1. LUX-Lung 3 clinical trial
LUX-Lung 3 is a multi-national, prospective, randomised, phase III trial of afatinib vs cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations
Treatment-naïve
Advanced NSCLC stage IIIB/IV adenocarcinoma
EGFR M+
ECOG 0 or 1
Afatinib
40 mg oral once daily n=230
Pemetrexed/cisplatin
75 mg/m2 / 500 mg/m2 IV d1,
q3w up to 6 cycles
n=115
Median follow-up:
For PFS: 16.4 months
For OS: 41 months
2:1 randomisation
ECOG=Eastern Cooperative Oncology Group.
Sequist LV et al. J Clin Oncol. 2013;31(27):

2. LUX-Lung 3 study endpoints
Primary endpoint
Progression-free survival (PFS) by independent review
Secondary endpoints included
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
EORTC=European Organisation for Research and Treatment of Cancer.
Sequist LV et al. J Clin Oncol. 2013;31(27):

3. Patient demographics and characteristics were well balanced between the 2 treatment arms
Afatinib (n=230)
Pem/cis (n=115)
Sex, n (%)
Male
83 (36.1)
38 (33.0)
Female
147 (63.9)
77 (67.0)
Age, years, median (range)
61.5 (28-86)
61.0 (31-83)
Race, n (%)
White
61 (26.5)
30 (26.1)
Eastern Asian
165 (71.7)
83 (72.2)
Other
4 (1.7)
2 (1.7)
Smoking status, n (%)
Never
155 (67.4)
81 (70.4)
Former
70 (30.4)
32 (27.8)
Current
5 (2.2)
ECOG PS, n (%)
92 (40.0)
41 (35.7) 1
138 (60.0)
73 (63.5) 2
0.0
1 (0.9)
Adenocarcinoma stage*, n (%)
IIIB (with pleural effusion)
20 (8.7)
17 (14.8) IV
210 (91.3)
98 (85.2)
EGFR mutation, n (%)
Exon 19 deletion
113 (49.1)
57 (49.6)
L858R
91 (39.6)
47 (40.9)
26 (11.3)
11 (9.6)
* By American Joint Committee on Cancer, sixth edition.
Sequist LV et al. J Clin Oncol. 2013;31(27):

4. LUX-LUNG 3
Efficacy

5. Afatinib significantly increased first-line PFS vs pemetrexed/cisplatin in common mutations (del19/L858R)
Del9/L858R mutations
Progression-free survival (primary endpoint)
LUX-Lung 3 preplanned subgroup analysis
PFS rate (%)
0.2
0.4
0.6
0.8
1.0
0.0
Afatinib (n=204)
13.6
months
Pemetrexed/cisplatin (n=104)
Hazard ratio 0.47
(95% CI, )
P<0.001
6.9
months 3 6 9 12 15 18 21 24 27
Time (months)
53% reduction in relative risk of death or tumour progression in patients with common mutations (HR 0.47; P<0.001)
In ITT population, median PFS was 11.1 and 6.9 months for afatinib and pemetrexed/ cisplatin, respectively (HR: 0.58; 95% CI, ; P<0.001)
ITT=intent to treat; PFS=progression-free survival.
Sequist LV et al. J Clin Oncol. 2013;31(27):

6. reduction in relative risk of death
Afatinib achieved over 1 year extended OS vs pemetrexed/cisplatin in subgroup of del19 patients
Del19 mutations
Overall survival (secondary endpoint)
LUX-Lung 3 preplanned subgroup analysis
Afatinib (n=112)
Estimated OS probability
0.2
0.4
0.6
0.8
1.0
0.0
Pemetrexed/cisplatin (n=57)
33.3
months
Hazard ratio 0.54
(95% CI, )
P=0.0015
>12 months
increase median OS
>12 months
increase median OS
21.1
months
46%
reduction in relative risk of death 3 6 9 18 21 30 36 39 45 12 15 24 27 33 42 48 51
Time of overall survival (months)
46% reduction in relative risk of death in del19 patients (HR 0.54; P=0.0015)
OS in ITT population (N=345) was 28.2 and 28.2 months for afatinib vs pemetrexed/cisplatin, respectively (HR 0.88; P=0.39)
ITT=intent to treat; OS=overall survival.
Yang JC et al. Lancet Oncol. 2015;16(2):

