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NEW TKI IN LUNG CANCER
R6 洪逸平Supervisor 顏厥全醫師
Some slide revised from Boehringer Ingelheim Afatinib Launch Meeting
KRAS
EGFR
ALKPIK3CABRAFMET
HER2MEK
ROS1RET
Unknown35%
Vandetanib?XL184? Sunitinib?
Actionable targets in lung adenocarcinomas
Unknown75%
1999 2005–2013
EGFR
2004
Unknown60%
SelumetinibTrametinib
GefitinibErlotinibAfatinibDacomitinibCO1686, AZD9291
Crizotinib, LDK378, CH5424802, AP26113
NRAS
Crizotinib
Selumetinib?
Afatinib?Dacomitinib?
MetMab?Dabrafenib, vemurafenibregorafenib, MEK inhibitors
MK2206?BKM120?
RETROS1
MEKHER2
MET BRAF PIK3CAALK
KRAS
EGFR
ALKPIK3CABRAFMET
HER2MEK
ROS1RET
Unknown35%
Vandetanib?XL184? Sunitinib?
Actionable targets in lung adenocarcinomas
Unknown75%
1999 2005–2013
EGFR
2004
Unknown60%
SelumetinibTrametinib
GefitinibErlotinibAfatinibDacomitinibCO1686, AZD9291
Crizotinib, LDK378, CH5424802, AP26113
NRAS
Crizotinib
Selumetinib?
Afatinib?Dacomitinib?
MetMab?Dabrafenib, vemurafenibregorafenib, MEK inhibitors
MK2206?BKM120?
RETROS1
MEKHER2
MET BRAF PIK3CAALK
HSP90 client oncoproteinAUY922, IPI504, ganetespib
PD1/PD-L1 expression Lambrolizumab, nivolumab, MPDL3280A, BMS936559
AntiangiogenesisBevacizumab, nintedanib*,motesanib
*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
你相信有平行世界嗎? 那些年,我們一起追的女孩 九把刀
EGFR mutation + EGFR mutation –
EGFR TKI Chemotherapy
Conversations in Oncology 2009 – Vienna
Tony Mok, Vienna, 2009.
Conversations in Oncology in Asia – 2013, Taipei
EGFR mut Alk-EML4 HER-2 K-ras ROS1--
RET-- B-Raf ??
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
Mok TS, et al. N Engl J Med 2009;361:947–57.
Gefitinib (n=91)
0 4 8 12 16 20 240.0
0.2
0.4
0.6
0.8
1.0
Prob
abili
ty P
FS
0 4 8 12 16 20 240.0
0.2
0.4
0.6
0.8
1.0
Prob
abili
ty o
f PFS
Months Months
Carboplatin/paclitaxel (n=129)
Gefitinib (n=132) Carboplatin/paclitaxel (n=85)
EGFR mutation-positiveHR: 0.48 p<0.001
EGFR mutation-negativeHR: 2.85 p<0.001
Treatment by subgroup interaction test, p<0.0001Qualitative interaction!!!
At risk:Gefitinib 132 108 71 31 11 3 0 C/P 129 103 37 7 2 1 0
91 21 4 2 1 0 0 85 58 14 1 0 0 0
USA (456)2–14%
(15–25%)
Brazil (2017)30%
Spain (2105)17%
France (1227)14%
Italy (860)
5% (10%)
India (2527)25–40%
(36%)
China (1068)24–39% (41–50%)
Korea (513)20–36% (38–48%)
Australia (83)
7% (14%)
Japan (1498)26–40% (41–49%)
Taiwan (267)34%
(56–62%)
Hong Kong (161)(47%)
Vietnam (120)(64%)
Thailand (403)(54%)
The Philippines (65)
(52%)
Qatar (25)
(32%)
EGFR mutations in NSCLC geographical map
Key: Country (N=) % mutation NSCLC (% mutation in adenocarcinoma). Parikh PM, Puri T. Ind J Cancer 2013.
