2. Introducción:
NSCLC avanzado

3. Lung Cancer: Incidence and Mortality
• New cases in 2013: 228,190
– 40% with stage IV disease at
presentation (~ 90,000)
• ~ 160,000 deaths in
2012, comparable to
prostate, pancreas, breast, and
colon cancer combined
• 5-yr relative survival rate: 15.7
% overall; 3.7% for patients
with distant-stage disease
180,000
Estimated Cancer Deaths
by Site, 2012
160,000
140,000
Prostate
120,000
100,000
80,000
Pancreas
Breast
Lung
cancer
60,000
40,000
20,000
Colon
0
Other Cancers
Lung Cancer
NCI. Non-small-cell lung cancer treatment (PDQ®). ACS. Cancer facts & figures: 2012. CDC. Lung cancer rates by race and
ethnicity. Howlader N, et al. SEER cancer statistics review.

5. Complexities of Lung Cancer Pathogenesis Result in
Diverse Histologic Subtypes
SCLC
(~ 15%)
Adenocarcinoma
(~ 45%)
LPA
(formerly BAC)
(~ 5% to 10%)
Large Cell
(~ 5% to 10%)
Sun S, et al. Nat Rev Cancer. 2007; 7:778-790.
Travis WD, et al. J Clin Oncol. 2013;[Epub ahead of print].
SCC
(~ 25%)
NOS
(~ 10% to 30%)

6. Lung Cancer: Histology
Small-cell
carcinoma
Adenocarcinoma
10%-15%
Large-cell
carcinoma
40%
10% to 15%
25% to 30%
Squamous cell
carcinoma
American Cancer Society. Lung cancer (non-small-cell). 2013.

7. Potential Oncogenic Drivers in NSCLC
Squamous Cell Carcinoma
Adenocarcinoma
Amplification
20-25
FGFR2
Mutation
5
Mutation
9
Mutation deletion
18
Amplification
8
Deletion/mutation
45
PDGFRA
Amplification
mutation
9
EGFR
KRAS
FGFR1
Amplification
10
MCL1
Amplification
10
BRAF
Mutation
3
DDR2
Mutation
4
ERBB2
Amplification
2
PTEN
Unknown
EGFR
Frequency, %
CCND1
KIF5B-RET
Event Type
PIK3CA
NRAS
ROS1 fusions
Gene
CDKN2A
MAP2K1
AKT1
PIK3CA
BRAF
HER2
ALK
fusions
Hammerman P, et al. IASLC WCLC 2011. Abstract PRS.1

8. NSCLC avanzado: Factores pronóstico
• En pacientes inoperables, el pronóstico se ve
afectado de forma adversa por:
– Mal PS
– Pérdida de peso > 10%
– Sexo masculino
• Edad avanzada: no afecta a pronóstico por sí
misma
NCI. Non-small-cell lung cancer treatment (PDQ®).

9. Equivalencia
Schiller; NEJM 2002; 346:92-98

10. Probabilidad de supervivencia
1.0
Cisplatino/Paclitaxel
Cisplatino/Gemcitabina
0.8
Cisplatino/Docetaxel
0.6
Carboplatino/Paclitaxel
0.4
0.2
0.0
0
5
10
15
Meses
20
25
30

11. 2013: First-line Treatment of Advanced/Metastatic NSCLC
75%
25%
Non-SCCa
Other
mutations
5% to 10%
Mutational analysis
EGFR mutation
KRAS or no other “actionable” mutation: 80%
+15%
SCCa
EGFR-TKI
10%
EML4/ALK
ROS1
TKI
90%
Any hemoptysis
No hemoptysis
Platinum + pemetrexed
Carboplatin + paclitaxel
+ bevacizumab or
platinum + pemetrexed
Crizotinib
Platinum +
paclitaxel, docetaxel
gemcitabine or
vinorelbine
nab-paclitaxel
(? cetuximab)