7. Patient-reported outcomes
LUX-LUNG 3
Patient-reported outcomes

8. Afatinib significantly improved dyspnoea and some pain symptoms compared with pemetrexed/cisplatin
Patients with improvement in symptoms (EORTC scores improved by ≥10 points)1*
>97% questionnaire completion
>97%
questionnaire completion
* 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 meaningful2
Yang JC et al. J Clin Oncol. 2013;31(27):
Osoba D et al. J Clin Oncol. 1998;16(1): )

9. Afatinib delayed time to worsening of clinically relevant symptoms vs pemetrexed/cisplatin
Median TTD of symptoms (EORTC QoL QLQ-C30 and QLQ LC-13)1,2
>97%
questionnaire completion
27.0 months
Cough
8.0
P=0.006
10.4 months
Dyspnoea
2.9
Afatinib (n=230)
P=0.013
Pem/cis (n=115)
4.2 months
Pain
3.1
P=0.188
>97% questionnaire completion
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.
Yang JC et al. J Clin Oncol. 2013;31(27):
Wu YL et al. Annals of Oncology (2014) 25 (suppl_4): iv426-iv /annonc/mdu349.

10. Afatinib significantly improved quality of life (QoL) vs pemetrexed/cisplatin
EORTC QLQ-C30 questionnaire scores
Favours afatinib
Favours pem/cis
Significant difference favouring afatinib
Favours pem/cis
Global health status/QoL
Physical functioning
Role functioning
Cognitive functioning
Emotional functioning
Social functioning
>97%
questionnaire completion
>97% questionnaire completion 10 5 -5
Differences in mean scores (95% confidence intervals)
Yang JC et al. J Clin Oncol. 2013;31(27):

11. LUX-LUNG 3
Adverse events

12. Manageable adverse event profile in LUX-Lung 3
The most common AEs with afatinib were diarrhoea, stomatitis, rash, acne, and paronychia
The most common adverse events with afatinib were generally manageable through supportive care
Treatment-related discontinuation due to any AE was low (8% vs 12% for pemetrexed/cisplatin)
Discontinuation due to diarrhoea and rash/acne with afatinib was 1.3% and 0%, respectively
AE=adverse event.
Sequist LV et al. J Clin Oncol. 2013;31(27):

13. Manageable adverse event profile in LUX-Lung 3
Afatinib (n=229)
Pem/cis (n=111)
All grades (%)
≥ grade 3 (%)
Diarrhoea
218 (95.2)
33 (14.4)
17 (15.3)
0 (0.0)
Rash/acne†
204 (89.1)
37 (16.2)
7 (6.3)
Stomatitis/mucositis†
165 (72.1)
20 (8.7)
17(15.3)
1 (0.9)
Paronychia
130 (56.8)
26 (11.4)
Dry skin
67 (29.3)
1 (0.4)
2 (1.8)
Decreased appetite
47 (20.5)
7 (3.1)
59 (53.2)
3 (2.7)
Pruritis
43 (18.8)
Nausea
41 (17.9)
2 (0.9)
73 (65.8)
4 (3.6)
Fatigue†
40(17.5)
3 (1.3)
52 (46.8)
14 (12.6)
Vomiting
39 (17.0)
47 (42.3)
Epistaxis
30 (13.1)
Cheilitis
28 (12.2)
Anaemia‡
31 (27.9)
Constipation
6 (2.6)
21 (18.9)
Leukopenia‡
4 (1.7)
9 (8.1)
Neutropenia‡
35 (31.5)
20 (18.0)
Events are included if reported in more than 10% of patients in either of the treatment groups and if there was at least 10% difference between the groups. Events are listed according to the incidence in the afatinib group.
† Group term.
‡ Numbers are based on the AEs reported by the investigator and not derived from the laboratory data.
Sequist LV et al. J Clin Oncol. 2013;31(27):