Afatinib versus gefitinib as first-line
treatment for patients with advanced
non-small cell lung cancer harboring
activating EGFR mutations: LUX-Lung 7
Keunchil Park, Eng-Huat Tan, Li Zhang, Vera Hirsh, Kenneth O’Byrne,
Michael Boyer, James Chih-Hsin Yang, Tony Mok, Miyoung Kim,
Dan Massey, Victoria Zazulina, Luis Paz-Ares
ESMO Asia 2015
Disclosures
• Employment: Samsung Medical Center
• Advisory Boards: Boehringer Ingelheim (uncompensated)
Background
• Afatinib and other EGFR-targeting agents, erlotinib and
gefitinib, are approved first-line treatments for
EGFR M+ NSCLC1
• Afatinib (second-generation TKI) irreversibly inhibits signaling
of EGFR, HER2-HER4, whereas gefitinib and erlotinib
(first-generation TKIs) reversibly inhibit EGFR2–4
• LUX-Lung 7 is the first prospective global randomized trial
evaluating two EGFR-directed therapies in patients with
EGFR M+ NSCLC
1. Sebastian M, et al. Eur Respir Rev 2014;23:92–105.
2. Costanzo R, et al. Expert Rev Anticancer Ther 2013;13(10):1207–18.
3. Li D, et al. Oncogene 2008;27:4702–11.
4. Solca F, et al. J Pharmacol Exp Ther 2012;343:342–50.
EGFR = epidermal growth factor receptor; M+ = mutation-positive;
HER = human epidermal growth factor receptor; NSCLC = nonsmall cell lung cancer; TKI = tyrosine kinase inhibitor
Study Design
• Stage IIIB/IV
adenocarcinoma of
the lung
• EGFR mutation
(Del19 and/or
L858R) in the
tumour tissue*
• No prior treatment
for advanced/
metastatic disease
Primary endpoints:
• PFS (independent)
• TTF
• OS
Afatinib 40 mg
once daily†
Stratified by
1:1 • Mutation type (Del19/L858R)
• Brain metastases (present/absent)
Gefitinib 250 mg
once daily
• ECOG PS 0/1
Secondary endpoints:
•
•
•
•
•
•
•
ORR
Time to response
Duration of response
Duration of disease control
Tumour shrinkage
HRQoL
Safety
• Treatment beyond progression allowed if deemed beneficial by investigator
• RECIST assessment performed at Weeks 4 and 8, and every 8 weeks thereafter until
Week 64, and every 12 weeks thereafter
* Central or local test.
† Dose modification to 50 mg, 30 mg, and 20 mg permitted in line with prescribing information.
Del19 = exon 19 deletions; ECOG PS = Eastern Cooperative
Oncology Group performance status; EGFR = epidermal growth factor
receptor; HRQoL = health-related quality of life; L858R = exon 21
L858R point mutation; ORR = objective response rate; OS = overall
survival; PFS = progression-free survival; RECIST = Response
Evaluation Criteria In Solid Tumors; TTF = time to treatment failure
Statistical Design
• Main study objective: to estimate the HR for PFS, TTF, and
OS* on afatinib, relative to gefitinib
• Sample size was based on controlling the width of the 95%
CI for the PFS HR, allowing for a width of ±0.25 on the log
scale after observing 250 events
• All statistical testing was at two-sided 5% alpha level with
no adjustment for multiplicity
• Time-to-event endpoints were analyzed via stratified Coxregression analysis and log-rank test
* At the time of PFS analysis, OS endpoint is still immature.
