1. LUX-Lung 8
A randomised, open-label phase III trial of afatinib versus erlotinib
in patients with advanced squamous cell carcinoma of the lung
as second-line therapy following first-line platinum-based chemotherapy
Procedure ID: XXXX – February 2016
European indication and usage:
Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF® and in the U.S. under the brand name GILOTRIF® for use in patients with distinct types of EGFR mutation-positive NSCLC. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. Afatinib is not approved in other indications.
NSCLC=non-small cell lung cancer; OS=overall survival.
Soria JC et al. Lancet Oncol. 2015;16(8):

2. Contents LUX-Lung clinical trials The ErbB Family in squamous NSCLC
LUX-Lung 8: study design
LUX-Lung 8: efficacy
LUX-Lung 8: tumour genetic analysis
LUX-Lung 8: adverse events
LUX-Lung 8: patient-reported outcomes
Conclusions

3. LUX-LUNG Clinical Trials
Overview

4. Afatinib has been studied in a comprehensive NSCLC clinical trial programme
EGFR TKI-naive
EGFR M+
EGFR TKI pre-treated
Treatment beyond progression
Squamous cell carcinoma chemotherapy pre-treated
LUX-Lung 2
Phase II
Published
LUX-Lung 1
Phase IIB/III – Pivotal trial
Published
LUX-Lung 5
Phase III Published
LUX-Lung 8
Phase III Published
LUX-Lung 3
Phase III – Pivotal trial Published
LUX-Lung 4
Phase I/II
Published
LUX-Lung 6
Phase III – Pivotal trial
Published
LUX-Lung 7
Phase IIb
Reported
LL1: Miller VA et al. Lancet Oncol. 2012;13(5):
LL2: Yang JC et al. Lancet Oncol. 2012;13(5):
LL3: Sequist LV et al. J Clin Oncol. 2013;31(27):
LL4: Katakami N et al. J Clin Oncol. 2013;31(27):
LL5: Schuler M et al. J Clin Oncol 2014;32:(suppl; abstr 8019).
LL6: Wu YL et al. Lancet Oncol. 2014;15(2):
LL7: Park K et al. Abstract LBA2 and oral presentation. European Society for Medical Oncology (ESMO) ASIA, Singapore, 20th December 2015.
LL8: Soria JC et al. Lancet Oncol. 2015;16(8):

5. The ErbB Family
in squamous NSCLC

6. Frequency of ErbB aberrations in squamous NSCLC
ErbB Family dysregulation plays an important role in the pathogenesis of squamous NSCLC
The ErbB Family of receptors is composed of 4 members: EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4
While ErbB Family dysregulation in adenocarcinoma is predominantly driven by mutations in EGFR, multiple oncogenic alterations across ErbB Family receptors, including overexpression, amplification/polysomy and mutation, have been demonstrated in squamous NSCLC
Frequency of ErbB aberrations in squamous NSCLC
ErbB aberrations
Frequency (%)
EGFR overexpression
57-82
EGFR amplification/polysomy
7-26
EGFRvlll mutation
3-5
EGFR kinase domain mutation
1-3
ErbB2 mutation/amplification 4
ErbB3 overexpression 28
ErbB3 mutation
1-2
ErbB4 mutation
Hall PE et al. Future Oncol. 2015;11(15):

7. Afatinib is the an irreversible ErbB Family Blocker
EGFR/ HER2
HER2/
ErbB3
ErbB3/
ErbB4
Gefitinib
Erlotinib
Afatinib
Afatinib
RAS
P13K
RAF
AKT
MEK
ERK
mTOR
PROLIFERATION
SURVIVAL
Whereas erlotinib reversibly inhibits EGFR,
afatinib irreversibly blocks signalling from all ErbB Family receptors1,2
Solca F et al. J Pharmacol Exp Ther. 2012;343(2):
TARCEVA® (erlotinib) Summary of Product Characteristics, 2014.

