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Treatment of
EGFR mutant
advanced NSCLC
Raffaele Califano
Department of Medical Oncology
The Christie and Manchester University Hospital
Manchester, UK
Outline
Data on first-line
Overcoming T790M mutation
Conclusion
EGFR-TKIs in
pre-treated NSCLC patients
Thatcher et al, Lancet 2005; Shepherd et al, NEJM 2005,
ISEL BR.21
EGFR activating mutations
Lynch et al, NEJM 2004
EGFR activating mutations
Sharma et al, Nat Rev Cancer 2007
Gefitinib
IPASS Trial
Never or light
ex-smoker withadenocarcinoma
PS 0–2
Stage IIIB or IV
chemo-naive NSCLC
N=1217
R
A
N
D
O
M
I
Z
E
Gefitinib (250 mg/day)
Carboplatin/Paclitaxelup to 6 cycles
Mok et al, NEJM 2009
PFS in ITT population
5.7 vs 5.8 months
Carboplatin /
paclitaxel
Gefitinib 609 212 76 24 5 0
608 118 22 3 1 0
363
412
0 4 8 12 16 20 24 Months
0.0
0.2
0.4
0.6
0.8
1.0Probabilityof PFS
At risk :
GefitinibCarboplatin /
paclitaxel
IPASS - Biomarker
analysis
N=1217(100%)
N=1038 biomarker
consent(85%) N=683
provided samples
(56%)N=437 evaluable for EGFR mutation
(36%)
PFS in EGFR M+ and M-
9.5 vs 6.3 months
EGFR mutation positive EGFR mutation negative
Treatment by subgroup interaction test, p<0.0001
HR (95% CI) = 0.48 (0.36, 0.64)
p<0.0001
Gefitinib (n=132)
Carboplatin / paclitaxel (n=129)
ITT populationCox analysis with covariates
HR (95% CI) = 2.85 (2.05, 3.98)
p<0.0001
132 71 31 11 3 0129 37 7 2 1 0
108103
0 4 8 12 16 20 24
GefitinibC / P
0.0
0.2
0.4
0.6
0.8
1.0
Pro
ba
bility
of p
rog
ress
ion
-fre
e s
urv
iva
l
At risk :91 4 2 1 0 085 14 1 0 0 0
2158
0 4 8 12 16 20 24
0.0
0.2
0.4
0.6
0.8
1.0
Pro
ba
bility
of p
rog
ress
ion
-fre
e s
urv
iva
l
Gefitinib (n=91)
Carboplatin / paclitaxel (n=85)
Months Months
Overall Survival
609 423 239 118 38 0
608 401 212 104 32 0
514
524
0 4 8 12 16 20 28 Months
Gefitinib
Carboplatin /
paclitaxel
0.0
0.2
0.4
0.6
0.8
1.0Probabilityof survival
At risk : 24
0
1
18.8 vs 17.4 months
HR 0.90; P = 0.109
Gefitinib
Carboplatin /
paclitaxel
ORR in EGFR M+ and WT
p=0.0148 p<0.0001 p=0.3037
% p
atie
nts
with
su
sta
ine
d
clin
ica
lly
re
lev
an
t im
pro
ve
me
nt
Quality of life
Gefitinib in Asian Studies