12. First-line Therapy: 2013
Column A
Cisplatin
Carboplatin
Column B
Vinorelbine
Gemcitabine
Paclitaxel
Docetaxel
Pemetrexed
Nab-paclitaxel
Irinotecan
Column C
Bevacizumab
Cetuximab?
Column D
Erlotinib
Crizotinib
Option 1: choose 1 from column A and 1 from column B
Option 2: choose 2 from column B
Option 3: option 1 + column C (for certain patients)
Option 4: choose 1 from column D (for selected patients)
National Comprehensive Cancer Network clinical practice guidelines in oncology: Non-small-cell lung cancer (v2.2013). www.nccn.org

13. Consideraciones para la primera línea
• PS
• Edad: comorbilidad
– Hemoptisis
• Histología
• Alteraciones moleculares
• Otras
– Metástasis SNC
• Tratº previo en la adyuvancia

14. Mutación de EGFR: factor predictivo de respuesta a EGFR-TKI
EGF
• 90% de las mutaciones son en los
exones 18–24
– Delecciones exon 19
– Mutación exon 21 (L858R)
Receptor
L domain
Furin-like
domain
Receptor
L domain
Extracellular domain
Transmembrane region
Intracellular domain
G719C
del E746–A750
del L747–T751insS
del L747–P753insS
L858R
Catalytic
kinase
domain
• Consecuencias:
- Activación constitutiva del receptor
- Dimerización con HER3 → activación
vía AKT/STAT
L861Q
Y1068
STAT3
MAPK
AKT
Sordella et al. Science 2004

15. GALICIA: Evolución de muestras enviadas
Plataforma 1DENTIFY
MÁS DE 2.000
DETERMINACIONES
2500
2000
1500
1000
500
0

16. Galicia
Nacional
Características de las muestras enviadas

17. Resultados de la determinación en el EGFR:
nacionales vs regionales EGFR M+
Nacional
NACIONAL
TOTAL TEST
Galicia
% SOBRE DET
VALORABLES
TOTAL
VALORABLES
18570
TOTAL NO
VALORABLES
MUTADOS
POSITIVOS
2398
12,91
1947
95,43
1855
4,57
890
100
GALICIA
100
19460
% SOBRE TOTAL
TEST
92
12,32
235
% SOBRE DET
VALORABLES
% SOBRE TOTAL
TEST
100
100
95,27
4,73
12,67
12,07

18. Resultados de la determinación en el EGFR:
nacionales vs regionales EGFR M+
Nacional
Galicia

19. Galicia
Nacional
Porcentaje de mutación en función de las
características clínicas: nacional vs regional

20. Porcentaje de mutación en función de las
características clínicas: nacional vs regional
NACIONAL
% M+
Muestras valorables
M+
Hombre / No fumador / Carcinoma escamoso
93
12
12,9
Hombre / No fumador / Adenocarcinoma
Hombre / No fumador / Carcinoma de células grandes
531
48
154
11
29
22,92
Hombre / Exfumador / Carcinoma escamoso
1097
50
4,56
Hombre / Exfumador / Adenocarcinoma
3402
298
8,76
Hombre / Exfumador / Carcinoma de células grandes
411
21
5,11
Hombre / Fumador / Carcinoma escamoso
795
27
3,4
Hombre / Fumador / Adenocarcinoma
2676
135
5,04
Hombre / Fumador / Carcinoma de células grandes
323
17
5,26
Hombre / Desconocido / Carcinoma escamoso
468
12
2,56
Hombre / Desconocido / Adenocarcinoma
1722
121
7,03
Hombre / Desconocido / Carcinoma de células grandes
247
6
2,43
Mujer / No fumador / Carcinoma escamoso
129
25
19,38
Mujer / No fumador / Adenocarcinoma
1690
783
46,33
Mujer / No fumador / Carcinoma de células grandes
102
44
43,14
Mujer / Exfumador / Carcinoma escamoso
70
5
7,14
Mujer / Exfumador / Adenocarcinoma
653
134
20,52
Mujer / Exfumador / Carcinoma de células grandes
70
12
17,14
Mujer / Fumador / Carcinoma escamoso
106
3
2,83
Mujer / Fumador / Adenocarcinoma
852
99
11,62
Mujer / Fumador / Carcinoma de células grandes
104
4
3,85
Mujer / Desconocido / Carcinoma escamoso
75
10
13,33
Mujer / Desconocido / Adenocarcinoma
Mujer / Desconocido / Carcinoma de células grandes
783
66
228
7
29,12
10,61

