NEW TKI IN LUNG CANCER
R6洪逸平
Supervisor 顏厥全醫師
Some slide revised from Boehringer Ingelheim Afatinib Launch Meeting
Actionable targets in lung adenocarcinomas
1999
2005–2013
Unknown
35%
Unknown
75%
2004
EGFR
Unknown
60%
KRAS
Selumetinib
Trametinib
Vandetanib?
NRAS
XL184?
Sunitinib?
Gefitinib
RET
RET
EGFR
Erlotinib
Crizotinib ROS1
ROS1
Afatinib
MEK
MEK
Dacomitinib
Selumetinib?
HER2
ALK
HER2
ALK
CO1686, AZD9291
MET
PIK3CA
MET BRAF
BRAF PIK3CA
Afatinib?
Dacomitinib?
MetMab?
MK2206?
Crizotinib, LDK378,
BKM120?
CH5424802, AP26113
Dabrafenib, vemurafenib
regorafenib, MEK inhibitors
Actionable targets in lung adenocarcinomas
2005–2013
1999
HSP90 client oncoprotein
AUY922, IPI504, ganetespib Selumetinib
Unknown
KRAS Trametinib
35% expression
PD1/PD-L1
Lambrolizumab, nivolumab,
MPDL3280A, BMS936559
Unknown
75%
2004
EGFR
Unknown
60%
Vandetanib?
NRAS
XL184?
Sunitinib?
Antiangiogenesis
Bevacizumab, nintedanib*, Gefitinib
RET
RET
EGFR
motesanib
Erlotinib
Crizotinib ROS1
ROS1
Afatinib
MEK
MEK
Dacomitinib
Selumetinib?
HER2
HER2
ALK
ALK
CO1686, AZD9291
MET
MET BRAF
PIK3CA
BRAF PIK3CA
Afatinib?
Dacomitinib?
MetMab?
MK2206?
Crizotinib, LDK378,
BKM120?
CH5424802, AP26113
Dabrafenib, vemurafenib
regorafenib, MEK inhibitors
*Nintedanib is an investigational compound and is not yet approved. Its safety and efficacy have not yet been fully established.
Austin Hospital surgical series: TxN0 only
Main mutations and survival in N0 patients
Percent survival
100
EGFR Mutant n=17
KRAS Mutant n=69
MET mutation n=8
WT n=139
PIK3CA Mutant n=13
P53 Mutant n=30
80
60
40
20
0
0
50
100
150
200
Cancer Specific Survival
250
你相信有平行世界嗎？
那些年，我們一起追的女孩 九把刀
Conversations in Oncology 2009 – Vienna
Tony Mok, Vienna, 2009.
EGFR mutation +
EGFR mutation –
EGFR TKI
Chemotherapy
Conversations in Oncology in Asia – 2013, Taipei
EGFR mut
Alk-EML4
HER-2
RET--
B-Raf
??
K-ras
ROS1--
Conversations in Oncology in Asia – 2013, Taipei
Chemotherapy
Antiangiogenesis
HSP90 inhibitors
PD1/PD-L1 antibodies
cMET/HGF inhibition
IGF/IGFR inhibition
IPASS: Progression-free survival in EGFR mutation
positive and negative patients
EGFR mutation-positive
EGFR mutation-negative
HR: 0.48
p<0.001
HR: 2.85
p<0.001
1.0
1.0
Gefitinib (n=132)
Probability of PFS
Probability PFS
0.8
Carboplatin/
paclitaxel
(n=129)
0.6
0.4
0.2
0.0
Carboplatin/paclitaxel
(n=85)
0.8
0.6
0.4
Gefitinib (n=91)
0.2
0.0
0
4
8
12
16
20
24
0
4
8
11
2
3
1
0
0
91
85
21
58
4
14
Months
At risk:
Gefitinib
C/P
132
129
108
103
71
37
31
7
12
Months
2
1
Treatment by subgroup interaction test, p<0.0001
Qualitative interaction!!!
Mok TS, et al. N Engl J Med 2009;361:947–57.
16
20
24
1
0
0
0
0
0
EGFR mutations in NSCLC geographical map
France
(1227)
14%
Italy
(860)
5% (10%)
Qatar
(25)
(32%)
India (2527)
25–40%
(36%)
China (1068)
24–39%
(41–50%)
Spain
(2105)
17%
Japan (1498)
26–40%
(41–49%)
USA (456)
2–14%
(15–25%)
Brazil
(2017)
30%
Korea (513)
20–36%
(38–48%)
Taiwan (267)
34%
(56–62%)
The Philippines
(65)
(52%)
Thailand
(403)
(54%)
Key: Country (N=) % mutation NSCLC (% mutation in adenocarcinoma).
Parikh PM, Puri T. Ind J Cancer 2013.
Vietnam
(120)
(64%)
Hong Kong
(161)
(47%)
Australia
(83)
7% (14%)
Developing a targeted agent that irreversibly blocks
signalling from the ErbB Family receptors
...from the bench to the clinic
Afatinib: An ErbB Family Blocker
Erlotinib and gefitinib
Afatinib
• Oral, small molecule TKI
• Covalently binds to and is highly specific for EGFR,
HER2, ErbB4 (ErbB family)
• Retains activity in erlotinib/gefitinib-resistant models
Molecular potency and selectivity (IC50)
EGFR
(nM)
0.5
HER2
(nM)
14
ErbB4
(nM)
1
HGFR
(nM)
VEGFR2
(nM)
Li D, et al. Oncogene 2008;27:4702–4711.
