrice Barlesi, Anatole Cessot, François

Chomy, Eric Dansin, Charles Dayen, Didier Debieuvre, Patrick Dumont, Sylvie Friard, Sylvestre Le Moulec, Hervé Lena, Anne Madroszyk, Patrick Merle, Olivier

Molinier, Isabelle Monnet, Elizabeth Quoix, Arnaud Scherpereel, Jean-Charles Soria, Gérard Zalcman; Germany: Lars Arne Berger, Nicolas Dickgreber, Wilfried

Eberhardt, Martin Faehling, Gerald Schmid-Bindert, Claus-Peter Schneider, Martin Sebastian, Monika Serke, Cornelius Waller, Rainer Wiewrodt; Greece:

Athanasios Athanasiadis, Vasilios Georgoulias, Christos Papandreou, Dimosthenis Skarlos, Konstantinos Syrigos; Hungary: Krisztina Bogos, Andrea Fulop,

Gabriella Herodek, Albert Istvan, Zsolt Kiraly, György Losonczy, Gyula Ostoros, Veronika Sarosi, Attila Somfay, Peter Szabo, Mark Zsuzsanna; India: Chanchal

Goswami, Minish Jain, Niti Raizada Narang, Rajiv Paliwal, Kumar Prabhash, Anita Ramesh, S Subramanian, Srinivasan Venkatesan; Ireland: Sinead Cuffe; Italy:

Alba Brandes, Federico Cappuzzo, Libero Ciuffreda, Adolfo Favaretto, Francesco Ferrau, Alessandro Morabito, Pasqualina Giordano, Rodolfo Passalacqua,

Armando Santoro, Angela Maria Sibau, Marcello Tiseo, Enrico Vasile; Mexico: Oscar Gerardo Arrieta Rodriguez, Ángel Gomez Villanueva, Francisco Alejo

Medina Soto; The Netherlands: Joachim Aerts, Bonne Biesma, Anne-Marie Dingemans, Gerarda Herder, JM Smit, Ben van den Borne; Portugal: Teresa

Almodovar, Isabel Azevedo, Fernando Barata, Bárbara Parente, Henrique Queiroga, Encarnacao Teixeira; Singapore: Yee Hong Chia, Eng Huat Tan; South

Korea: Eun Kyung Cho, Jin-Hyoung Kang, Hoon-Gu Kim, Hoon Kyo Kim, Sang-We Kim, Jong-Seok Lee, Ki Hyeong Lee, Keunchil Park, Joo Min Young, Spain:

Manuel Cobo, Javier De Castro, Enriqueta Felip, Amelia Insa, Rosario García Campelo, Jose Luis Gonzalez Larriba, Delores Isla, Margarida Majem, Jose

Manuel Trigo; Taiwan: Gee-Chen Chang, Te-Chun Hsia, Chun-Liang Lai, Chun-Ming Tsai, Chin-Chou Wang, Cheng-Ta Yang, James Chin-Hsin Yang; Turkey:

Isikdogan Abdurrahman, Mehmet Aliustaoglu, Hasan Coskun, Evrensel Turkkan, Erdem Göker, Salih Guclu, Murat Kiyik, Alper Sevinc; UK: Rachael Barton,

Ekaterini Boleti, Samual Chan, Sanjay Popat, Vanessa Potter, Riyaz Shah, Nicola Steele, Elizabeth Toy, Ian Woolhouse; USA: Athanassios Argiris, Maria

Baggstrom, Lyudmila Bazhenova, Deepti Behl, Nagarajan Chandrasekaran, Shirish Gadgeel, Jerome Goldschmidt, Stephen Graziano, Sucharu Prakash, Missak

Haigentz, Paul Hesketh, Sujith Kalmadi, Barry Kaplan, Farrah Khan, Waseemullah Khan, Leonard Klein, Goetz Kloecker, Ira Oliff, Gregory Otterson, John

Paschold, Taral Patel, Nathan Pennell, Bilal Piperdi, Luis Raez, Mark Rarick, Edgardo Santos, Pedro Sanz-Altamira, Deric Savior

Acknowledgments

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