1. LUX-Lung 6 clinical trial
LUX-Lung 6 is a multi-national, prospective, randomised, phase III trial of afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced NSCLC harbouring EGFR mutations
Asian patients
Treatment-naïve
Advanced NSCLC stage IIIB/IV adenocarcinoma
EGFR M+
ECOG PS 0 or 1
Afatinib
40 mg oral once daily n=242
Gemcitabine/cisplatin
1000 mg/m2 D1, D8+75mg/m2
i.v. q21days up to 6 cycles
n=122
2:1 randomisation
Median follow-up:
For PFS: 16.6 months
For OS: 33 months
ECOG=Eastern Cooperative Oncology Group.
Wu et al. Lancet Oncol. 2014;15(2):

2. LUX-Lung 6 study endpoints
Primary endpoint
Progression-free survival (PFS) by independent review
Overall survival (OS)
Objective response rate
Disease control rate
Duration of response
Patient-reported outcomes, including symptom control and health-related quality of life as measured through EORTC questionnaires
Secondary endpoints included
EORTC=European Organisation for Research and Treatment of Cancer.
Wu et al. Lancet Oncol. 2014;15(2):

3. Patient demographics and characteristics were well balanced between the 2 treatment arms
Afatinib (n=242)
Gem/cis (n=122)
Sex, n (%)
Male
87 (36)
39 (32)
Female
155 (64)
83 (68)
Age, years, median (range)
58 (49–65)
58 (49–62)
Race, n (%)
South-east Asian
14 (6)
10 (8)
South Korean
11 (5)
2 (2)
Chinese
217 (90)
110 (90)
Smoking status, n (%)
Never smoked
181 (75)
99 (81)
Other current or ex-smoker
53 (22)
19 (16)
<15 pack-years and stopped >1 year ago
8 (3)
4 (3)
ECOG PS, n (%)
48 (20)
41 (34) 1
194 (80)
81 (66)
Adenocarcinoma stage*, n (%)
IIIB (wet)
16 (7)
6 (5) IV
226 (93)
116 (95)
EGFR mutation, n (%)
Exon 19 deletion
124 (51)
62 (51)
L858R
92 (38)
46 (38)
Other
26 (11)
14 (11)
* By American Joint Committee on Cancer, sixth edition.
Wu et al. Lancet Oncol. 2014;15(2):

4. LUX-LUNG 6
Efficacy

5. Afatinib significantly increased first-line PFS vs gemcitabine/cisplatin
Progression-free survival (primary endpoint)
All EGFR mutations
PFS rate (%)
0.2
0.4
0.6
0.8
1.0
0.0
Afatinib (n=242)
11.0
months
Gemcitabine/cisplatin (n=122)
Hazard ratio 0.28
(95% CI, )
P<0.0001
5.6
months 3 6 9 12 15 18 21 24 27
Time (months)
72% reduction in relative risk of death or tumour progression (HR 0.28, P<0.0001)
PFS consistently in favour of afatinib in all pre-specified subgroups (including gender, age, mutation etc.), achieving statistical significance in the subgroups of sufficient size
PFS=progression-free survival.
Wu et al. Lancet Oncol. 2014;15(2):

6. Afatinib demonstrated 13
Afatinib demonstrated 13.7 months median first-line PFS in investigator review
Progression-free survival (primary endpoint)
0.2
0.4
0.6
0.8
1.0
0.0
PFS rate (%)
Afatinib (n=242)
Gemcitabine/cisplatin (n=122)
Hazard ratio 0.26 (95% CI, )
P<0.0001
13.7
months
5.6
months
Time (months) 3 6 9 12 15 18 21 24 27
74% reduction in relative risk of death or tumour progression (HR 0.26, P<0.0001)
PFS=progression-free survival.
Wu et al. Lancet Oncol. 2014;15(2):

7. reduction in relative risk of death
Afatinib achieved over 1 year extended first-line OS vs gemcitabine/cisplatin in subgroup of del19 patients
LUX-Lung 6 preplanned subgroup analysis
Del19 mutations
Estimated OS probability
0.2
0.4
0.6
0.8
1.0
0.0
Afatinib (n=124)
31.4
months
Gemcitabine/cisplatin (n=62)
Hazard ratio 0.64
(95% CI, )
P=0.023
>12 months
increase median OS
>12 months
increase median OS
18.4
months
36%
reduction in relative risk of death 3 6 9 18 21 30 36 39 45 12 15 24 27 33 42
Time of overall survival (months)
36% reduction in relative risk of death in del19 patients (HR 0.64; P=0.0229)
OS in ITT population (N=364) was 23.1 and 23.5 months for afatinib vs gemcitabine/cisplatin, respectively (HR 0.93; P=0.61)
ITT=intent to treat; OS=overall survival.
Yang JC et al. Lancet Oncol. 2015;16(2):