8. LUX-LUNG 8
Study design

9. Key secondary endpoint Secondary endpoints included
Afatinib was studied vs erlotinib in a head-to-head trial in squamous NSCLC
LUX-Lung 8: a large, multi-national, prospective, randomised phase III trial
Afatinib
40 mg oral once daily
n=398
Advanced NSCLC (Stage IIIB/IV)
Squamous histology*
≥4 cycles of a first-line platinum doublet
ECOG PS 0–1
Adequate organ function
Randomization 1:1 N=795
Erlotinib
150 mg oral once daily
n=397
Median follow-up for:
• Primary PFS analysis: 6.7 months
• Primary OS and follow-up PFS analysis: 18.4 months
Progression-free survival (PFS), measured by an independent central radiology review
Primary endpoints
Key secondary endpoint
Overall survival (OS)
Objective response rate
Disease control rate
Tumour shrinkage
Patient-reported outcomes, including symptom control and health-related quality of life as measured through EORTC questionnaires
Secondary endpoints included
* Including mixed histology.
ECOG=Eastern Cooperative Oncology Group; EORTC=European Organisation for Research and Treatment of Cancer.
Soria JC et al. Lancet Oncol. 2015;16(8):

10. LUX-Lung 8 – 183 cancer centres in 23 countries
Canada
Mexico
USA
NORTH AMERICA
Austria, Denmark, France, Germany, Greece, Hungary, Ireland, Italy, Netherlands, Portugal, Spain, Turkey, UK
EUROPE
China India Korea Singapore Taiwan
ASIA
Argentina Chile
SOUTH AMERICA
Soria JC et al. Lancet Oncol. 2015;16(8):

11. Patient demographics and characteristics were well balanced between the 2 treatment arms
Afatinib
(n=398)
Erlotinib
(n=397)
Sex
Male
Female
335 (84%)
63 (16%)
331 (83%)
66 (17%)
Median age (years, range)
65.0 (36–84)
64.0 (35–88)
Age group
<65 years
≥65 years
189 (47%)
209 (53%)
210 (53%)
187 (47%)
Baseline ECOG PS 1 2*
126 (32%)
269 (68%)
3 (<1%)
134 (34%)
262 (66%)
1 (<1%)
Ethnic origin
Non-eastern Asian
Eastern Asian
312 (78%)
86 (22%)
311 (78%)
Smoking status
Never smoker
Light ex-smoker†
Current and other ex-smoker‡
26 (7%)
11 (3%)
361 (91%)
18 (5%)
12 (3%)
367 (92%)
Median time since diagnosis (years, range)
0.8 (0.2–9.3)
0.7 (0.2–13.5)
Tumour histology§
Squamous
Mixed
381 (96%)
17 (4%)
382 (96%)
15 (4%)
Previous platinum doublet
Carboplatin-based
Cisplatin-based
Other
249 (63%)
163 (41%)
5 (1%)
229 (58%)
198 (50%)
8 (2%)
Clinical stage at screening
IIIA
IIIB IV
48 (12%)
349 (88%)
4 (1%)
345 (87%)
Best response to chemotherapy¶
CR or PR SD
Unknown
186 (47%)
161 (40%)
47 (12%)
185 (47%)
167 (42%)
42 (11%)
Data are n (%), unless stated otherwise. ECOG PS=Eastern Cooperative Oncology Group performance status. CR=complete response. PR=partial response. SD=stable disease. *Protocol violations. † <15 pack-years and stopped >1 year before diagnosis. ‡ 71 (18%) versus 85 (21%) were current smokers. §Three patients in the erlotinib group had undifferentiated tumour histology but were considered to be squamous by the treating investigator. ¶ Seven patients (four in the afatinib group and three in the erlotinib group) had a best response of progressive disease on chemotherapy.
Soria JC et al. Lancet Oncol. 2015;16(8):

12. LUX-LUNG 8
Efficacy

13. Afatinib significantly increased PFS vs erlotinib
Progression-free survival by independent review (primary endpoint)
At time of OS analysis
1.0
Afatinib (n=398)
Erlotinib (n=397)
0.8
2.6
months
Hazard ratio 0.81
(95% CI, )
P=0.0103
0.6
Progression-free survival (%)
0.4
1.9
months
0.2 3 6 9 12 15 18 21 24 27
Months
At the time of primary PFS analysis (2014), median PFS was 2.4 months for afatinib vs 1.9 months for erlotinib (HR 0.82; P=0.0427)
OS=overall survival; PFS=progression-free survival.
Soria JC et al. Lancet Oncol. 2015;16(8):