EGFR M+
Study N Regimen RR (%) PFS HR
NEJ002 230 G 73.7 10.80.30
C/P 30.7 5.4
WJTOG
3405
177G 62.1 9.2
0.48
C/D 32.2 6.3
Maemondo et al, NEJM 2010; Mitsudomi et al, Lancet Oncol 2010
Erlotinib
Erlotinib in EGFR M+
Study N Regimen RR (%) PFS HR
OPTIMAL 165 E 83 13.10.16
C/G 36 4.6
EURTAC 174E 56 9.7
0.37Platinum
doublet15 5.2
Zhou et al, Lancet Oncol 2011; Rosell et al, Lancet Oncol 2012;
Afatinib
Primary endpoint: PFS (IRR)
Pemetrexed/Cisplatin
q21d up to 6 cycles
(n=115)
Afatinib 40mg OD
(n=230)Stage IIIB/IV Adeno
PS 0–1
Chemotherapy-naïve
EGFR mutant
(n=345)
R
LUX-LUNG 3
Sequist LV, et al, JCO 2013
2:1
Primary endpoint: PFS (IRR)
Only East Asia
Cisplatin/Gemcitabine
up to 6 cycles (n=122)
Afatinib 40mg OD
(n=242)Stage IIIB/IV
PS 0–1
Chemotherapy-naïve
EGFR mutant
(n=364)
R
LUX-LUNG 6
Wu Y-L, et al, Lancet Oncol 2014
2:1
LUX-Lung 3 and 6
Efficacy
LUX-LUNG 3 LUX-LUNG 6
Afatinib
n=230
Cis/pem
n=115
Afatinib
n=242
Cis/gem
n=122
ORR (%) 56.1 22.5 66.9 23
Median PFS (mos) 11.1 6.9 11.0 5.6
HR (95% CIl)0.58 (0.43–0.78)
p=0.0004
0.28 (0.20-0.39)
P<0.0001
Other Endpoints
Better tolerated
↑Symptom control
↑Global health status/QoL
Afatinib arm
LUX-Lung 3 and 6:
Updated OS
LUX-Lung 3 (n=345) LUX-Lung 6 (n=364)
Recruitment period Aug 09 – Feb 11 Apr 10 – Nov 11
Primary PFS analysis Feb 12 (221 events) Oct 12 (221 events)
Required maturity of OS At least 209 events At least 237 events
OS analysis Dec 13 (213 events;
61.7%)
Jan 14 (246 events;
67.6%)
Median OS follow-up 41 months 33 months
OS result, overall
population
28.2 vs 28.2 months
HR=0.88, p=0.3850
23.1 vs 23.5 months
HR=0.93, p=0.6137
Yang, et al, Lancet Oncol 2015
Trials of EGFR-TKIs vs CT in M+
Study N Median PFS (mos) Median OS (mos)
TKI Chemo HR (95 % CI) TKI Chemo
IPASS 261 9.5 6.3 0.48 (0.36-0.64) 21.6 21.9
First Signal 42 8.0 6.3 0.54 (0.26-1.10) 27.2 25.6
NEJ002 194 10.4 5.5 0.35 (0.25-0.50) 27.7 26.6
WJTOG 172 9.2 6.3 0.48 (0.33-0.71) 36 39
OPTIMAL 154 13.7 4.6 0.16 (0.10-0.26) 22.6 28.8
EURTAC 174 10.4 5.1 0.34 (0.25–0.54) 19.3 19.5
LUX-LUNG 3 345 11.1 6.9 0.58 (0.43-0.78) 28.2 28.2
LUX-LUNG 6 364 11.1 5.6 0.28 (0.20-0.39 23.1 23.5
What’s the best EGFR-TKI?