Developing a targeted agent that irreversibly blocks signalling from the ErbB Family receptors
...from the bench to the clinic
Afatinib: An ErbB Family Blocker
AfatinibErlotinib 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) 0.5HER2 (nM) 14ErbB4 (nM) 1HGFR (nM) >10,000VEGFR2 (nM) >100,000
Molecular potency and selectivity (IC50)EGFR L858R
EGFR L858R/T790M
Afatinib 0.4 10
Gefitinib 0.8 1013
Erlotinib 1 1520
Li D, et al. Oncogene 2008;27:4702–4711.
ErbB-dependent tumours
Over-expression
Gen
e am
plifi
catio
n EGFR HER2
ErbB3 ErbB4
Mutation
Chromosomal polysomy
NSCLCBreastHead and neck GastricOesophagealPancreaticBiliaryEndometrialOvarianGlioblastomaMelanoma
Metastatic/ recurrent
Locally advancedadjuvant
HNSCC
EGFRmutation positive
Head-to-head trials
Erlotinib/gefitinibpretreated
NSCLC/adenocarcinoma NSCLC / SCC
LUX-Lung 1 LUX-Lung 2 LUX-Lung 7
LUX-Lung 4 LUX-Lung 3
LUX-Lung 5 LUX-Lung 6
LUX-Lung 8 LUX-HN 1 LUX-HN 2
LUX-HN 3 LUX-HN 4
LUX trial programme
Yang JC, Taipei, August 2013.
Continued EGFR inhibition
Afatinib in NSCLC: Key trials
Improve outcomes in EGFR M+ 1st/2nd line
Improve outcomes in (EGFR M+) 3rd/4th line
Squamous cell NSCLC
Irreversible vs. reversible EGFR blockade
Improve on monotherapy effect in EGFR M+ 3rd/4th lineAfa + Cet
LL5
LL1 & 4
LL2, 3 & 6
LL7 & 8
LL8
EGFR-TKI pretreated
EGFR-TKI naïve
LUX-LungProgramme
LUX-Lung 1: Post erlotinib/gefitinib – third/fourth line
Miller V, et al. Lancet Oncol 2012;13:528–538.
Stage IIIB/IV adenocarcinoma of the lungProgressed 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)
Primary endpoint: OSSecondary endpoints: PFS, ORR, QoL (LC13/C30), safety
Oral placebo once daily + BSC
Oral afatinib 50 mg once daily + BSC
LUX-Lung 1: OS and PFS
Updated OS analysis (February 2012) PFS (independent review)Afatinib
n=390Placebon=195
Median OS (months) 10.9 11.7
HR 1.01 p=0.54
Miller V, et al. Lancet Oncol 2012;13:528–538.
Afatinib n=390
Placebo
n=195
Median PFS (months) 3.3 1.1
HR 0.38 p<0.0001
LUX-Lung 1: OS and subsequent systemic treatment
Miller V, et al. Lancet Oncol 2012;13:528–538.
Estim
ated
sur
viva
l pr
obab
ility
(%)
100
80
60
40
20
0
Time since randomization (months)0 3 6 9 12 15 18 21 24
100
80
60
40
20
0
Time since randomization (months)0 3 6 9 12 15 18 21 24
Afatinib=5.8 monthsPlacebo=4.6 monthsHR=0.66; p=0.027
Patients with no subsequent therapy (n=191)
Patients with ≥1 subsequent therapy (n=394)
Afatinib=12.7 monthsPlacebo=14.4 monthsHR=1.09; p=0.535
Estim
ated
sur
viva
l pr
obab
ility
(%)
LUX-Lung 1: PFS and likelihood of EGFR mutation
Afatinib=4.4 months Placebo=1.0 months
Afatinib=2.8 months Placebo=1.8 months
Estim
ated
PFS
pro
babi
lity
(%)
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
Time since randomization (months)0 3 6 9 12 15
134 6 2 1 0 0257 111 49 10 7 3
Number at riskPlaceboAfatinib
Time since randomization (months)0 3 6 9 12 15
61 9 2 1 0 0133 41 16 6 2 0
Number at riskPlaceboAfatinib
Estim
ated
PFS
pro
babi
lity
(%)
Boehringer Ingelheim. Data on file.
