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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
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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
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
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
• 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
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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)
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
• 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
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
• 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
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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)
Favours afatinib Favours erlotinib
0.5 0 1.5 2.0 1.0 2.5
SV
s
CN
As
Pre
defined fam
ilies:
any
aberr
ation
Favours afatinib Favours erlotinib
0.5 0 1.5 2.0 2.5 1.0
• There was no observed predictive association between genetic alterations and OS or PFS
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
• 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
Goss GD, et al. Abstract #3084 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 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,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
Congress (ECC), Vienna, Austria, 25–29 September 2015
• 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
Popat S, et al. Abstract #3085 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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
Popat S, et al. Abstract #3085 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
• 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
Popat S, et al. Abstract #3085 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
• 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
Popat S, et al. Abstract #3085 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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
Popat S, et al. Abstract #3085 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
• 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
Popat S, et al. Abstract #3085 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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 (
%)
Popat S, et al. Abstract #3085 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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
Popat S, et al. Abstract #3085 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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
Median (months) 2.6 1.9
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
Popat S, et al. Abstract #3085 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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
Median (months) 2.5 2.4
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
Popat S, et al. Abstract #3085 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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
Favours afatinib Favours erlotinib
• 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
Popat S, et al. Abstract #3085 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
• 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
Popat S, et al. Abstract #3085 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
• 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
Popat S, et al. Abstract #3085 presented at the European Cancer
Congress (ECC), Vienna, Austria, 25–29 September 2015
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)
CI, confidence interval; HR, hazard ratio
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)
CI, confidence interval; HR, hazard ratio
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
Favors afatinib Favors erlotinib
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
Best response to first-line
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)
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)
OS subgroup analysis
Favors afatinib Favors erlotinib
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