Molecular potency and selectivity (IC50)
EGFR
L858R
EGFR
L858R/T790M
Afatinib
0.4
10
>10,000
Gefitinib
0.8
1013
>100,000
Erlotinib
1
1520
ErbB-dependent tumours
EGFR
HER2
ErbB3
ErbB4
Chromosomal polysomy
Over-expression
Gene amplification
Mutation
NSCLC
Breast
Head and neck
Gastric
Oesophageal
Pancreatic
Biliary
Endometrial
Ovarian
Glioblastoma
Melanoma
LUX trial programme
NSCLC/adenocarcinoma
Erlotinib/gefitinib
pretreated
NSCLC / SCC
EGFR
mutation positive
HNSCC
Metastatic/
recurrent
Locally
advanced
adjuvant
LUX-HN 1
LUX-HN 2
LUX-HN 3
LUX-HN 4
Head-to-head trials
LUX-Lung 1
LUX-Lung 2
LUX-Lung 4
LUX-Lung 3
LUX-Lung 5
LUX-Lung 6
Yang JC, Taipei, August 2013.
LUX-Lung 7
LUX-Lung 8
Afatinib in NSCLC: Key trials
LL1 & 4
Improve outcomes in (EGFR M+) 3rd/4th line
LL2, 3 & 6
Improve outcomes in EGFR M+ 1st/2nd line
LL5
LUX-Lung
Programme
LL7 & 8
LL8
Afa + Cet
Continued EGFR inhibition
Irreversible vs. reversible
EGFR blockade
Squamous cell NSCLC
Improve on monotherapy effect in EGFR M+ 3rd/4th line
EGFR-TKI
pretreated
EGFR-TKI
naïve
LUX-Lung 1: Post erlotinib/gefitinib – third/fourth line
Stage IIIB/IV adenocarcinoma of the lung
Progressed after one or two lines of chemotherapy
(including one platinum-based regimen) and ≥12 weeks of treatment
with erlotinib or gefitinib
ECOG PS 0–2
Randomization 2:1
(double blind)
Oral afatinib 50 mg once daily
+ BSC
Oral placebo once daily
+ BSC
Primary endpoint: OS
Secondary endpoints: PFS, ORR, QoL (LC13/C30), safety
Miller V, et al. Lancet Oncol 2012;13:528–538.
LUX-Lung 1: OS and PFS
Updated OS analysis (February 2012)
Median OS (months)
HR
Miller V, et al. Lancet Oncol 2012;13:528–538.
Afatinib
n=390
Placebo
n=195
10.9
11.7
1.01
p=0.54
PFS (independent review)
Median PFS (months)
HR
Afatinib
n=390
Placebo
n=195
3.3
1.1
0.38
p<0.0001
Patients with no subsequent therapy
(n=191)
Patients with ≥1 subsequent therapy
(n=394)
100
100
Afatinib=5.8 months
Placebo=4.6 months
80
HR=0.66; p=0.027
60
40
20
0
Estimated survival
probability (%)
Estimated survival
probability (%)
LUX-Lung 1: OS and subsequent systemic treatment
Afatinib=12.7 months
Placebo=14.4 months
80
HR=1.09; p=0.535
60
40
20
0
0
3
6
9
12
15
18
21
Time since randomization (months)
Miller V, et al. Lancet Oncol 2012;13:528–538.
24
0
3
6
9
12
15
18
21
Time since randomization (months)
24
Afatinib=4.4 months
Placebo=1.0 months
1.0
0.8
0.6
0.4
0.2
0.0
0
3
6
9
12
15
Time since randomization (months)
Number at risk
Placebo
134
Afatinib
257
6
111
2
49
1
10
0
7
0
3
Estimated PFS probability (%)
Estimated PFS probability (%)
LUX-Lung 1: PFS and likelihood of EGFR mutation
Afatinib=2.8 months
Placebo=1.8 months
1.0
0.8
0.6
0.4
0.2
0.0
0
3
6
9
12
15
Time since randomization (months)
Number at risk
Placebo
61
Afatinib
133
9
41
2
16
1
6
0
2
0
0
CR or PR to prior EGFR-TKI or ≥48 weeks duration of prior EGFR-TKI
YES
High (>80%) likelihood of mutant EGFR
Boehringer Ingelheim. Data on file.
NO
Lower (<30%) likelihood of mutant EGFR
LUX-Lung 1: Key learnings
• Afatinib significantly improved PFS compared to
placebo
– Post erlotinib/gefitinib failure
• EGFR mutation-positive patients do better
– Predictive for afatinib efficacy
– Prognostic (longer OS in the trial population)
• Impact of subsequent therapy on OS
– Was OS an appropriate endpoint for this setting?