Lux-Lung 7
Afatinib
40 mg OD
Gefitinib 250
mg OD
1:1
Stage IIIB/IV adenocarcinoma
EGFR mutation (Del19 and/or L858R)
No prior treatment for advanced/metastatic disease
ECOG PS 0/1N= 319
Stratified by
Mutation type (Del19/L858R)
Brain metastases (present/absent)
Primary endpoints: PFS (IRR), TTF, OSPaz-Ares et al, Ann Oncol 2017
Treatment
beyond
progression
allowed
Efficacy
Afatinib
(n=160)
Gefitinib
(n=159)
HR
(95%CI)p
PFS (months)11.0 10.9 0.74
(0.57–0.95)
0.0178
TTF (months)13.7 11.5 0.75 (0.60-
0.94)
0.0136
OS (months)27.9 24.5 0.86
(0.66–1.12)
0.2580
ORR and DOR
p=0.002
Afatinib
n=112/160
Gefitinib
n=89/159
Afatinib
(n=112)
Gefitinib
(n=89)
Median DoR (mos)
10 .1 8.3
95% CI (8.2–11.1) (7.3–10.2)
73% 56%
Adverse Events
Events, %
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*
Drug-related AEs leading to
discontinuation6.3 6.3
Serious AEs 44.4 37.1
Drug-related serious AEs 10.6 4.4†
Drug-related fatal AE - 0.6‡
*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
ARCHER 1050
Advanced NSCLC
• Adenocarcinoma
• EGFR exon 19/21
mut+
• First-line treatment
• PS 0-1
• No brain metastases
N=440
R
A
N
D
O
M
I
Z
E
Dacomitinib
45mg qd
Gefitinib
250mg qd
Primary endpoint: PFS
Wu et al, lancet oncology 2017
ARCHER 1050: PFS (IRR)
SAEs and dose modification
OutcomeDacomitinib
(n = 227)
Gefitinib
(n = 224)
Serious AE, n (%)Any
Treatment related
Causing discontinuation
Causing death
62 (27.3)
21 (9.3)
22 (9.7)
2 (0.9)
50 (22.3)
10 (4.5)
15 (6.7)
1 (0.4)
Median duration of dose
reduction, mos (range)11.3 (0.1-33.6) 5.2 (0.3-17.8)
Reduced dose given, n (%) 30 mg/day
15 mg/day
87 (38.3)
63 (27.8)
NA
Pts requiring dose reduction, n (%) 150 (66.1) 18 (8.0)
Mechanism of resistance to
1st/2nd generation EGFR-TKIs
Camidge DR et al. Nat Rev Clin Oncol. 2014
Tackling T790M
resistance mutation
Osirmetinib
Inhibition of T790M
Inhibition of EGFRm
Low activity on wt EGFR Lower incidence of rash and diarrhoea
Overcome resistance
Continue targeting sensitizing mutations
Potential to…
wt EGFR T790MEGFRm
TAGRISSO
Cross DAE, et al. Cancer Discovery 2014
Osirmetinib
Clinical development
AURA2 (n=210)Osimertinib 80 mg QD
T790M positive
T790M negative
Central T790M mutation testing* of biopsy sample collected following confirmed disease
progression
Patients with confirmed EGFRm locally advanced or metastatic NSCLC who have
progressed following prior therapy with an approved EGFR-TKI
Escalation
Expansion
Phase I
AURA Phase II Extension (n=201)Osimertinib 80 mg QD
Cohort 120 mg
Negative
Cohort 240 mg
Cohort 5240 mg
Rolling six design
Cytology
Tablet
Negative
Cohort 3 80 mg n=63
Negative
Cohort 4 160 mg
Positive Positive PositivePositive Positive
Biopsy† Biopsy
First-line First-line
AURA Ph I/II AURA2 Ph II