14. PFS benefit was consistent across clinically relevant subgroups
Progression-free survival by subgroups
Events/patients
Median progression-free survival, months (95% CI)
HR (95% Cl)
P interaction
Afatinib
Erlotinib
Total
605/795
2·6 (2·0–2·9)
1·9 (1·9–2·1)
0·81 (0·69–0·96)
Ethnic origin 
Non-eastern Asian
487/623
2·5 (2·0–2·9)
2·0 (1·9–2·2)
0·90 (0·75–1·07)
0·0122
Eastern Asian
118/172
2·8 (1·9–7·4)
1·9 (1·9–2·8)
0·54 (0·37–0·79)
Sex 
Male
512/666
2·0 (1·9–2·3)
0·83 (0·70–0·99)
0·3863
Female
93/129
2·7 (1·9–3·8)
1·9 (1·8–2·1)
0·74 (0·49–1·11)
Best response to first-line chemotherapy 
CR or PR
287/371
2·7 (2·0–3·1)
1·9 (1·9–2·3)
0·87 (0·69–1·10)
0·2815 SD
246/328
2·6 (1·9–3·3)
2·0 (1·9–2·7)
0·83 (0·64–1·06)
Unknown
65/89
2·8 (1·9–5·6)
1·9 (1·8–2·8)
0·54 (0·33–0·90)
Interval between end of first-line and beginning of second-line 
<16 weeks
340/436
1·9 (1·9–2·4)
1·9 (1·9–2·0)
0·87 (0·71–1·08)
0·5556
≥16 weeks
265/359
3·3 (2·7–3·7)
2·2 (1·9–2·8)
0·77 (0·60–0·98)
Histology 
Squamous histology
579/763
0·82 (0·70–0·97)
0·1955
Mixed squamous histology
26/32
1·9 (0·9–5·3)
1·6 (0·4–2·8)
0·61 (0·28–1·33)
Smoking history 
Never smoker
32/44
1·8 (1·5–5·5)
0·55 (0·27–1·11)
0·1506
Light ex-smoker*
14/23
5·6 (1·0–NR)
1·9 (1·6–6·3)
0·44 (0·14–1·37)
Current and other ex-smoker
559/728
2·6 (2·0–2·8)
1·9 (1·9–2·2)
0·85 (0·72–1·01)
ECOG PS at baseline
207/260
3·0 (2·0–4·3)
0·68 (0·51–0·89)
0·2488 1
395/531
2·5 (1·9–2·8)
0·87 (0·72–1·06)
Age 
<65 years
301/399
0·81 (0·65–1·02)
0·7657
≥65 years
304/396
2·8 (2·4–3·7)
2·0 (1·9–2·4)
0·83 (0·66–1·04)
Maintenance therapy received No
566/750
0·81 (0·68–0·95)
0·7159
Yes
39/45
2·0 (1·7–4·3)
1·9 (1·3–3·0)
0·88 (0·47–1·68)
0.25 1 4 16
0.0625
Favours afatinib
Favours erlotinib
PFS=progression-free survival.
Soria JC et al. Lancet Oncol. 2015;16(8):
HR=hazard ratio. CR=complete response. PR=partial response. SD=stable disease. ECOG PS=Eastern Cooperative Oncology Group performance status. NR=not reached. *<15 pack-years and stopped >1 year before diagnosis.

15. Afatinib significantly increased OS vs erlotinib
Overall survival (key secondary endpoint)
Overall survival (%)
0.2
0.4
0.6
0.8
1.0
0.0
Afatinib (n=398)
7.9
months
Erlotinib (n=397)
Hazard ratio 0.81
(95% CI, )
P=0.0077
6.8
months 3 6 9 12 15 18 21 24 27 30
Time (months)
19% relative reduction in the risk of death vs erlotinib (HR 0.81, 95% CI ; P=0.0077)
The survival benefit was evident from the first pre-specified time point measured at 6 months and maintained at 18 months
OS unlikely to have been affected by subsequent therapies as a similar proportion of patients in both arms received additional treatment(s)
OS=overall survival.
Soria JC et al. Lancet Oncol. 2015;16(8):