LUX-Lung 4: Phase I/II single arm in Japan
Japanese NSCLC patients
Failure of conventional treatment or no therapy of proven efficacy
ECOG PS 0 or 1
Progressed after one or two lines of chemotherapy (including one platinum-based regimen)
and ≥12 weeks of treatment with erlotinib or gefitinib (Phase II)
Afatinib
N=90 in Phase I/II; MTD: 50 mg/day
Results (Phase II, n=62)
ORR=8.2%
Median PFS 4.4 months
Median OS 19 months
• Population and results: Similar to LUX-Lung 1
Murakami H, et al. Cancer Chemother Pharmacol 2012;69:891–899; Katakami N, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
LUX-Lung 5: Continued EGFR inhibition
Phase III trial, Part B blinded and still recruiting
PFS
OS
PRO
LUX-Lung 5: PFS in Part A
Overall
By histology
By likelihood
of(n=1154)
EGFR mutation
mPFS: 3.3 months
Adenoca
(n=985 ):2.8
3.3months
months
Lower (n=556):
Squamous
(n=91):
3.7
months
Higher (n=598): 4.2 months
Schuler
J Clin
Oncol
2012;30(Suppl.):Abstract/Poster
7557.
Kim J-H,M,
et et
al.al.
J Clin
Oncol
2012;30(Suppl.):Abstract/Poster
7558.
LUX-Lung 2: Phase II in EGFR M+ first/second line
Adenocarcinoma of the lung Stage IIIB/IV
EGFR mutation
Chemotherapy naïve or progressive disease following
first-line chemotherapy
EGFR-TKI naïve
ECOG PS 0–2
Oral afatinib;
starting dose 50 mg/day or 40 mg/day
Primary endpoint: ORR
Secondary endpoints: PFS, OS
Yang CH, et al. Lancet Oncol 2012;13:539–548.
LUX-Lung 2: PFS, ORR, tumour shrinkage, OS
Progression free survival (%)
100
80
Median PFS (months)
Independent / Investigator
First line (n=61)
Second line (n=68)
12 / 15.6
8 / 10.5
60
40
20
0
First line
Second line
61
68
ORR (%)
65.6
57.4
DCR (%)
86.9
77.9
OS (month)
NA
23.3
Treated
• Comparable activity in first-/second-line treatment
of EGFR mutation-positive NSCLC
Yang CH, et al. Lancet Oncol 2012;13:539–548; Boehringer Ingelheim. Data on file.
LUX-Lung 3 and 6: First-line EGFR M+ NSCLC
Stage IIIB(wet)/IV NSCLC adenocarcinoma
EGFR mutation positive tumour (central test)
ECOG PS 0‒1
Randomization 2:1
Afatinib 40 mg
once daily continuously
Cisplatin + pemetrexed (LL3)
Cisplatin + gemcitabine (LL6)
up to 6 cycles
Primary endpoint: PFS (independent review)
Secondary endpoints: ORR, DCR, OS, PRO
Yang CH, et al. J Clin Oncol 2012;30(Suppl.):Abstract/Oral presentation LBA7500; Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print];
Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract/Poster 8016.
LUX-LUNG 3
LUX-Lung 3: Study design
Stage IIIB (wet)/IV lung adenocarcinoma (AJCC version 6)
EGFR mutation in tumour
(central lab testing; Therascreen EGFR29* RGQ PCR)
Randomization 2:1
Stratified by:
EGFR mutation (Del19/L858R/other)
Race (Asian/non-Asian)
Afatinib 40
mg/day†
Cisplatin + pemetrexed
75 mg/m2 + 500 mg/m2 i.v.
every 21 days, up to 6 cycles
Primary endpoint: PFS (RECIST 1.1, independent review)‡
Secondary endpoints: ORR, DCR, DoR, tumour shrinkage, OS, PRO§, safety, PK
*EGFR29: 19 deletions in exon 19, three insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I; †Dose escalated to
50 mg if limited AE observed in cycle 1. Dose reduced by 10 mg decrements in case of related Grade 3 or prolonged Grade 2 AE; ‡Tumour assessments:
every 6 weeks until Week 48 and every 12 weeks thereafter until progression/start of new therapy; §Patient-reported outcomes: Q-5D, EORTC QLQ-C30
and QLQ-LC13 at randomization and every 3 weeks until progression or new anti-cancer therapy.
Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
LUX-Lung 3: The largest global trial in the EGFR
mutation-positive NSCLC population
345 patients from 133 sites in 25 countries
NORTH AMERICA
USA
Canada
EUROPE
Austria, Belgium, France, Germany,
Hungary, Ireland, Italy, Romania,
Russia, Ukraine, UK
ASIA
Hong Kong
Japan
Korea
Malaysia
Philippines
Taiwan
Thailand
SOUTH AMERICA
Argentina, Brazil,
Chile, Peru
Australia
LUX-Lung 3: Patient demographics/characteristics
Gender, n (%)
Afatinib
(n=230)
Cis/pem
(n=115)
Total
(n=345)
Male
83 (36)
38 (33)
121 (35)
Female
147 (64)
77 (67)
224 (65)
62 (28–86)
61 (31–83)
61 (28–86)
Caucasian
61 (27)
30 (26)
91 (26)
Eastern Asian
165 (72)
83 (72)
248 (72)
4 (1)
2 (2)
6 (2)
Never smoked
155 (67)
81 (70)
236 (68)
Ex-smoker
70 (30)
32 (28)
102 (30)
Current smoker
5 (2)
2 (2)
7 (2)
IIIB (wet)
20 (9)
17 (15)
37 (11)
IV
210 (91)
98 (85)
308 (89)
0
92 (40)
41 (36)
133 (39)
1
138 (60)
73 (64)
211 (61)
2
0
1 (1)
1 (<1)
Del19
113 (49)
57 (49)
170 (49)
L858R
91 (40)
47 (41)
138 (40)
Other
26 (11)
11 (10)
37 (11)
Age, years, median (range)
Race, n (%)
Other
Smoking status, n (%)
Stage (AJCC 6.0), n (%)
ECOG PS, n (%)
EGFR mutation, n (%)
Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
Primary endpoint: Afatinib improved PFS versus
chemotherapy
Independent review – all randomized patients
Progression-free survival (probability)
1.0
Afatinib
n=230
Cis/pem
n=115
PFS event, n (%) 152 (66)
0.8
Median PFS (months)
69 (60)
11.1
Hazard ratio (95% CI)
6.9
0.58 (0.43–0.78)
p=0.0004
0.6
47%
0.4
0.2
22%
0.0
0
Number at risk
Afatinib
230
Cis/Pem
115
3
6
180
72
151
41
9
12
15
18
Progression-free survival (months)
120
21
77
11
50
7
31
3
21
24
27
10
2
3
0
0
0
Median follow-up: 16.4 months; 221 independently reviewed PFS events. At the time of data cut-off for primary analysis of PFS,
45 (20%) patients in the afatinib arm and three (3%) patients in the chemotherapy arm were known to be alive and progression-free.
Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
LUX-Lung 3: PFS subgroup analysis
Independent review – all randomized patients
Factors
Total
Gender
Male
Female
Age at baseline: <65 vs. ≥65 years
<65 years
≥65 years
Race stratification factor
Non-Asian
Asian
EGFR mutation category
Del19/L858R (common)
Del19
L858R
Baseline ECOG score
0
1
Smoking history
Never smoked
<15 packet years + stop >1 year
Other current/ex-smoker
Number of
patients
345
Hazard ratio
(95% confidence interval)
0.58 (0.43–0.78)
121
224
0.61 (0.37–1.01)
0.54 (0.38–0.78)
211
134
0.53 (0.36–0.76)
0.64 (0.39–1.03)
96
249
0.68 (0.39–1.19)
0.54 (0.38–0.76)
308
170
138
0.47 (0.34–0.65)
0.28 (0.18–0.44)
0.73 (0.46–1.17)
133
211
0.50 (0.31–0.82)
0.63 (0.43–0.91)
236
30
79
0.47 (0.33–0.67)
0.50 (0.19–1.34)
1.04 (0.54–1.98)
Favours afatinib
1/16
Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
1/4
Favours cis/pem
1
4
16
LUX-Lung 3: Updated OS analysis
Afatinib
(n=230)
Cis/pem
(n=115)
116 (50.4%)
59 (51.2%)
28.1
28.2
(24.6, 33.0)
(20.7, 33.2)
Overall survival*
Number of Deaths, N (%)
Median Overall Survival (months)
95% CI
HR (95% CI)
Stratified Log-Rank Test P-value*
0.91 (0.66, 1.25)
0.55
*At the time of cutoff, only 98 (28%) had died. Hence, OS data are considered
preliminary. Median OS has not yet been reached for any group.
Boehringer Ingelheim International GmbH; July 2013. Available online: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf
[Last accessed 24/07/13]
Afatinib improved PFS versus chemotherapy in patients
with common mutations (Del19/L858R)
Independent review – patients with Del19/L858R (n=308)
Progression-free survival (probability)
1.0
Afatinib
n=204
Cis/pem
n=104
PFS event, n (%) 130 (64)
0.8
Median PFS (months)
61 (59)
13.6
Hazard ratio (95% CI)
6.9
0.47 (0.34–0.65)
p<0.0001
0.6
51%
0.4
0.2
21%
0.0
0
Number at risk
Afatinib
204
Cis/Pem
104
3
6
169
62
143
35
9
12
15
18
Progression-free survival (months)
Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
115
17
75
9
49
6
30
2
21
24
27
10
2
3
0
0
0
Afatinib improved rates of response versus chemotherapy
All patients
Afatinib
/通用格式 p<0.001
p<0.001
/通用格式
Patients, %
/通用格式
/通用格式
Cis/pem
/通用格
式
/通用格
式
Afatinib
/通用格式 p<0.0001
p<0.0001
/通用格
式
/通用格式
/通用格式
Cis/pem
/通用格
式
/通用格式
/通用格
式
/通用格式
/通用格式
/通用格式
/通用格式
Patients, %
/通用格式
Common mutations (Del19/L858R)
/通用格
式
/通用格式
/通用格式
/通用格
式
/通用格式
/通用格式
/通用格式
/通用格式
/通用格式
/通用格式
/通用格式
Independent
Investigator
/通用格
式
Independent
Median duration of response: 11.1 vs. 5.5 months
(all patients; independent review)
Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
Investigator
LUX-Lung 3: Most frequent related adverse events
>20% difference between treatment arms
Afatinib
(n=229)
Cis/pem
(n=111)
All Gr† (%)
Gr 3 (%)
Gr 4 (%)
All Gr† (%)
Gr 3 (%)
Gr 4 (%)
Diarrhoea
218 (95.2)
33 (14.4)
0
17 (15.3)
0
0
Rash/acne*
204 (89.1)
37 (16.2)
0
7 (6.3)
0
0
Stomatitis/mucositis*
165 (72.1)
19 (8.3)
1 (0.4)
17 (15.3)
1 (0.9)
0
Paronychia
130 (56.8)
26 (11.4)
0
0
0
0
Dry skin
67 (29.3)
1 (0.4)
0
2 (1.8)
0
0
Nausea
41 (17.9)
2 (0.9)
0
73 (65.8)
4 (3.6)
0
Decreased appetite
47 (20.5)
7 (3.1)
0
59 (53.2)
3 (2.7)
0
Fatigue*
40 (17.5)
3 (1.3)
0
52 (46.8)
14 (12.6)
0
Vomiting
39 (17.0)
7 (3.1)
0
47 (42.3)
3 (2.7)
0
Neutropenia
2 (0.9)
1 (0.4)
0
35 (31.5)
17 (15.3)
3 (2.7)
Anaemia
7 (3.1)
1 (0.4)
0
31 (27.9)
5 (4.5)
2 (1.8)
*Grouped term; †No Grade 5 events for the presented AEs.
Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
Afatinib delayed the worsening of lung
cancer-related symptoms
Dyspnoea
Cough
Pain
NE, not estimated.
Yang J.C-H, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
Quality of life: EORTC QoL C-30
Difference in mean scores over time (longitudinal analysis)
Treatment difference
Global health status/QoL
3.28
Overall health
3.52
Quality of life
3.13
Physical functioning
4.83
Role functioning
4.50
Emotional functioning
0.85
Cognitive functioning
3.24
Social functioning
1.18
10
5
0
Favours afatinib
Yang J.C-H, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
–5
Favours cis/pem
LUX-LUNG 3:
ASIAN PATIENTS
Primary endpoint: PFS – Asian patients
Independent review
All Asian patients
Asian patients with Del19/L858R
Afatinib Cis/pem
n=166
n=83
PFS event, n (%) 112 (68)
1.0
Median PFS (months)
HR (95% CI)
50 (60)
PFS event, n (%)
1.0
6.9
0.54 (0.38–0.76)
p=0.0003
0.8
0.6
0.4
49%
0.2
22%
98 (66)
44 (59)
13.6
6.9
Median PFS (months)
HR (95% CI)
PFS (probability)
PFS (probability)
0.8
11.3
Afatinib Cis/pem
n=149
n=75
0.44 (0.30–0.63)
p<0.0001
0.6
52%
0.4
0.2
20%
0.0
0.0
0
3
Number at risk
Afatinib 166
137
Cis/pem 83
50
6
113
30
9
12 15 18
PFS (months)
91
16
60
8
40
5
21
26
2
24
8
1
27
0
3
Number at risk
3 Afatinib 149
130
0 Cis/pem 75
43
Mok T, et al. 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.
6
108
26
9
12 15 18
PFS (months)
87
13
58
6
39
4
21
25
1
24
8
1
27
3
0
LUX-Lung 3: Objective response
All patients
Afatinib
/通用格式 p<0.0001
Patients, %
/通用格式
p<0.0001
/通用格
式
/通用格式
/通用格式
Cis/pem
/通用格
式
/通用格式
/通用格式
Afatinib
/通用格式 p<0.0001
Cis/pem
p<0.0001
74.7
/通用格式
/通用格式
62.7
/通用格式
/通用格
式
/通用格式
/通用格式
Patients, %
/通用格式
Asian patients
/通用格式
43.4
/通用格式
/通用格
式
/通用格式
20.5
/通用格式
/通用格式
/通用格式
/通用格式
/通用格式
/通用格式
Independent
Investigator
Median duration of response:
11.1 vs. 5.5 months
(independent review)
Independent
Investigator
Median duration of response:
11.2 vs. 4.2 months
(independent review)
Mok T, et al. 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.
LUX-Lung 3: Most frequent related AEs – Asian patients
Afatinib
Asian (n=165)
Non-Asian (n=64)
All Gr† (%)
Gr 3 (%)
Gr 4 (%)
All Gr† (%)
Gr 3 (%)
Gr 4 (%)
Diarrhea
96
16
0
94
11
0
Rash/acne*
91
17
0
84
14
0
Stomatitis/mucositis*
85
9
0
39
6
1.6
Paronychia
65
14
0
36
5
0
Dry skin
33
0.6
0
19
0
0
Decreased appetite
26
4
0
6
1.6
0
Pruritus
21
0
0
14
1.6
0
Cis/pem
Asian (n=80)
Non-Asian (n=31)
All Gr† (%)
Gr 3 (%)
Gr 4 (%)
All Gr† (%)
Gr 3 (%)
Gr 4 (%)
Nausea
66
4
0
65
3
0
Decreased appetite
64
4
0
26
0
0
Vomiting
48
4
0
29
0
0
Fatigue*
45
9
0
52
23
0
Neutropenia
34
15
4
26
16
0
Anemia
30
5
1.3
23
3
3
Leukopenia
24
11
0
7
0
0
Constipation
21
0
0
13
0
0
*Grouped term; †No Grade 5 events for the presented AEs. Mok T, et al. 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.