Not eligiblefor enrollment
Patients with T790M-positive aNSCLC whose disease has progressed following either one prior therapy with an EGFR-TKI or following treatment
with both EGFR-TKI and other anticancer therapy
Pooled Phase II
Janne PA et al, NEJM 2015; Goss et al, Lancet Oncol 2016
AURA Ph I (80 mg)N=63
AURA pooled Ph II (80 mg) N=411
Median PFS*, months (95% CI) 9.7 (8.3, 13.6) 11.0 (9.6, 12.4)
Remaining alive and progression-free,† % (95% CI)12 months18 months24 months
41 (29, 53)29 (18, 41)17 (8, 30)
48 (42, 53)NCNC
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Pro
babi
lity
of P
FS
441 332 271 205 161 38 0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.01.0
0.0
Pro
babi
lity
of P
FS
1
Number of patients at risk:
Osimertinib 80 mg
Month0 3 6 9 12 15 18
63 55 48 36 25 20
21 24 27
15 9 5
Number of patients at risk:
Osimertinib 80 mg
0 3 6 9 12 15 18 21 24 27
Month
AURA Ph I AURA pooled Ph II
Progression-Free Survival
Yang JCH, et al. ELCC 2016
Adverse Events
AE category, all causality, n (%) AURA Ph I (80 mg)N=63*
AURA pooled Ph II (80 mg)
N=411†
Any AE 62 (98) 406 (99)
Any AE ≥Grade 3 29 (46) 149 (36)
Any AE leading to death 1 (2) 14 (3)
Any AE leading to dose interruption
16 (25) 87 (21)
Any AE leading to dose reduction 1 (2) 16 (4)
Any AE leading to discontinuation 3 (5) 26 (6)
Any serious AE 18 (29) 107 (26)
AE category, causally-related‡
Any AE 57 (91) 364 (89)
Any AE ≥Grade 3 11 (18) 56 (14)
Any AE leading to discontinuation 0 16 (4)
Any serious AE 3 (5) 23 (6)
Yang JCH, et al. ELCC 2016
AURA3 study
Key eligibility criteria
• Locally advanced or
metastatic NSCLC
• Evidence of disease
progression following first-line
EGFR-TKI therapy
• Documented EGFRm and
central confirmation of tumour
EGFR T790M mutation after first-
line EGFR-TKI treatment
• PS 0 or 1
• No more than one prior line of
treatment for advanced
NSCLC
• Stable asymptomatic CNS
metastases allowed
R
2:1
Osimertinib
80 mg OD
(n=279)
Platinum-
pemetrexed
+/-
maintenance
pemetrexed
(n=140)
Optional crossover: Protocol
amendment allowed patients on
chemotherapy to begin post-
BICR confirmed progression
open-label osimertinib treatment
Endpoints Primary:
•PFS by investigator assessment
(RECISTv1.1)
Secondary and exploratory:
•OS
•ORR
•DoR
•DCR
•Tumour shrinkage
•BICR-assessed PFS
•PROs
•Safety and tolerability
Mok TS et al, NEJM 2016
Progression-free Survival
(investigator)Pro
ba
bility
of
Pro
gre
ssio
n-f
ree
Su
rviv
al 1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18
Months
Osimertinib (n=279)
Platinum-pemetrexed
(n=140)
HR for disease progression or death,
0.30 (95% Cl, 0.23–0.41) P<0.001
Median PFS (95% Cl)
10.1 (8.3–12.3)
4.4 (4.2–5.6)
Response Rate
Osimertinib
(n=279)
Platinum-