16. OS benefit was consistent across clinically relevant subgroups
Overall survival by subgroups
0.25 1 4 16
0.0625
HR (95% Cl)
Events/patients
P interaction
Median overall survival, months (95% CI)
Afatinib
Erlotinib
Total
632/795
7·9 (7·2–8·7)
6·8 (5·9–7·8)
0·81 (0·69–0·95)
Ethnic origin 
Non-eastern Asian
500/623
7·5 (6·7–8·4)
6·7 (5·8–7·8)
0·87 (0·73–1·03)
0·1101
Eastern Asian
132/172
9·6 (7·3–14·1)
7·2 (4·9–8·9)
0·62 (0·44–0·88)
Sex 
Male
533/666
8·1 (7·2–9·0)
6·9 (5·9–8·0)
0·82 (0·69–0·97)
0·7032
Female
99/129
7·3 (5·4–10·9)
5·8 (4·6–8·2)
0·77 (0·51–1·14)
Best response to first-line chemotherapy
CR or PR
285/371
8·5 (7·3–10·7)
8·4 (6·9–10·2)
0·91 (0·72–1·15)
0·2584 SD
271/328
7·4 (6·5–8·7)
5·8 (4·7–6·9)
0·71 (0·56–0·90)
Unknown
69/89
8·3 (6·3–10·9)
5·8 (3·7–9·4)
0·72 (0·44–1·17)
Interval between end of first-line and beginning of second-line 
<16 weeks
366/436
6·6 (5·6–7·7)
5·6 (4·9–6·4)
0·78 (0·63–0·96)
0·4493
≥16 weeks
266/359
9·2 (7·9–11·6)
8·9 (7·8–10·1)
0·88 (0·69–1·12)
Histology
Squamous histology
602/763
8·0 (7·2–8·8)
6·9 (6·2–8·0)
0·82 (0·70–0·96)
0·1997
Mixed squamous histology
30/32
7·4 (0·9–16·5)
3·6 (1·4–5·3)
0·55 (0·26–1·17)
Smoking history
Never smoker
34/44
7·6 (3·2–15·4)
6·8 (1·8–13·2)
0·77 (0·37–1·57)
0·8177
Light ex-smoker*
19/23
12·4 (4·9–17·0)
8·2 (3·5–10·8)
0·43 (0·16–1·12)
Current and other ex-smoker
579/728
7·8 (7·1–8·7)
0·81 (0·69–0·96)
ECOG PS at baseline
197/260
12·0 (8·0–14·1)
9·6 (7·4–11·6)
0·76 (0·51–1·01)
0·9088 1
431/531
6·7 (6·1–8·1)
5·7 (5·1–6·7)
0·80 (0·66–0·97)
Age
<65 years
327/399
8·4 (7·2–11·2)
6·1 (5·3–7·3)
0·68 (0·55–0·85)
0·0498
≥65 years
305/396
7·4 (6·4–8·6)
7·7 (6·4–8·8)
0·95 (0·76–1·19)
Maintenance therapy received No
599/750
7·8 (7·2–8·7)
6·8 (5·8–7·8)
0·79 (0·68–0·93)
0·4135
Yes
33/45
8·4 (6·5–13·8)
7·0 (2·1–24·7)
1·07 (0·52–2·17)
Favours afatinib
Favours erlotinib
OS=overall survival.
Soria JC et al. Lancet Oncol. 2015;16(8):
HR=hazard ratio. CR=complete response. PR=partial response. SD=stable disease. ECOG PS=Eastern Cooperative
Oncology Group performance status. *<15 pack-years and stopped >1 year before diagnosis.