CI = confidence interval; HR = hazard ratio; OS = overall
survival; PFS = progression-free survival; TTF = time to
treatment failure
Study Conduct:
64 Sites / 13 Countries
Canada
France, Germany, Ireland, Norway, Spain,
Sweden, United Kingdom
Australia
China
Republic of Korea
Singapore
Taiwan
• Recruitment: December 2011–August 2013
• Median follow-up for PFS: 27.3 months
PFS = progression-free survival
Patient Disposition
Screened, n = 571
Randomized, n = 319
Treated with afatinib
n = 160
Stopped treatment
n = 140 (87.5%)
Treated with gefitinib
n = 159
TTF event
Stopped treatment
n = 149 (93.7%)
On treatment
n = 20 (12.5%)
On treatment
n = 10 (6.3%)
PFS event
By investigator: 131 (81.9%)
By independent: 124 ( 77.5%)
PFS event
By investigator: 135 (84.9%)
By independent: 122 (76.7%)
As of August 21, 2015
PFS = progression-free survival; TTF = time to treatment failure
Baseline Characteristics
Afatinib
(n = 160)
Gefitinib
(n = 159)
63 (30–86)
63 (32–89)
57 / 43
67 / 33
59
41
55
45
16
16
Smoking status, %
Never smoked
Light ex-smoker
Current / other ex-smoker
66
13
21
67
12
21
Baseline ECOG PS, %
0
1
32
68
30
70
NSCLC stage, %
IIIB
IV
5
95
2
98
EGFR mutation, %
Del19
L858R
58
42
58
42
Median age, years (range)
Gender, %
Female / Male
Race, %
Asian
Non-Asian
Brain metastases*, %
PFS in overall population
* Stable brain metastases: Incidentally found asymptomatic brain metastases not
requiring any local brain radiation and steroid therapy. Asymptomatic brain metastases
previously radiated and >1 week off corticosteroids and/or anti-convulsants treatment
before study randomization. Concomitant brain radiation not allowed.
Del19 = exon 19 deletions; ECOG PS = Eastern Cooperative Oncology Group
performance status; EGFR = epidermal growth factor receptor; L858R = exon 21
L858R point mutation; NSCLC = non-small cell lung cancer
PFS by Independent Review
0.8
Afatinib
(n = 160)
Gefitinib
(n = 159)
11.0
10.9
Median PFS (months)
PFS in overall population
Estimated PFS probability
1.0
HR (95% CI)
0.6
p-value
0.4
p = 0.0176
27%
p = 0.0184
0.73 (0.57–0.95)
0.0165
18%
0.2
15%
8%
0
No. of patients
Afatinib
Gefitinib
0
3
6
9
12
15
160
159
142
132
112
106
94
83
67
52
47
22
18 21 24 27
Time (months)
34
14
27
9
21
7
13
5
30
33
36
39
42
6
3
3
3
1
1
0
1
0
0
CI = confidence interval; HR = hazard ratio; PFS = progression-free survival
PFS in Prospectively Defined Subgroups
Factors
N
HR (95% CI)
319
0.73 (0.57–0.95)
L858R
133
0.71 (0.48–1.06)
Del19
186
0.76 (0.55–1.06)
Brain
metastases
Absent
268
0.74 (0.56–0.98)
Present
51
0.76 (0.41–1.44)
Baseline ECOG PS
0
98
0.89 (0.54–1.47)
1
221
0.71 (0.52–0.95)
Male
122
0.88 (0.59–1.31)
Female
197
0.65 (0.47–0.91)
EGFR mutation
Gender
Age
Race
Smoking history
<65 years
PFS in overall population
Total
PFS
177
0.68 (0.48–0.97)
≥65 years
142
0.85 (0.59–1.22)
Non-Asian
137
0.72 (0.49–1.06)
Asian
182
0.76 (0.54–1.06)
Never smoked
212
0.80 (0.58–1.10)
Light ex-smoker
40
1.09 (0.56–2.14)
Current or other ex-smokers
67
0.48 (0.27–0.85)
1/4
Favours afatinib
1
4
Favours gefitinib
CI = confidence interval; Del19 = exon 19 deletions; ECOG PS = Eastern Cooperative Oncology Group performance status; EGFR = epidermal
growth factor receptor; HR = hazard ratio; L858R = exon 21 L858R point mutation; PFS = progression-free survival
Time to Treatment Failure
0.8
Afatinib
(n = 160)
Gefitinib
(n = 159)