YESHigh (>80%) likelihood of mutant EGFR
NOLower (<30%) likelihood of mutant EGFR
CR or PR to prior EGFR-TKI or ≥48 weeks duration of prior EGFR-TKI
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
• Population and results: Similar to LUX-Lung 1
Japanese NSCLC patients Failure of conventional treatment or no therapy of proven efficacy
ECOG PS 0 or 1Progressed after one or two lines of chemotherapy (including one platinum-based regimen)
and ≥12 weeks of treatment with erlotinib or gefitinib (Phase II)
ORR=8.2%Median PFS 4.4 months Median OS 19 months
Results (Phase II, n=62)
Afatinib N=90 in Phase I/II; MTD: 50 mg/day
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
PFSOS
PRO
LUX-Lung 5: PFS in Part A
Schuler M, et al. J Clin Oncol 2012;30(Suppl.):Abstract/Poster 7557.
Overall (n=1154)
mPFS: 3.3 monthsAdenoca (n=985 ): 3.3 monthsSquamous (n=91): 3.7 months
By histology
Lower (n=556): 2.8 monthsHigher (n=598): 4.2 months
By likelihood of EGFR mutation
Kim J-H, et al. J Clin Oncol 2012;30(Suppl.):Abstract/Poster 7558.Schuler M, et al. J Clin Oncol 2012;30(Suppl.):Abstract/Poster 7557.
LUX-Lung 2: Phase II in EGFR M+ first/second line
Yang CH, et al. Lancet Oncol 2012;13:539–548.
Adenocarcinoma of the lung Stage IIIB/IVEGFR mutation
Chemotherapy naïve or progressive disease following first-line chemotherapy
EGFR-TKI naïveECOG PS 0–2
Primary endpoint: ORRSecondary endpoints: PFS, OS
Oral afatinib; starting dose 50 mg/day or 40 mg/day
LUX-Lung 2: PFS, ORR, tumour shrinkage, OS
First line Second line
Treated 61 68
ORR (%) 65.6 57.4
DCR (%) 86.9 77.9
OS (month) NA 23.3
Yang CH, et al. Lancet Oncol 2012;13:539–548; Boehringer Ingelheim. Data on file.
• Comparable activity in first-/second-line treatment of EGFR mutation-positive NSCLC
Median PFS (months) Independent / Investigator
First line (n=61)Second line (n=68)
12 / 15.68 / 10.5
Prog
ress
ion
free
surv
ival
(%)
0
40
20
60
80
100
LUX-Lung 3 and 6: First-line EGFR M+ NSCLC
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.
Stage IIIB(wet)/IV NSCLC adenocarcinomaEGFR mutation positive tumour (central test)
ECOG PS 0‒1
Randomization 2:1
Primary endpoint: PFS (independent review) Secondary endpoints: ORR, DCR, OS, PRO
Cisplatin + pemetrexed (LL3)Cisplatin + gemcitabine (LL6)
up to 6 cycles
Afatinib 40 mgonce daily continuously
LUX-LUNG 3
LUX-Lung 3: Study design
*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].
Randomization 2:1 Stratified by:
EGFR mutation (Del19/L858R/other) Race (Asian/non-Asian)
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
Stage IIIB (wet)/IV lung adenocarcinoma (AJCC version 6)
EGFR mutation in tumour(central lab testing; Therascreen EGFR29* RGQ PCR)
Afatinib 40 mg/day†
ASIAHong Kong
JapanKorea
Malaysia Philippines
Taiwan Thailand
LUX-Lung 3: The largest global trial in the EGFR mutation-positive NSCLC population
NORTH AMERICAUSA
Canada
SOUTH AMERICA Argentina, Brazil,
Chile, Peru
EUROPEAustria, Belgium, France, Germany,
Hungary, Ireland, Italy, Romania, Russia, Ukraine, UK
Australia
345 patients from 133 sites in 25 countries
LUX-Lung 3: Patient demographics/characteristics
Afatinib (n=230)
Cis/pem (n=115)
Total (n=345)
Gender, n (%) Male 83 (36) 38 (33) 121 (35)
Female 147 (64) 77 (67) 224 (65)
Age, years, median (range) 62 (28–86) 61 (31–83) 61 (28–86)
Race, n (%) Caucasian 61 (27) 30 (26) 91 (26)
Eastern Asian 165 (72) 83 (72) 248 (72)
Other 4 (1) 2 (2) 6 (2)
Smoking status, n (%) Never smoked 155 (67) 81 (70) 236 (68)
Ex-smoker 70 (30) 32 (28) 102 (30)
Current smoker 5 (2) 2 (2) 7 (2)
Stage (AJCC 6.0), n (%) IIIB (wet) 20 (9) 17 (15) 37 (11)
IV 210 (91) 98 (85) 308 (89)
ECOG PS, n (%) 0 92 (40) 41 (36) 133 (39)
1 138 (60) 73 (64) 211 (61)
2 0 1 (1) 1 (<1)
EGFR mutation, n (%) Del19 113 (49) 57 (49) 170 (49)
L858R 91 (40) 47 (41) 138 (40)
Other 26 (11) 11 (10) 37 (11)
Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
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].