17. Similar proportion of patients in both arms received additional systemic treatment(s)
Across all subsequent lines of therapy, n (%)
Afatinib
(n=392)
Erlotinib
(n=395)
Subsequent systemic treatment
182 (46.4)
192 (48.6)
Chemotherapy
176 (44.9)
185 (46.8)
Docetaxel
93 (23.7)
103 (26.1)
Platinum-based doublet
44 (11.2)
43 (10.9)
Gemcitabine
41 (10.5)
Vinorelbine
37 (9.4)
34 (8.6)
EGFR-targeted
12 (3.1)
8 (2.0)
9 (2.3)
2 (0.5)
0 (0.0)
Immune checkpoint inhibitor
1 (0.3)
Other
5 (1.3)
11 (2.8)
Soria JC et al. Lancet Oncol. 2015;16(8):

18. Disease control rate and duration of response (secondary endpoints)
Afatinib provided greater and more durable tumour control than erlotinib
Disease control rate and duration of response (secondary endpoints)
Disease control rate
Afatinib (n=398)
Erlotinib (n=397)
Duration of response
P=0.002
Objective response rate (ORR) by independent review was 6% for afatinib vs 3% for erlotinib (P=0.0551)
ORR by investigator review was 11% for afatinib vs 4% for erlotinib (P=0.0005)
Soria JC et al. Lancet Oncol. 2015;16(8):

19. Tumour genetic analysis
LUX-LUNG 8
Tumour genetic analysis

20. Tumour samples were analysed as part of an on-going biomarker analysis
Performed on 238 (~30%) patients retrospectively selected based on efficacy endpoints with an enrichment of patients with long PFS (>2 months) in both treatment arms
Archival tumour tissue was assessed using the Foundation Medicine FoundationOne™ platform
Analysed ~300 cancer-related genes for copy number variations, gene rearrangements, and point mutations
Aimed to identify predictive marker(s) for patients benefitting on afatinib/erlotinib
Primary PFS analysis
1.0
Group 2 (control): Patients with little or no benefit from afatinib/erlotinib
0.8
0.6
Estimated PFS probability
Group 1: Patients benefiting from afatinib/erlotinib
0.4
0.2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time (months)
Soria JC et al. Oral presentation ORAL32.01 at 16th World Conference on Lung Cancer, Denver, 2015.
Soria JC et al. Lancet Oncol. 2015;16(8):

21. No significant differences in frequency of genetic anomalies observed between groups
LL8 subset*
(n=238)
Group 1†
PFS >2 months (n=144)
Group 2†
PFS ≤2 months (n=94)
SVs
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
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
CNAs
SOX2
43.7
49.3
KLHL6
40.3
46.5
30.9
PIK3CA
37.0
42.4
28.7
MAP3K13
36.1
BCL6
31.1
34.0
26.6
FGF12
30.6
25.5
10.1
9.7
10.6
6.3
7.6
HER 2
3.8
2.1
6.4
Predefined families:
any aberration
ErbB
29.0
31.9
24.5
FGF
58.8
56.3
62.8
SV=single nucleotide variants; CNA=copy number alterations.
* Tumour 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
Soria JC et al. Oral presentation ORAL32.01 at 16th World Conference on Lung Cancer, Denver, 2015.
Soria JC et al. Lancet Oncol. 2015;16(8):

22. Aberration present (%)
Specified genetic alterations not predictive of PFS benefit with afatinib vs erlotinib
Subgroup
Aberration present (%)
HR (95% CI)†
LL8
LL8 subset* (n=238)
0.81 (0.69–0.96)
0.65 (0.48–0.87)
SVs
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)
CNAs
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
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
0.69 (0.49–0.97)
0.57 (0.31–1.05)
Predefined families:
any aberration
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)
0.5
1.0
2.0
1.5
2.5
Favours afatinib
Favours erlotinib
SV=single nucleotide variants; CNA=copy number alterations.
* Tumour genetic analysis subset; † Interaction p values between yes/no on all markers >0.05
Soria JC et al. Oral presentation ORAL32.01 at 16th World Conference on Lung Cancer, Denver, 2015.
Soria JC et al. Lancet Oncol. 2015;16(8):