LUX-LUNG 3:
SUMMARY
LUX-Lung 3: Summary
• LUX-Lung 3 is the largest* global prospective trial in
EGFR mutation-positive lung cancer and the first
using cisplatin and pemetrexed as the comparator
• LUX-Lung 3 met its primary endpoint with median
PFS (independent review):
– Overall population: 11.1 vs. 6.9 months
– Common mutations: 13.6 vs. 6.9 months
– Consistent efficacy in all relevant subgroups
• Afatinib significantly improved rates of response
versus chemotherapy
• Efficacy findings from the Asian subgroup are in line
with those from the overall trial population
*n=345.
Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print]; Mok T, et al. Presented at the 5th Annual Meeting of Asian Pacific Lung Cancer Congress,
2013. Oral presentation.
LUX-Lung 3: Summary (continued)
• First-line afatinib significantly prolonged PFS,
with associated delay in worsening of lung cancerrelated symptoms and improvement in quality of life
• Safety profile of afatinib consistent with previous
studies
– Overall population: Diarrhoea and rash were the most
frequent AEs; manageable with low treatment
discontinuation rate
– Asian patients: Diarrhoea and rash were the most
frequent AEs; no treatment discontinuations for rash
and only one Asian patient discontinued for diarrhoea
Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print]; Mok T, et al. Presented at the 5th Annual Meeting of Asian Pacific Lung Cancer Congress,
2013. Oral presentation.
LUX-LUNG 6
LUX-Lung 6: Study design
Asian patients (China, South Korea, Thailand)
Stage IIIB (wet)/IV lung adenocarcinoma
EGFR mutation in tumour
(central lab testing; Therascreen EGFR29* RGQ PCR)
Randomization 2:1
Stratified by:
EGFR mutation (Del19/L858R/other)
Afatinib 40
mg/day†
Gemcitabine + cisplatin
1000 mg/m2 D1, D8 + 75 mg/m2
i.v. q21 days, up to 6 cycles
Primary endpoint: PFS (RECIST 1.1, independent review)‡
Secondary endpoints: ORR, DCR, DoR, tumour shrinkage, OS, PRO§, safety
*Central lab testing; Therascreen EGFR29 RGQ PCR detecting 19 deletions in exon 19, three insertions in exon 20, L858R, L861Q, T790M, G719S, G719A
and G719C (or G719X), S768I; †Dose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10 mg decrements in case of related Grade 3
or prolonged Grade 2 AE; ‡Tumour assessments: every 6 weeks until Week 48 and every 12 weeks thereafter until progression/start of new therapy;
§Patient-reported outcomes: EQ-5D, EORTC QLQ-C30 and QLQ-LC13 at randomization and every 3 weeks until progression or new anti-cancer therapy.
Wu Y-L, et al. J Clin Oncol 2013; 31 (suppl): Abstract 8016 and poster.
LUX-Lung 6: Patient disposition
910 screened
471 EGFR mutation (+)
364 randomized
242 assigned to afatinib
• 3 did not receive treatment
182 (76%) stopped treatment
PFS event at data cut-off
• 169 (70%) by investigator assessment
• 157 (65%) by independent assessment
57 (24%)
on treatment
Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8016 and poster.
107 did not meet
eligibility criteria
or did not enter
122 assigned to cisplatin + pemetrexed
• 9 did not receive treatment
113 (100%) stopped or completed treatment
PFS event at data cut-off
• 78 (64%) by investigator assessment
• 64 (53%) by independent assessment
0
on treatment
LUX-Lung 6: Patient demographics/characteristics
Gender, n (%)
Afatinib
(n=242)
Gem/cis
(n=122)
Total
(n=364)
Male
87 (36)
39 (32)
126 (35)
Female
155 (64)
83 (68)
238 (65)
58 (29–79)
58 (27–76)
58 (27–79)
Never smoked
181 (75)
99 (81)
280 (77)
Ex-smoker
44 (18)
13 (11)
57 (16)
Current smoker
17 (7)
10 (8)
27 (7)
IIIB (wet)
16 (7)
6 (5)
22 (6)
IV
226 (93)
116 (95)
342 (94)
0
48 (20)
41 (34)
89 (24)
1
194 (80)
81 (66)
275 (76)
Del19
124 (51)
62 (51)
186 (51)
L858R
92 (38)
46 (38)
138 (38)
Other
26 (11)
14 (12)
40 (11)
Age, years, median (range)
Smoking status, n (%)
Stage (AJCC 6.0), n (%)
ECOG PS, n (%)
EGFR mutation, n (%)
Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8016 and poster.
Primary endpoint: Afatinib improved PFS versus
chemotherapy
Independent review – all randomized patients
Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8016 and poster.
LUX-Lung 6: PFS subgroup analysis
Independent review – all randomized patients
Factors
Total
Gender
Male
Female
Age at baseline
<65 years
≥65 years
EGFR mutation category
Del19/L858R (common)
Del19
L858R
Other (uncommon)
Baseline ECOG PS
0
1
Smoking history
Never smoked
<15 pack–years + stop >1 year
Other current/ex-smoker
Number of
patients
364
Hazard ratio
(95% confidence interval)
0.28 (0.20–0.39)
126
238
0.36 (0.21–0.63)
0.24 (0.16–0.35)
278
86
0.30 (0.21–0.43)
0.16 (0.07–0.40)
324
186
138
40
0.25 (0.18–0.35)
0.20 (0.13–0.33)
0.32 (0.19–0.52)
0.55 (0.22–1.43)
89
275
0.22 (0.12–0.41)
0.29 (0.20–0.43)
280
12
72
0.24 (0.16–0.34)
0.39 (0.07–2.41)
0.46 (0.22–1.00)
1/16
1/4
Favours afatinib
Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8016 and poster.