Primary endpoint: Afatinib improved PFS versus chemotherapy
Number at riskAfatinib 230 180 151 120 77 50 31 10 3 0Cis/Pem 115 72 41 21 11 7 3 2 0 0
Progression-free survival (months)
Afatinib
n=230Cis/pem
n=115
PFS event, n (%) 152 (66) 69 (60)
Median PFS (months) 11.1 6.9Hazard ratio (95% CI) 0.58 (0.43–0.78)
p=0.0004
Prog
ress
ion-
free
sur
viva
l (pr
obab
ility
)
1.0
0.8
0.6
0.4
0.2
0.00 3 6 9 12 15 18 21 24 27
47%
22%
Independent review – all randomized patients
Factors Number of patients
Hazard ratio(95% confidence interval)
Total 345 0.58 (0.43–0.78)Gender Male Female
121224
0.61 (0.37–1.01)0.54 (0.38–0.78)
Age at baseline: <65 vs. ≥65 years <65 years ≥65 years
211134
0.53 (0.36–0.76)0.64 (0.39–1.03)
Race stratification factor Non-Asian Asian
96249
0.68 (0.39–1.19)0.54 (0.38–0.76)
EGFR mutation category Del19/L858R (common) Del19 L858R
308170138
0.47 (0.34–0.65)0.28 (0.18–0.44)0.73 (0.46–1.17)
Baseline ECOG score 0 1
133211
0.50 (0.31–0.82)0.63 (0.43–0.91)
Smoking history Never smoked <15 packet years + stop >1 year Other current/ex-smoker
2363079
0.47 (0.33–0.67)0.50 (0.19–1.34)1.04 (0.54–1.98)
1/16 5/8 6 1/4
LUX-Lung 3: PFS subgroup analysis
Favours afatinib Favours cis/pem
Independent review – all randomized patients
Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
LUX-Lung 3: Updated OS analysis
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 (n=230)
Cis/pem (n=115)
Overall survival*
Number of Deaths, N (%) 116 (50.4%) 59 (51.2%)
Median Overall Survival (months) 28.1 28.2
95% CI (24.6, 33.0) (20.7, 33.2)
HR (95% CI) 0.91 (0.66, 1.25)
Stratified Log-Rank Test P-value* 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.