23. Aberration present (%)
Specified genetic alterations not predictive of OS benefit with afatinib vs erlotinib
Subgroup
Aberration present (%)
HR (95% CI)†
LL8
LL8 subset* (n=238)
0.82 (0.71–0.96)‡
0.73 (0.56–0.96)
SVs
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)
CNAs
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
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
0.76 (0.55–1.04)
0.77 (0.45–1.32)
Predefined families:
any aberration
ERBB
No (71.0)
Yes (29.0)
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)
Favours afatinib
Favours erlotinib
0.5
1.0
2.0
1.5
2.5
SV=single nucleotide variants; CNA=copy number alterations. * Tumour genetic analysis subset; † Interaction p values between yes/no on all markers >0.05. ‡ For this analysis, all available OS information was used, and data after 632 deaths were not censored.
Soria JC et al. Oral presentation ORAL32.01 at 16th World Conference on Lung Cancer, Denver, 2015.
Soria JC et al. Lancet Oncol. 2015;16(8):

24. Tumour genetic analysis conclusions
Squamous NSCLC has a high somatic mutation burden and complex tumour 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
Specified tumour genetic alterations:
are not predictive of benefit with afatinib treatment compared with erlotinib
do not appear to be associated with longer PFS/OS, regardless of treatment
It is unlikely that the improved survival outcomes with afatinib were driven by molecular aberrations of EGFR
Survival improvements might be a result of the higher potency and broader irreversible ErbB blockade of afatinib in this setting compared with EGFR inhibition alone
Soria JC et al. Oral presentation ORAL32.01 at 16th World Conference on Lung Cancer, Denver, 2015.
Soria JC et al. Lancet Oncol. 2015;16(8):

25. LUX-LUNG 8
Adverse events

26. Pattern of AEs consistent with the known profiles of both agents
The overall rate of adverse events and CTCAE ≥ grade 3 events was similar for both treatments (afatinib vs erlotinib: 99% vs 97%; 57% vs 57%, respectively)
The most common AEs differed between treatment arms: diarrhoea, rash/acne, stomatitis and fatigue with afatinib; rash/acne, diarrhoea, fatigue and pruritus with erlotinib
Treatment-related discontinuation due to any AE was similar in both arms (20% vs 17% for afatinib vs erlotinib)
The most common AEs with afatinib were predictable and generally manageable through supportive care and dose reduction
Afatinib (n=392)
Erlotinib (n=395)
Grade 1
Grade 2
Grade 3
Grade 4
Diarrhoea
165 (42%)
68 (17%)
39 (10%)
2 (<1%)
94 (24%)
28 (7%)
9 (2%)
1 (<1%)
Rash/acne†
157 (40%)
83 (21%)
23 (6%)
0 (0%)
142 (36%)
41 (10%)
Stomatitis†
65 (17%)
32 (8%)
16 (4%)
21 (5%)
13 (3%)
Fatigue†
33 (8%)
20 (5%)
6 (2%)
24 (6%)
17 (4%)
7 (2%)
Nausea
35 (9%)
4 (1%)
5 (1%)
3 (<1%)
Decreased appetite
31 (8%)
15 (4%)
Paronychia†
11 (3%)
Dry skin
34 (9%)
Pruritus
22 (6%)
37 (9%)
10 (3%)
Vomiting
8 (2%)
Dehydration
Includes events that occurred in >10% of patients with grade 1-2 adverse events, or >1% patients with grade 3-5 adverse events in any treatment group. † Group term.
AE=adverse event.
Soria JC et al. Lancet Oncol. 2015;16(8):

27. Patient-reported outcomes
LUX-LUNG 8
Patient-reported outcomes

28. Assessment of Patient-Reported Outcomes
Assessed using the EORTC core quality of life questionnaire, QLQ-C30, and its lung cancer-specific module, QLQ-LC13
At the first visit of each treatment course
And at the end of treatment
Scores were converted to a scale and analysed in line with EORTC scoring algorithms
Prespecified symptoms relevant to lung cancer (cough, dyspnoea, and pain) were analysed alongside GHS/QoL for status change, TTD, and change in scores over time
Cough: Question (Q)1 from QLQ-LC13
Dyspnoea: Q3-Q5 from QLQ-LC13
Pain: Q9, Q19 from QLQ-C30
GHS/QoL: Q29, Q30 from QLQ-C30
Questionnaire completion rates were high throughout treatment
Afatinib: range 77.3%-99.0%; erlotinib: range 68.7%-99.0%
EORTC=European Organisation for Research and Treatment of Cancer; TTD = time to deterioration.
Aaronson et al. J Natl Cancer Inst. 1993;85(5):
Bergman et al. Eur J Cancer. 1994;30A(5):
Gadgeel et al. ASCO Abstract 8100, Poster 425.