pemetrexed
(n=140)
ORR, % (95% CI) 71% (65, 76) 31% (24, 40)
Odds ratio* (95% CI) 5.39 (3.47, 8.48); P<0.001
Complete response, n (%)
Partial response, n (%)
Stable disease ≥6 weeks, n (%)
Progression, n (%)
RECIST progression, n (%)
Death
Not evaluable, n (%)
4 (1)
193 (69)
63 (23)
18 (6)
15 (5)
3 (1)
1 (<1)
2 (1)
42 (30)
60 (43)
26 (19)
22 (16)
4 (3)
10 (7)
DCR, % (95% CI) 93 (90, 96) 74 (66, 81)
Odds ratio (95% CI) 4.76 (2.64, 8.84); P<0.001
Median time to response,
weeks (95% CI)6.1 (NC, NC) 6.4 (6.3, 7.0)
Median DoR, months (95% CI) 9.7 (8.3, 11.6) 4.1 (3.0, 5.6)
Safety AE category*, n (%) Osimertinib (n=279) Platinum-pemetrexed
(n=136)
Any AE 273 (98) 135 (99)
Any AE Grade ≥3 63 (23) 64 (47)
Any AE leading to death 4 (1) 1 (1)
Any serious AE 50 (18) 35 (26)
Any AE leading to
discontinuation
19 (7) 14 (10)
AE category, possibly causally related†, n (%)
Any AE 231 (83) 121 (89)
Any AE Grade ≥3 16 (6) 46 (34)
Any AE leading to death 1 (<1) 1 (1)
Any serious AE 8 (3) 17 (13)
Any AE leading to
discontinuation
10 (4) 12 (9)
Adverse EventsN (%)
15% cut-off
Osimertinib (n=279) Platinum-pemetrexed
(n=136)
Any grade Grade ≥3 Any grade Grade ≥3
Any AE 273 (98) 63 (23) 135 (99) 64 (47)
Diarrhoea 113 (41) 3 (1) 15 (11) 2 (1)
Rash† 94 (34) 2 (1) 8 (6) 0
Dry skin† 65 (23) 0 6 (4) 0
Paronychia† 61 (22) 0 2 (1) 0
Decreased appetite 50 (18) 3 (1) 49 (36) 4 (3)
Cough 46 (16) 0 19 (14) 0
Nausea 45 (16) 2 (1) 67 (49) 5 (4)
Fatigue 44 (16) 3 (1) 38 (28) 1 (1)
Stomatitis 41 (15) 0 21 (15) 2 (1)
Constipation 39 (14) 0 47 (35) 0
Vomiting 31 (11) 1 (<1) 27 (20) 3 (2)
Thrombocytopaenia† 28 (10) 1 (<1) 27 (20) 10 (7)
Neutropaenia† 22 (8) 4 (1) 31 (23) 16 (12)
Leukopenia† 22 (8) 0 20 (15) 5 (4)
Anaemia† 21 (8) 2 (1) 41 (30) 16 (12)
Asthenia 20 (7) 3 (1) 20 (15) 6 (4)
Select adverse eventsInterstitial lung disease† 10 (4) 1 (<1) 1 (1) 1 (1)
QT prolongation 10 (4) 1 (<1) 1 (1) 0
Stratification
by mutation
status
(Exon 19
deletion /
L858R)
and race
(Asian /
non-Asian) Crossover was allowed for patients in the SoC arm, who
could receive open-label osimertinib upon central
confirmation of progression and T790M positivity
Patients with locally
advanced or metastatic
NSCLC
Key inclusion criteria
•≥18 years*
•WHO performance status 0 /
1
•Exon 19 deletion / L858R
(enrolment by local# or
central‡ EGFR testing)
•No prior systemic anti-cancer
/
EGFR-TKI therapy
•Stable CNS metastases
allowed
• Primary endpoint: PFS (investigator)• Secondary endpoints: objective response rate, duration of response, disease control rate, depth
of response, overall survival, patient reported outcomes, safety
Randomised 1:1
RECIST 1.1 assessment every 6 weeks until objective
progressive disease
EGFR-TKI SoC§;
Gefitinib (250 mg p.o.