Prog
ress
ion-
free
sur
viva
l (pr
obab
ility
)
1.0
0.8
0.6
0.4
0.2
0.0
Number at riskAfatinib 204 169 143 115 75 49 30 10 3 0Cis/Pem 104 62 35 17 9 6 2 2 0 0
Progression-free survival (months)0 3 6 9 12 15 18 21 24 27
Afatinib
n=204Cis/pem
n=104
PFS event, n (%) 130 (64) 61 (59)
Median PFS (months) 13.6 6.9Hazard ratio (95% CI) 0.47 (0.34–0.65)
p<0.0001
Afatinib improved PFS versus chemotherapy in patients with common mutations (Del19/L858R)
51%
21%
Independent review – patients with Del19/L858R (n=308)
Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
Afatinib improved rates of response versus chemotherapy
Independent InvestigatorCE/ 通用格式
CE/ 通用格式
CE/ 通用格式
CE/ 通用格式CE/ 通用格式
CE/ 通用格式
CE/ 通用格式
AfatinibCis/pem
All patients Common mutations (Del19/L858R)
Independent InvestigatorCE/ 通用格式
CE/ 通用格式
CE/ 通用格式
CE/ 通用格式CE/ 通用格式
CE/ 通用格式
CE/ 通用格式
AfatinibCis/pem
Median duration of response: 11.1 vs. 5.5 months (all patients; independent review)
p<0.001 p<0.001 p<0.0001 p<0.0001
Patie
nts,
%
Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
Patie
nts,
%
*Grouped term; †No Grade 5 events for the presented AEs.Sequist LV, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
LUX-Lung 3: Most frequent related adverse events
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)
>20% difference between treatment arms
NE, not estimated.Yang J.C-H, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
Afatinib delayed the worsening of lung cancer-related symptoms
Pain
Cough Dyspnoea
Yang J.C-H, et al. J Clin Oncol 2013 Jul 1; [Epub ahead of print].
Quality of life: EORTC QoL C-30
10 5 0 –5
Global health status/QoL
Overall health
Quality of life
Physical functioning
Role functioning
Emotional functioning
Cognitive functioning
Social functioning
Treatment difference3.28
3.52
3.13
4.83
4.50
0.85
3.24
1.18
Favours afatinib Favours cis/pem
Difference in mean scores over time (longitudinal analysis)
LUX-LUNG 3:ASIAN PATIENTS
Primary endpoint: PFS – Asian patients Independent review
PFS
(pro
babi
lity)
1.0
0.8
0.6
0.4
0.2
0.0
PFS (months)0 3 6 9 12 15 18 21 24 27
PFS (months)
PFS
(pro
babi
lity)
1.0
0.8
0.6
0.4
0.2
0.00 3 6 9 12 15 18 21 24 27
Number at riskAfatinib 166 137 113 91 60 40 26 8 3Cis/pem 83 50 30 16 8 5 2 1 0
Number at riskAfatinib 149 130 108 87 58 39 25 8 3Cis/pem 75 43 26 13 6 4 1 1 0
Afatinib
n=166
Cis/pem
n=83
PFS event, n (%) 112 (68) 50 (60)
Median PFS (months) 11.3 6.9
HR (95% CI) 0.54 (0.38–0.76)p=0.0003
Afatinib
n=149
Cis/pem
n=75
PFS event, n (%) 98 (66) 44 (59)
Median PFS (months) 13.6 6.9
HR (95% CI) 0.44 (0.30–0.63)p<0.0001
All Asian patients Asian patients with Del19/L858R
49%
22%
52%
20%
Mok T, et al. 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.
LUX-Lung 3: Objective response
Independent InvestigatorCE/ 通用格式
CE/ 通用格式
CE/ 通用格式
CE/ 通用格式CE/ 通用格式
CE/ 通用格式
CE/ 通用格式
AfatinibAll patients
Median duration of response: 11.1 vs. 5.5 months
(independent review)
p<0.0001 p<0.0001
Patie
nts,
%
Independent InvestigatorCE/ 通用格式
CE/ 通用格式
CE/ 通用格式
62.7
20.5
AfatinibAsian patients
p<0.0001 p<0.0001
Median duration of response:11.2 vs. 4.2 months
(independent review)
74.7
43.4
Mok T, et al. 5th Annual Meeting of Asian Pacific Lung Cancer Congress, 2013. Oral presentation.
Patie
nts,
%
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
LUX-Lung 3: Most frequent related AEs – Asian patients
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 0Vomiting 48 4 0 29 0 0Fatigue* 45 9 0 52 23 0Neutropenia 34 15 4 26 16 0Anemia 30 5 1.3 23 3 3Leukopenia 24 11 0 7 0 0Constipation 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 cancer-related 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
*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.