29. Afatinib significantly improved cough and quality of life vs erlotinib
Patients with improvement in symptoms (EORTC scores improved by ≥10 points)
P=0.061
Afatinib (n=398)
Erlotinib (n=397)
P=0.029
P=0.775
P=0.041
The number of patients reporting improved GHS/QoL and cough was significantly higher with afatinib than erlotinib
While more patients reported improved dyspnoea with afatinib, the different was not statistically significant as the effect was primarily concentrated in those reporting improvement in “dyspnoea walked” (34.6% vs 26.5%, P=0.022)
Improvement in pain was similar across both treatment arms
Improvement=a linear transformation was applied to standardise the raw score to a range from 0 to 100. A 10-point change is accepted as the threshold for being clinically meaningful (Osoba D et al. J Clin Oncol. 1998;16(1):139-44).
EORTC=European Organisation for Research and Treatment of Cancer.
Soria JC et al. Lancet Oncol. 2015;16(8):
Gadgeel et al. Abstract 8100 and poster 425 presented at the American Society of Clinical Oncology (ASCO) congress 2015, Chicago, US.

30. Afatinib significantly delayed deterioration of dyspnoea vs erlotinib
Time to deterioration
1.0
Afatinib
Erlotinib
0.8
Hazard ratio 0.79
(95% CI, )
P=0.0078
2.6
months
0.6
Estimated Probability
0.4
1.9
months
0.2
0.0 3 6 9 12 15 18 21 24 27
Time (months)
Trend toward delayed TTD of cough with afatinib vs erlotinib (median 4.5 vs 3.7 months; HR 0.89, 95% CI 0.72–1.09, P=0.2562)
TTD of pain was similar across both treatment arms (median 2.5 vs 2.4 months; HR 0.99, 95% CI 0.82–1.18, P=0.8690)
TTD=time to deterioration, the time from randomisation to first appearance of a score ≥10 points lower than the baseline score.
Soria JC et al. Lancet Oncol. 2015;16(8):
Gadgeel et al. Abstract 8100 and poster 425 presented at the American Society of Clinical Oncology (ASCO) congress 2015, Chicago, US.

31. Adjusted Mean Difference
Mean scores for cough, dyspnoea and pain over time favoured afatinib vs erlotinib
No. of Patients
Adjusted Mean Difference
P Value
Coughing (Q1 from QLQ-C13)
604
-3.5
0.009
Dyspnoea (Q3-Q5 from QLQ-LC13)
603
0.002
Pain (Q9, Q19 from QLQ-C30)
609
-2.7
0.038
GHS/QoL (Q29-Q30 from QLQ-C30)
602
-1.6
-20
-10 10 20
Favours afatinib
Favours Erlotinib
There were no significant differences between afatinib and erlotinib for changes in GHS/QoL over time but, with the exception of social functioning, changes in functional scales over time significantly favoured afatinib
GHS=global health status.
Gadgeel et al. Abstract 8100 and poster 425 presented at the American Society of Clinical Oncology (ASCO) congress 2015, Chicago, US.

32. CONCLUSIONS

33. Afatinib significantly increased OS vs erlotinib in squamous NSCLC
LUX-Lung 8 is the largest prospective trial comparing two EGFR targeting agents for second-line treatment of patients with squamous NSCLC
Afatinib demonstrated superior efficacy vs erlotinib:
Significantly increased PFS (median 2.6 vs 1.9 months; HR 0.81; P=0.0103)
Significantly extended OS (median 7.9 vs 6.8 months; HR=0.81; P=0.0077)
Significantly improved disease control rate (51% vs 40%; P=0.002)
PFS and OS consistent across clinically relevant subgroups
Afatinib significantly improved cough and global health status/health-related quality of life vs erlotinib
Afatinib and erlotinib demonstrated a pattern of AEs consistent with the known profiles of both agents
Afatinib represents a new treatment option for 2nd-line squamous NSCLC patients
Soria JC et al. Lancet Oncol. 2015;16(8):