13.7
11.5
Median TTF (months)
PFS in overall population
Probability of being on treatment
1.0
HR (95% CI)
0.73 (0.58–0.92)
p-value
0.6
0.0073
0.4
0.2
0
No. of patients
Afatinib
Gefitinib
0
3
6
9
12
15
160
159
148
144
133
120
113
103
91
74
68
59
18 21 24 27
Time (months)
56
43
48
30
40
21
25
11
30
33
36
39
42
18
6
9
6
5
2
0
2
0
0
CI = confidence interval; HR = hazard ratio; TTF = time to treatment failure
Objective Response and Duration
of Response (Independent Review)
80%
80
p = 0.0083
ORR
ORR (%)
70%
Median DoR (months)
56%
Gefitinib
(n = 89)
10.1
8.4
(7.8–11.1)
(7.4–10.9)
PFS in overall population
60
60%
Afatinib
(n = 112)
95% CI
40
40%
20%
20
0%0
Afatinib
AfatinibGefitinib
n = 89/159
n = 112/160
CI = confidence interval; DoR = duration of response; ORR = objective response rate
Efficacy in Patients With Del19 Mutation
Median PFS
(months)
12.7
HR (95% CI)
0.76 (0.55–1.06)
11.0
PFS in overall population
0.8
p-value
0.6
0.1071
0.4
0.2
0
–20
–40
–60
–80
≥20% increase (n = 0)
≥0–<20% increase (n = 3)
>0–<30% decrease (n = 15)
≥30–<50% decrease (n = 29)
≥50% decrease (n = 41)
70 (80%)
with ≥30%
reduction
40
0
0
3 6
9 12 15 18 21 24 27 30 33 36 39 42
Time (months)
No. of patients
Afatinib 93 83 67 58 43 31 22 18 14 9
Gefitinib 93 76 64 53 32 17 11 7 6 4
Afatinib
(n = 93)
Gefitinib
(n = 93)
PFS in overall population
ORR
Afatinib
20
–100
73%
66%
4
3
2
3
1
1
0
1
0
0
Maximum decrease from baseline (%)
Estimated PFS probability
40
Gefitinib
Maximum decrease from baseline (%)
Afatinib
1.0
Gefitinib
20
0
–20
–40
–60
–80
–100
≥20% increase (n = 0)
≥0–<20% increase (n = 2)
>0–<30% decrease (n = 18)
≥30–<50% decrease (n = 27)
≥50% decrease (n = 41)
68 (77%)
with ≥30%
reduction
CI = confidence interval; Del19 = exon 19 deletions; HR = hazard ratio; ORR = objective response rate; PFS = progression-free survival
Efficacy in Patients With L858R Mutation
Gefitinib
Median PFS
(months)
10.9
10.8
HR (95% CI)
0.71 (0.47–1.06)
PFS in overall population
0.8
p-value
0.6
0.0856
0.4
0.2
0
–20
–40
–60
–80
≥20% increase (n = 1)
≥0–<20% increase (n = 3)
>0–<30% decrease (n = 12)
≥30–<50% decrease (n = 21)
≥50% decrease (n = 24)
45 (74%)
with ≥30%
reduction
40
0
0
3 6
9 12 15 18 21 24 27 30 33 36 39 42
Time (months)
No. of patients
Afatinib 67 59 45 36 24 16 12 9
Gefitinib 66 56 42 30 20 5 3 2
Afatinib
(n = 67)
Gefitinib
(n = 66)
PFS in overall population
ORR
Afatinib
20
–100
66%
42%
7
1
4
1
2
0
1
0
0
0
0
0
0
0
Maximum decrease from baseline (%)
Estimated PFS probability
40
Maximum decrease from baseline (%)
Afatinib
1.0
Gefitinib
20
0
–20
–40
–60
–80
–100
≥20% increase (n = 4)
≥0–<20% increase (n = 4)
>0–<30% decrease (n = 23)
≥30–<50% decrease (n = 19)
≥50% decrease (n = 13)
32 (51%)
with ≥30%
reduction
CI = confidence interval; HR = hazard ratio; L858R = exon 21 L858R point mutation; ORR = objective response rate; PFS = progression-free survival
Overall Summary of AEs
Afatinib
(n = 160)
Gefitinib
(n = 159)
Any AE
98.8
100.0
Drug-related AEs
97.5
96.2
AEs leading to dose reduction*
41.9
1.9*
Events, %
PFS in overall population
Drug-related AEs leading to
discontinuation
Serious AEs
Drug-related serious AEs
Drug-related fatal AE
* No dose reductions foreseen for gefitinib according to prescribing information.
† Including four patients with drug-related ILD (no drug-related ILD on afatinib).
‡ One patient died of hepatic failure.