Randomization 2:1 Stratified by:
EGFR mutation (Del19/L858R/other)
Gemcitabine + cisplatin1000 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
Asian patients (China, South Korea, Thailand)Stage IIIB (wet)/IV lung adenocarcinoma
EGFR mutation in tumour(central lab testing; Therascreen EGFR29* RGQ PCR)
Afatinib 40 mg/day†
LUX-Lung 6: Patient disposition
Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8016 and poster.
910 screened
471 EGFR mutation (+)
364 randomized
107 did not meet eligibility criteria or did not enter
242 assigned to afatinib•3 did not receive treatment
57 (24%)on treatment
PFS event at data cut-off •169 (70%) by investigator
assessment•157 (65%) by independent
assessment
122 assigned to cisplatin + pemetrexed•9 did not receive treatment
0 on treatment
PFS event at data cut-off•78 (64%) by investigator
assessment•64 (53%) by independent
assessment
182 (76%) stopped treatment 113 (100%) stopped or completed treatment
LUX-Lung 6: Patient demographics/characteristics
Afatinib (n=242)
Gem/cis (n=122)
Total(n=364)
Gender, n (%) Male 87 (36) 39 (32) 126 (35)Female 155 (64) 83 (68) 238 (65)
Age, years, median (range) 58 (29–79) 58 (27–76) 58 (27–79)Smoking status, n (%) Never smoked 181 (75) 99 (81) 280 (77)
Ex-smoker 44 (18) 13 (11) 57 (16)Current smoker
17 (7) 10 (8) 27 (7)
Stage (AJCC 6.0), n (%) IIIB (wet) 16 (7) 6 (5) 22 (6)IV 226 (93) 116 (95) 342 (94)
ECOG PS, n (%) 0 48 (20) 41 (34) 89 (24)1 194 (80) 81 (66) 275 (76)
EGFR mutation, n (%) Del19 124 (51) 62 (51) 186 (51)L858R 92 (38) 46 (38) 138 (38)Other 26 (11) 14 (12) 40 (11)
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 analysisIndependent review – all randomized patients
Factors Number of patients
Hazard ratio(95% confidence interval)
Total 364 0.28 (0.20–0.39)Gender Male Female
126238
0.36 (0.21–0.63)0.24 (0.16–0.35)
Age at baseline <65 years ≥65 years
27886
0.30 (0.21–0.43)0.16 (0.07–0.40)
EGFR mutation category Del19/L858R (common) Del19 L858R Other (uncommon)
32418613840
0.25 (0.18–0.35)0.20 (0.13–0.33)0.32 (0.19–0.52)0.55 (0.22–1.43)
Baseline ECOG PS 0 1
89275
0.22 (0.12–0.41)0.29 (0.20–0.43)
Smoking history Never smoked <15 pack–years + stop >1 year Other current/ex-smoker
2801272
0.24 (0.16–0.34)0.39 (0.07–2.41)0.46 (0.22–1.00)
Favours afatinib Favours gem/cis 1/16 5/8 6 1/4
Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8016 and poster.
LUX-Lung 6: Best overall tumour response Randomized patients
Response
Independentreview
Investigatorreview
Afatinib (n=242)
Gem/cis (n=122)
Afatinib (n=242)
Gem/cis (n=122)
Objective response (CR+PR), %
66.9 23.0 74.4 31.1
Median duration of response (months) (95% CI)
9.7 (8.3, 12.5)
4.3 (2.8, 5.8)
12.4 (11.2, 12.9)
4.0(2.8, 4.9)
Disease control (CR+PR+SD), %
92.6 76.2 93.0 75.4
Median duration of disease control (months) (95% CI)
11.1 (9.7, 13.8)
5.7 (5.5, 6.9)
13.8 (12.5, 14.9)
6.4 (5.5, 6.9)
Wu Y-L, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8016 and poster.
*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: 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
*Grouped term. 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
NE, not estimated.Geater SL, et al. J Clin Oncol 2013;31(Suppl.):Abstract 8061 and poster.
Afatinib delayed the worsening of lung cancer-related symptoms
Pain
Cough Dyspnoea
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 trialsIndependent review – all randomized patients
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
12-month PFS 47% vs. 22% 47% vs. 2%
LUX-Lung 3 LUX-Lung 6
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 mutation-positive NSCLC
LUX-Lung 7 and LUX-Lung 8: Irreversible versus reversible EGFR blockade
Recruiting…
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.