qd) or Erlotinib (150 mg
p.o. qd)
(n=277)
Osimertinib
(80 mg p.o. qd)
(n=279)
FLAURA
Soria JC et al, NEJM 2017
Progression-free Survival
Median PFS, months (95% CI)
18.9 (15.2, 21.4)
10.2 (9.6, 11.1)
1.0Pro
ba
bility
of p
rog
ress
ion
-fre
e s
urv
iva
l
0.2
0.4
0.6
0.8
0.0
0 3 6 9 12 15 18 21 24 27
Time from randomisation (months)
279
277
262
239
233
197
210
152
178
107
139
78
71
37
26
10
4
2
0
0
No. at risk
Osimertinib
SoC
Osimertinib
SoC
HR 0.46
(95% CI 0.37, 0.57)
p<0.0001
Safety
AE, any cause, n (%) Osimertinib (n=279) SoC (n=277)
Any AE 273 (98) 271 (98)
Any AE Grade ≥3 94 (34) 124 (45)
Any AE leading to death 6 (2) 10 (4)
Any serious AE 60 (22) 70 (25)
Any AE leading to
discontinuation
37 (13) 49 (18)
AE, possibly causally related, n (%)
Any AE 253 (91) 255 (92)
Any AE Grade ≥3 49 (18) 78 (28)
Any AE leading to death 0 1 (<1)
Any serious AE 22 (8) 23 (8)
Safety
AEs n (%)
Osimertinib (n=279) SoC (n=277)
Any grade
Grade 1 Grade 2 Grade 3 Grade 4Any
gradeGrade 1 Grade 2 Grade 3 Grade 4
Diarrhoea161 (58)
120 (43)
35 (13) 6 (2) 0159 (57)
116 (42)
35 (13) 6 (2) 0
Dry skin 88 (32) 76 (27) 11 (4) 1 (<1) 0 90 (32) 70 (25) 17 (6) 3 (1) 0
Paronychia 81 (29) 37 (13) 43 (15) 1 (<1) 0 80 (29) 46 (17) 32 (12) 2 (1) 0
Stomatitis 80 (29) 65 (23) 13 (5) 1 (<1) 1 (<1) 56 (20) 47 (17) 8 (3) 1 (<1) 0
Dermatitis acneiform
71 (25) 61 (22) 10 (4) 0 0134 (48)
71 (26) 50 (18) 13 (5) 0
Decreased appetite
56 (20) 27 (10) 22 (8) 7 (3) 0 51 (18) 24 (9) 22 (8) 5 (2) 0
Pruritis 48 (17) 40 (14) 7 (3) 1 (<1) 0 43 (16) 30 (11) 13 (5) 0 0
Cough 46 (16) 34 (12) 12 (4) 0 0 42 (15) 25 (9) 16 (6) 1 (<1) 0
Constipation 42 (15) 33 (12) 9 (3) 0 0 35 (13) 28 (10) 7 (3) 0 0
AST increased 26 (9) 18 (6) 6 (2) 2 (1) 0 68 (25) 38 (14) 18 (6) 12 (4) 0
ALT increased 18 (6) 11 (4) 6 (2) 1 (<1) 0 75 (27) 31 (11) 19 (7) 21 (8) 4 (1)
Safety
Take Home Message
EGFR-TKIs are standard of care in EGFR M+
Look for T790M resistance mutation
Osirmetinib: a new option for 1st line treatment
Backup Slides
Aura 3 – EGFR Plasma ctDNA
Plasma ctDNA test results, n
Tissue T790M
positive
(n=399)
Tissue Exon 19
deletion
positive (n=427)
Tissue L858R
positive (n=253)
Plasma positive 184 273 139
Plasma negative 175 60 67
No plasma test / invalid 37 / 3 91 / 3 47 / 0
Percent agreement using
tissue test as reference, %
(95% CI)*
Positive percent agreement
(sensitivity)51 (46, 57) 82 (77, 86) 68 (61, 74)
Negative percent
agreement (specificity)77 (71, 83) 98 (96, 100) 99 (98, 100)
Overall concordance 61 (57, 65) 89 (86, 91) 88 (85, 90)
Patients with tissue sample available at screening (n=756)
AURA3: Efficacy in pts with plasma
and tumour tissue T790M+ status
Tumour T790M-positive (ITT) Plasma T790M-positive status
OsimertinibPlatinum-
pemetrexed
PFS HR (95% CI) 0.42 (0.29, 0.61)
Median PFS, months
(95% CI)8.2 (6.8, 9.7)
4.2 (4.1,
5.1)
ORR†, % (95% CI) 77 (68, 84) 39 (27, 53)