1
4
Favours gem/cis
16
LUX-Lung 6: Best overall tumour response
Randomized patients
Independent
review
Response
Objective response
(CR+PR), %
Median duration of response
(months) (95% CI)
Disease control
(CR+PR+SD), %
Median duration of disease
control (months) (95% CI)
Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8016 and poster.
Investigator
review
Afatinib
(n=242)
Gem/cis
(n=122)
Afatinib
(n=242)
Gem/cis
(n=122)
66.9
23.0
74.4
31.1
9.7
(8.3, 12.5)
4.3
(2.8, 5.8)
12.4
(11.2, 12.9)
4.0
(2.8, 4.9)
92.6
76.2
93.0
75.4
11.1
(9.7, 13.8)
5.7
(5.5, 6.9)
13.8
(12.5, 14.9)
6.4
(5.5, 6.9)
LUX-Lung 6: Summary of adverse events
Afatinib
n=239
Gem/cis
n=113
Median treatment duration (days)
398
89
Drug-related AEs (%)
98.7
99.1
Drug-related AEs Grade ≥3 (%)
36.0
60.2
Drug-related AEs leading to dose reduction (%)
32.2
26.5*
Drug-related AEs leading to discontinuation (%)
5.9†
39.8
Drug-related SAEs (%)
5.4
7.0
Related AEs leading to death‡ (%)
0.4
0.9
*36% of gemcitabine/cisplatin patients had dose delay of ≥6 days; †2% discontinued afatinib due to rash, no discontinuations for diarrhoea;
‡Related deaths: sudden death (afatinib) and cardiac failure (gemcitabine/cisplatin).
Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8016 and poster.
LUX-Lung 6: Most frequent related adverse events
Afatinib (n=239)
Gem/cis (n=113)
All grade (%)
Grade 3 (%)
Grade 4 (%)
All grade (%)
Grade 3 (%)
Grade 4 (%)
Diarrhoea
88.3
5.4
0
10.6
0
0
Rash/acne*
80.8
14.2
0.4
8.8
0
0
Stomatitis/mucositis*
51.9
5.4
0
5.3
0
0
Paronychia
32.6
0
0
0
0
0
ALT increase
20.1
1.7
0
15.9
1.8
0.9
Vomiting
9.6
0.8
0
80.5
15.9
3.5
Nausea
7.5
0
0
75.2
7.1
0.9
Neutropenia
2.1
0.4
0
54.0
17.7
8.8
Leukopenia
3.3
0.4
0
51.3
13.3
1.8
Decreased appetite
10.0
1.3
0
40.7
1.8
0
Fatigue*
10.0
0.4
0
36.3
0.9
0
Anaemia
5.4
0.4
0
27.4
7.1
1.8
Neutrophil count decreased
0.8
0
0
25.7
7.1
2.7
WBC decreased
0.8
0
0
23.9
6.2
0
*Grouped term.
Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8016 and poster.
Afatinib delayed the worsening of lung
cancer-related symptoms
Cough
Dyspnoea
Pain
NE, not estimated.
Geater SL, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8061 and poster.
LUX-Lung 6: Summary and conclusions
• In EGFR mutation-positive Asian patients,
afatinib significantly prolonged PFS compared with
gemcitabine/cisplatin
– Median PFS of 11.0 vs. 5.6 months (HR=0.28; p<0.0001)
(independent review)
• PFS benefit was observed across all prespecified
subgroups
• Treatment with afatinib was associated with significant
improvements in ORR, DCR, symptom control and quality
of life compared with chemotherapy
• Safety profile was as expected in both treatment arms
• Afatinib had a more favourable safety profile compared with
chemotherapy
• LUX-Lung 6 is the largest prospective first-line trial in EGFR
mutation-positive lung cancer patients
OVERALL SUMMARY
Afatinib PFS benefit consistent across both trials
Independent review – all randomized patients
LUX-Lung 3
LUX-Lung 6
LUX-Lung 3, n=345
(afatinib vs. pem/cis )
LUX-Lung 6, n=364
(afatinib vs. gem/cis)
Median PFS
11.1 vs. 6.9
11.0 vs. 5.6
HR for PFS
0.58
0.28
47% vs. 22%
47% vs. 2%
12-month PFS
Afatinib for the treatment of EGFR mutation-positive
NSCLC
• Afatinib significantly prolonged PFS compared with
cisplatin/pemetrexed in EGFR mutation-positive
patients (LUX-Lung 3)
• Afatinib significantly prolonged PFS compared with
gemcitabine/cisplatin in EGFR mutation-positive
Asian patients (LUX-Lung 6)
• The results of LUX-Lung 3 and LUX-Lung 6 support
the strategy of genotype-directed therapy with afatinib
in previously untreated patients with EGFR mutationpositive NSCLC
LUX-Lung 7 and LUX-Lung 8:
Irreversible versus reversible EGFR blockade
Recruiting…
EGFR M+ NSCLC adenocarcinoma
ECOG PS 0–1
First-line setting
Squamous NSCLC
ECOG PS 0–1
Second-line setting (post chemo)
Randomization 1:1
Randomization 1:1
Afatinib
40 mg/day
Gefitinib
250 mg/day
Co-primary: PFS, TTF and OS at 24 months
Secondary: ORR, DCR, QoL at 24 months
LUX-Lung 7: http://clinicaltrials.gov/ct2/show/NCT01466660?term=1200.123&rank=1;
LUX-Lung 8: http://clinicaltrials.gov/ct2/show/NCT01523587?term=1200.125&rank=1;
Goss G, et al. Ann Oncol 2012;23(9):ix174, 509TiP.