Co-primary: PFS, TTF and OS at 24 monthsSecondary: ORR, DCR, QoL at 24 months
EGFR M+ NSCLC adenocarcinomaECOG PS 0–1
First-line setting
Afatinib 40 mg/day
Gefitinib 250 mg/day
Randomization 1:1
Primary: PFSSecondary: OS, PRO
Squamous NSCLCECOG PS 0–1
Second-line setting (post chemo)
Afatinib 40 mg/day
Erlotinib150 mg/day
Randomization 1:1
LUX-Lung trial programme
Adenocarcinoma EGFR-TKI pretreatedLikely EGFR mutation
LUX Lung 5
LUX Lung 1
LUX Lung 4
Third/fourth line
AdenocarcinomaEGFR-TKI naïve
EGFR mutation positive
LUX Lung 3
LUX Lung 7
LUX Lung 2
LUX Lung 6
First/second line
First line
Squamous cellEGFR-TKI naïve
LUX Lung 8
Second line
Afatinib beyond LUX-Lung programme
• Focus on rational targeted combinations:
– Improve monotherapy effect– Delay resistance– Overcome resistance
Afatinib
Anti-EGFR antibodies
MET inhibitors
PI3K/mTOR inhibitors
HDAC inhibitors
IGF inhibitors
MEKinhibitors
...investigation continues
Afatinib + cetuximab
Afatinib 40 mg daily + cetuximab 500 mg/m2 q2w
Define MTD
ORR, PFS
EGFR M+ lung adenocarcinoma with acquired resistance to
erlotinib/gefitinib
Janjigian YY, et al. Ann Oncol 2012;23(9):ix401, 1227O.
• In a heavily pretreated population with EGFR M+ tumours: T790M+ or T790M‒
– ORR = 30% (median DOR = 8 months)– DCR = 75%– Median PFS = 4.7 months
Continuous and simultaneous EGFR inhibition
非有以御其內,其勢不止;非有以治其外,疾未易為也。 明 方孝儒 指喻
Summary
• LUX-Lung programme is investigating afatinib in NSCLC
– Addressing different questions– Different settings– Different patient subgroups– Different combinations
• Afatinib demonstrates efficacy in EGFR mutation-positive NSCLC
– Irrespective of line of treatment– Irrespective of prior treatment with EGFR-TKIs
• Investigation continues...
First-line treatment algorithm for advancedNSCLC (2013)
EGFR mutation positiveor ALK fusion positive
Poor PSGood PS
Gefitinib, erlotinibor crizotinib
(to progression)
Molecular Clinical (PS)
Non-squamous Squamous Single-agent or combinationchemotherapy
Bevacizumab eligible
Bevacizumab ineligible
Platinum/pemetrexed (or other*) ± bevacizumab
Platinum/pemetrexed
(or other*)
Platinum doublet*
Histological
Clinical
*With docetaxel, paclitaxel, gemcitabine, vinorelbine or nab-paclitaxel.Adapted from Gandara DR, et al. Clin Lung Cancer 2009;10:392–394.
Diagnosis
(No CT)
(No TKI)
Schematic of patients with activating EGFR mutationreceiving EGFR TKI, CT and BSC in various sequences
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 1Taiwan, 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 KoreaFirst 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 First patient enrolled in LUX-Lung 7 head-to-head comparison with gefitinib in treatment-naïve NSCLC patients with EGFR mutationFirst afatinib global study to be led from Asia OPU (BI Korea)Study completing recruitment and data analysis planned for Q1 2015
2011 NPU programme started In Asia, so far 1545 patients have received afatinib under NPUIn Taiwan alone, 837 patients have received afatinib under NPU
2012 First global Phase III trial (LUX-Lung 8) in squamous NSCLC was initiatedChina, Taiwan, Korea, India and Singapore are currently recruiting patients So far, Asian contribution is 25% of global recruitment
First positive regulatory appraisals for afatinib
Giotrif/Gilotrif (US)
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