6.3
6.3
44.4
37.1
10.6
4.4†
-
0.6‡
AE = adverse event; ILD = interstitial lung disease
Drug-Related AEs (>10%)
Afatinib (n = 160)
All
Grade 3
All
Grade 3
Diarrhea
90.0
11.9†
61.0
1.3
Rash/acne*
88.8
9.4
81.1
3.1
Stomatitis*
64.4
4.4
23.9
-
Paronychia*
55.6
1.9
17.0
0.6
Dry skin
32.5
-
37.1
-
Pruritus
23.1
-
22.6
-
Fatigue*
20.6
5.6
14.5
-
Decreased appetite
16.3
0.6
11.9
-
Nausea
16.3
1.3
13.8
-
Alopecia
10.6
-
15.1
-
Vomiting
10.6
-
3.8
0.6
ALT increased
9.4
-
23.9
7.5‡
AST increased
6.3
-
20.8
2.5
* Grouped terms of AEs.
† Plus one case of grade 4 diarrhea.
‡ Plus one case of grade 4 increased ALT.
PFS in overall population
AE category, %
Gefitinib (n = 159)
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase
Drug-Related AEs Leading to
Discontinuation in >1 Patient
5.0%
5.0
4.5%
Afatinib
4.0%
4.0
Gefitinib
Patients (%)
3.5%
5 (3.1%)
5 (3.1%)
3.0%
3.0
4 (2.5%)
2.5%
3 (1.9%)
2.0%
2.0
2 (1.3%)
1.5%
2 (1.3%)
1.0%
1.0
0.5%
0.0%
0.0
0%
A
G
0%
Diarrhoea
Diarrhea
* Grouped terms of AEs.
A
G
Fatigue+
Fatigue*
A
0%
0%
G
A
0%
G
A
0%
G
Toxic skin ALT increase
AST
AST
ALT
Toxic skin
eruption
increase
increase
increase
eruption
A
ILD
ILD
G
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ILD = interstitial lung disease
Summary and Conclusion
• Afatinib significantly improved PFS of patients with EGFR M+ NSCLC relative to
gefitinib. Results are consistent across subgroups
• Afatinib treatment was associated with a significant improvement in response
rate and TTF
• Improvement in efficacy was observed in both Del19 and L858R populations
• OS data were immature (current HR: 0.87, 95% CI: 0.66–1.15)
• AEs in both groups were consistent with previous experience and were
manageable, leading to equally low rates of treatment discontinuation
• LUX-Lung 7 confirms the benefit of irreversible ErbB blockade with afatinib over
reversible EGFR inhibition with gefitinib in treatment of EGFR M+ NSCLC
AE = adverse event; CI = confidence interval; Del19 = exon 19 deletions; EGFR = epidermal
growth factor receptor; ErbB = erythroblastic leukemia viral oncogene; HR = hazard ratio;
L858R = exon 21 L858R point mutation; M+ = mutation-positive; NSCLC = non-small cell lung
cancer; OS = overall survival; PFS = progression-free survival; TTF = time to treatment failure
Acknowledgments
Thank you to all of the patients and their
families, and the LUX-Lung 7 study
investigators and their teams for
participating in this study
Back-Up
Maximum decrease from baseline (%)
Maximum decrease from baseline (%)
Tumour Shrinkage (Independent Review)
40
Afatinib
20
0
–20
–40
–60
–80
–100
115 (77%)
with ≥30%
reduction
≥20% increase, n = 1 (<1%)
≥0–<20% increase, n = 6 (4%)
>0–<30% decrease, n = 27 (18%)
≥30–<50% decrease, n = 50 (34%)
≥50% decrease, n = 65 (44%)
40
Gefitinib
20
0
–20
–40
–60
–80
–100
≥20% increase, n = 4 (3%)
≥0–<20% increase, n = 6 (4%)
>0–<30% decrease, n = 41 (27%)
≥30–<50% decrease, n = 46 (30%)
≥50% decrease, n = 54 (36%)
100 (66%)
with ≥30%
reduction
PFS With TKI in Common Mutation:
LUX-Lung 3/6 and LUX-Lung 7
0.8
Median PFS
(months)
HR (95% CI)
0.6
LL3
Afatinib
(n = 204)
LL6
Afatinib
(n = 216)
13.6
11.0
LL7
Afatinib Gefitinib
(n = 160) (n = 159)
11.0
10.9
PFS in overall population
Estimated PFS probability
1.0
p-value
N/A
N/A
0.73 (0.57–0.95)
N/A
N/A
0.0165
Afatinib (n = 204)
Aftatinib (n = 216)
Afatinib (n = 160)
Gefitinib (n = 159)
0.4
0.2
0
0
3
6
9
12
15 18 21 24
Time (months)
27
30
33
36
CI = confidence interval; HR = hazard ratio; N/A = not applicable; PFS = progression-free survival