8. Patient-reported outcomes
LUX-LUNG 6
Patient-reported outcomes

9. Proportion of patients (%) with improvement
Afatinib significantly improved disease-related cough, dyspnoea and pain compared with gemcitabine/cisplatin
afatinib (n=242)
Patients with improvement in symptoms (EORTC scores improved by ≥10 points)
P<0.0001
Afatinib (n=242)
P<0.0001
P=0.003
Gem/cis (n=122)
P=0.006
P=0.021
P=0.140
P=0.092
Proportion of patients (%) with improvement
Improvement: score improved by at least 10 points from baseline (0 to 100 point scale) at any time during the trial.
EORTC=European Organisation for Research and Treatment of Cancer.
Wu et al. Lancet Oncol. 2014;15(2):

10. Afatinib delayed time to deterioration of clinically relevant symptoms vs gemcitabine/cisplatin
Median TTD of symptoms (EORTC QoL QLQ-C30 and QLQ LC-13)1,2
31.1 months
Cough
10.3
P<0.001
7.7 months
Dyspnoea
1.7
Afatinib (n=242)
P<0.001
Gem/cis (n=122)
6.9 months
Pain
3.4
P=0.022
Median TTD (months)
TTD=time to deterioration, the time from randomisation to first appearance of a score ≥10 points lower than the baseline score.
EORTC=European Organisation for Research and Treatment of Cancer.
Wu et al. Lancet Oncol. 2014;15(2):
Wu YL et al. Annals of Oncology (2014) 25 (suppl_4): iv426-iv /annonc/mdu349.

11. Afatinib significantly improved QoL vs gemcitabine/cisplatin
Differences in mean scores over time (EORTC QLQ-C30)
Favours afatinib
Favours gem/cis
Significant difference favouring afatinib
Favours pem/cis
Global health status/QoL
Physical functioning
Role functioning
Emotional functioning
Cognitive functioning
Social functioning
-15 -5 5
Adjusted mean difference (95% confidence intervals)
QoL=quality of life.
Geater et al. J Thorac Oncol Apr 27. [Epub ahead of print]

12. LUX-LUNG 6
Adverse events

13. Manageable adverse event profile in LUX-Lung 6
The most common AEs with afatinib were diarrhoea, rash/acne, stomatitis and nail effects
The most common AEs with afatinib were generally manageable through supportive care
Treatment-related discontinuation due to any AE was low (5.9% vs 40% for gemcitabine/cisplatin)
Discontinuation due to rash/acne with afatinib was 2.1%
No treatment discontinuation due to diarrhoea
AE=adverse event.
Wu et al. Lancet Oncol. 2014;15(2):

14. Manageable adverse event profile in LUX-Lung 6
Afatinib (n=239)
Gem/cis (n=113)
All grades (%)
Grade 3 (%)
Grade 4 (%)
Diarrhoea
211 (88.3%)
13 (5.4%)
12 (10.6%)
0 (0%)
Rash or acne†
193 (80.8%)
34 (14.2%)
1 (0.4%)
10 (8.8%)
Stomatitis or mucositis†
124 (51.9%)
6 (5.3%)
Paronychia
78 (32.6%)
Epistaxis
30 (12.6%)
1 (0.9%)
Pruritus
26 (10.9%)
Decreased appetite
24 (10.0%)
3 (1.3%)
46 (40.7%)
2 (1.8%)
Fatigue†
41 (36.3%)
Vomiting
23 (9.6%)
2 (0.8%)
91 (80.5%)
18 (15.9%)
4 (3.5%)
Nausea
18 (7.5%)
85 (75.2%)
8 (7.1%)
Constipation
4 (1.7%)
14 (12.4%)
Anaemia‡
31 (27.4%)
8 (7.1%)
Leucopenia‡
8 (3.3%)
58 (51.3%)
15 (13.3%)
Neutropenia‡
5 (2.1%)
61 (54.0%)
20 (17.7%)
Haemoglobin concentration decreased‡
3 (2.7%)
Neutrophil count decreased‡
29 (25.7%)
White blood cell count decreased‡
27 (23.9%)
7 (6.2%)
Thrombocytopenia‡
21 (18.6%)
† Group term.
‡ Numbers are based on the adverse events reported by the investigator, not derived from the laboratory data.
Events are included if reported in more than 10% of patients in either treatment group and if there was at least 10% difference between the groups. Events are listed according to the incidence in the GIOTRIF® group. CTCAE Grade 5 drug-related AEs were experienced by 1 patient in each group.
Grades defined by Common Terminology Criteria for Adverse Events (CTCAE)
Wu et al. Lancet Oncol. 2014;15(2):