OsimertinibPlatinum-
pemetrexed
PFS HR (95% CI) 0.30 (0.23, 0.41)*, p<0.001
Median PFS, months
(95% CI)10.1 (8.3, 12.3)
4.4 (4.2,
5.6)
ORR†, % (95% CI) 71 (65, 76) 31 (24, 40)
1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18
Months
Osimertinib (n=279)
Platinum-pemetrexed (n=140)
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18Months
Osimertinib (n=116)
Platinum-pemetrexed
(n=56)P
rob
ab
ilit
y o
f
pro
gre
ssio
n-f
ree s
urv
ival
Pro
bab
ilit
y o
f
pro
gre
ssio
n-f
ree s
urv
ival
AURA3 Subgroup analysis CNS mets
≥1 measurable
CNS metastases
n = 30 (11%)
≥1 measurable
CNS metastases
n = 16 (11%)
cEFR
Pts with ≥1 measurable CNS
metastases
CNS tumour assessment by BICR
R
2:1
Osimertinib
80 mg orally
once daily
n = 279
Platinum-
pemetrexed
n = 140
cFAS
Pts with measurable and/or non-
measurable CNS metastases
N = 419
CNS metastases
n = 75 (27%)
CNS metastases
n = 41 (29%)
n = 116 (28%)
Key Eligibility Criteria:
• Locally advanced or
metastatic NSCLC
• Disease progression following
first-line EGFR TKI therapy
• Documented EGFRm and
central confirmation of tumour
EGFR T790M mutation after
first-line EGFR TKI
• No more than 1 prior line of
treatment for advanced
NSCLC
• Stable* asymptomatic CNS
metastases allowed
ENDPOINTS
CNS ORR
CNS duration of response
ENDPOINTS
CNS PFS
by RECIST v1.1
• 1. Mok TS, et al. N Engl J Med. 2017; 376:629-640. 2. Suppl. Info for: Mok TS, et al. N Engl J Med. 2017; 376:629-640.
AURA3: PFS in patients with or
without CNS metastases at baseline
1. Mok TS, et al. N Engl J Med. 2017; 376:629-640. 2. Suppl. Info for: Mok TS, et al. N Engl J Med. 2017; 376:629-640.
With CNS metastases1 Without CNS metastases2
93
51
No. at risk
Osimertinib
Platinum-pemetrexed
80
32
46
9
27
4
14
2
4
0
0
0Months Months
18
6
89
16
0
61
11
6
35
61
13
36
5
9
1
0
0
Median PFS, months (95% Cl)
10.8 (8.3-12.5)
5.6 (4.2-6.8)
1.
0
0.
8
0.
6
0.
4
0.
2
0
0 3 6 9 12 15 18
Pro
ba
bil
ity o
fP
rog
res
sio
n-f
ree
Su
rviv
al
Osimertinib (n=93)
Platinum-pemetrexed
(n=51)
Median PFS, months (95% Cl)
8.5 (6.8-12.3)
4.2 (4.1-5.4)
1.
0
0.
8
0.
6
0.
4
0.
2
0
Pro
ba
bilit
y o
fP
rog
res
sio
n-f
ree
Su
rviv
al
Osimertinib (n=186)
Platinum-pemetrexed
(n=89)
0 3 6 9 12 15 18
Hazard ratio for disease
progression or death,
0.32 (95% Cl, 0.21–0.49)
Hazard ratio for disease
progression or death,
0.40 (95% Cl, 0.29–0.55)
AURA 3: subgroup analysis
CNS metastases
Osimertinib
80 mg
n = 30
Chemotherapy
n = 16
CNS ORR (95% CI) 70% (51-85) 31% (11-59)
Odds ratio (95% CI) 5.13 (1.44-20.64); P = .015
Median time to response, wk 6.1 6.1
Median DoR, mo (95% CI) 8.9 (4.3-NC) 5.7 (NC-NC)
DCR (95% CI) 93% (78-99) 63% (35-85)
Patients with CNS metastases were stable and asymptomatic
• 1. Mok TS, et al. N Engl J Med. 2017; 376:629-640. 2. Suppl. Info for: Mok TS, et al. N Engl J Med. 2017; 376:629-640.