Afatinib
40 mg/day
Erlotinib
150 mg/day
Primary: PFS
Secondary: OS, PRO
LUX-Lung trial programme
Adenocarcinoma
Adenocarcinoma
EGFR-TKI naïve
EGFR mutation positive
EGFR-TKI pretreated
Likely EGFR mutation
First/second line
LUX Lung 2
Third/fourth line
LUX Lung 1
First line
LUX Lung 3
LUX Lung 6
LUX Lung 7
LUX Lung 4
LUX Lung 5
Squamous cell
EGFR-TKI naïve
Second line
LUX Lung 8
Afatinib beyond LUX-Lung programme
• Focus on rational targeted
combinations:
Anti-EGFR
antibodies
MEK
inhibitors
MET
inhibitors
– Improve monotherapy effect
– Delay resistance
– Overcome resistance
Afatinib
IGF
inhibitors
PI3K/mTOR
inhibitors
HDAC
inhibitors
...investigation continues
Afatinib + cetuximab
Continuous and simultaneous EGFR inhibition
EGFR M+ lung adenocarcinoma with
acquired resistance to
erlotinib/gefitinib
Define MTD
Afatinib 40 mg daily +
cetuximab 500 mg/m2 q2w
• In a heavily pretreated population with
EGFR M+ tumours: T790M+ or T790M‒
ORR, PFS
– ORR = 30% (median DOR = 8 months)
– DCR = 75%
非有以御其內，其勢不止；非有以治其外， – Median PFS = 4.7 months
疾未易為也。
明 方孝儒 指喻
Janjigian YY, et al. Ann Oncol 2012;23(9):ix401, 1227O.
Summary
• LUX-Lung programme is investigating afatinib in
NSCLC
– Addressing different questions
– Different settings
– Different patient subgroups
– Different combinations
• Afatinib demonstrates efficacy in EGFR mutationpositive NSCLC
– Irrespective of line of treatment
– Irrespective of prior treatment with EGFR-TKIs
• Investigation continues...
First-line treatment algorithm for advanced
NSCLC (2013)
Diagnosis
Molecular
Clinical (PS)
EGFR mutation
positive
or ALK fusion positive
Good PS
Poor PS
Histological
Non-squamous
Gefitinib, erlotinib
or crizotinib
(to progression)
Squamous
Clinical
Bevacizumab
eligible
Bevacizumab
ineligible
Platinum
doublet*
Platinum/pemetrexed (or
other*) ± bevacizumab
Platinum/pemetrexed
(or other*)
*With docetaxel, paclitaxel, gemcitabine, vinorelbine or nab-paclitaxel.
Adapted from Gandara DR, et al. Clin Lung Cancer 2009;10:392–394.
Single-agent
or combination
chemotherapy
Schematic of patients with activating EGFR mutation
receiving EGFR TKI, CT and BSC in various sequences
(No CT)
(No TKI)
Mok T, et al. J Clin Oncol 2013;31:1081–1088.
Asian contribution to development of afatinib in NSCLC:
Re-look into history
2007
First Asian patient enrolled in Taiwan for Phase II trial, LUX-Lung 2
About 80% of patients in study were enrolled from 7 sites in Taiwan
2008
First patient enrolled in Japan for Phase II trial, LUX-Lung 4
2008
First patient enrolled in Asia for Phase III trial, LUX-Lung 1
Taiwan, Korea, China, Hong Kong, Singapore and Thailand contributed 61% of randomized patients
2009
First patient enrolled in Asia for Phase III trial, LUX-Lung 3
Taiwan, Korea, Hong Kong, Malaysia, Thailand and the Philippines contributed 50% of total patients
2009
First Phase II study in EGFR wild-type patients initiated in Korea
First afatinib study to be led by OPU in Asia
2010
First patient enrolled into LUX-Lung 5
China, Taiwan, Korea and India contributed 45% of total patients
2010
First patient enrolled in Asian regional study, LUX-Lung 6
First afatinib Phase III study led by China OPU; China, Korea and Thailand contributed all patients
Asian contribution to development of afatinib in NSCLC:
Current activities
2011
2011
2012
First patient enrolled in LUX-Lung 7 head-to-head comparison with gefitinib in
treatment-naïve NSCLC patients with EGFR mutation
First afatinib global study to be led from Asia OPU (BI Korea)
Study completing recruitment and data analysis planned for Q1 2015
NPU programme started
In Asia, so far 1545 patients have received afatinib under NPU
In Taiwan alone, 837 patients have received afatinib under NPU
First global Phase III trial (LUX-Lung 8) in squamous NSCLC was initiated
China, Taiwan, Korea, India and Singapore are currently recruiting patients
So far, Asian contribution is 25% of global recruitment
Very recent news!
First positive regulatory
appraisals for afatinib
Giotrif/Gilotrif (US)
072
Thanks for Your Attention!!