AURA3: competing risk analysis
Mok T. et al. Presented at ASCO Annual Meeting 2-6 June 2017; Chicago, IL USA. J Clin Oncol. 2017;35 suppl:abstr 9005.
The probability of experiencing a CNS progression
event was lower for osimertinib than for chemotherapy
at both 3 and 6 monthsa
aconditional on the patient not experiencing a competing risk at that time.
LUX-Lung 3 and 6:
OS in common mutations
1.0
0.8
0.6
0.4
0.2
0
Est
ima
ted
OS p
rob
ab
ility
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time (months)
LUX-Lung 3
Afatinib
n=203
Pem/Cis
n=104
Median,
months31.6 28.2
HR (95%CI),
p-value
0.78 (0.58–1.06),
p=0.1090
LUX-Lung 6
Afatinib
n=216
Gem/Cis
n=108
Median,
months23.6 23.5
HR (95%CI),
p-value
0.83 (0.62–1.09),
p=0.1756
1.0
0.8
0.6
0.4
0.2
0
Est
ima
ted
OS p
rob
ab
ility
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Time (months)
OS in Del19 subgroup
1.0
0.8
0.6
0.4
0.2
0
Est
ima
ted
OS p
rob
ab
ility
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time (months)
1.0
0.8
0.6
0.4
0.2
0
Est
ima
ted
OS p
rob
ab
ility
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Time (months)
LUX-Lung 3
Afatinib
n=112
Pem/Cis
n=57
Median,
months33.3 21.1
HR (95%CI),
p-value
0.54 (0.36–0.79),
p=0.0015
LUX-Lung 6
Afatinib
n=124
Gem/Cis
n=62
Median,
months31.4 18.4
HR (95%CI),
p-value
0.64 (0.44–0.94),
p=0.0229
Combined OS analysis:
common mutations (n=631)
Afatinib n=419
Chemo n=212
Median , months 27.3 24.3
HR (95%CI), p-value
0.81 (0.66–0.99), p=0.0374
1.0
0.8
0.6
0.4
0.2
0
Est
ima
ted
OS p
rob
ab
ility
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time (months)
Combined OS analysis:
mutation categories
1.0
0.8
0.6
0.4
0.2
0
Est
ima
ted
OS p
rob
ab
ility
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time (months)
1.0
0.8
0.6
0.4
0.2
0
Esti
mat
ed O
S p
rob
abili
ty
Time (months)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Del19Afatinib
n=236
Chemo
n=119
Median,
months31.7 20.7
HR (95%CI),
p-value
0.59 (0.45–0.77),
p=0.0001
L858RAfatinib
n=183
Chemo
n=93
Median,
months22.1 26.9
HR (95%CI),
p-value
1.25 (0.92–1.71),
p=0.1600
LUX-Lung 3 LUX-Lung 6
Afatinib (n=203)
Pem/Cis (n=104)
Afatinib (n=216)
Gem/Cis (n=108)
Discontinued treatment, n (%) 184 (100) 104 (100) 194 (100) 108 (100)
Subsequent systemic therapy, n (%) 144 (78) 88 (85) 123 (63) 70 (65)
Chemotherapy, n (%) 131 (71) 49 (47) 114 (59) 29 (27)
EGFR TKI therapy, n (%)
Erlotinib
Gefitinib
Afatinib
AZD9291
Dacomitinib
Icotinib
EGFR TKI combinations
81 (44)
61 (33)
28 (15)
2 (1)
2 (1)
–
–
5 (3)
78 (75)
46 (42)
44 (42)
7 (7)
1 (1)
1 (1)
–
9 (9)
50 (26)
21 (11)
19 (10)
–
–
–
11 (6)
5 (3)
61 (56)
22 (20)
39 (36)
–
–
–
3 (3)
3 (3)
Other systemic therapy, n (%) 5 (3) 2 (2) 3 (2) 4 (4)
Radiotherapy, n (%) 32 (17) 21 (20) 4 (2) 0 (0)
Treatment at progression