21. Porcentaje de mutación en función de las
características clínicas: nacional vs regional
Muestras
valorables
M+
% M+
Hombre / No fumador / Carcinoma escamoso
13
3
23,08
Hombre / No fumador / Adenocarcinoma
61
19
31,15
Hombre / No fumador / Carcinoma de células grandes
3
1
33,33
GALICIA
Hombre / Exfumador / Carcinoma escamoso
128
5
3,91
Hombre / Exfumador / Adenocarcinoma
370
27
7,3
Hombre / Exfumador / Carcinoma de células grandes
23
0
0
Hombre / Fumador / Carcinoma escamoso
102
2
1,96
Hombre / Fumador / Adenocarcinoma
314
15
4,78
Hombre / Fumador / Carcinoma de células grandes
28
0
0
Hombre / Desconocido / Carcinoma escamoso
27
0
0
Hombre / Desconocido / Adenocarcinoma
Hombre / Desconocido / Carcinoma de células grandes
140
5
14
0
10
0
Mujer / No fumador / Carcinoma escamoso
18
6
33,33
Mujer / No fumador / Adenocarcinoma
Mujer / No fumador / Carcinoma de células grandes
187
9
85
1
45,45
11,11
Mujer / Exfumador / Carcinoma escamoso
4
0
0
Mujer / Exfumador / Adenocarcinoma
Mujer / Exfumador / Carcinoma de células grandes
47
0
11
0
23,4
0
Mujer / Fumador / Carcinoma escamoso
13
1
7,69
Mujer / Fumador / Adenocarcinoma
Mujer / Fumador / Carcinoma de células grandes
91
5
9
2
9,89
40
Mujer / Desconocido / Carcinoma escamoso
Mujer / Desconocido / Adenocarcinoma
Mujer / Desconocido / Carcinoma de células grandes
10
59
2
1
17
0
10
28,81
0

22. Resultados de la determinación en SANGRE del EGFR
M+: nacional vs regional
GALICIA
15 DETERMINACIONES
DE SANGRE
180
160
140
120
EGFR+
100
EGFR-
80
60
40
20
0
NACIONAL
DETERMINACIONES EN SANGRE
GALICIA
NACIONAL
TOTALES
177
EGFR M+
28
TASA POSITIVIDAD
15,8%

23. 2013: First-line Treatment of Advanced/Metastatic NSCLC
75%
25%
Non-SCCa
Other
mutations
5% to 10%
Mutational analysis
EGFR mutation
KRAS or no other “actionable” mutation: 80%
+15%
SCCa
EGFR-TKI
10%
EML4/ALK
ROS1
TKI
90%
Any hemoptysis
No hemoptysis
Platinum + pemetrexed
Carboplatin + paclitaxel
+ bevacizumab or
platinum + pemetrexed
Crizotinib
Platinum +
paclitaxel, docetaxel
gemcitabine or
vinorelbine
nab-paclitaxel
(? cetuximab)

24. TKI en CNMP con mutación EGFR
Study
EGFR TKI
Sample
size
Response
rate (%)
Median PFS
(months)
HR
IPASS1
Gefitinib
261
71 vs 47
9.8 vs 6.4
0.48
First-SIGNAL2
Gefitinib
NR
85 vs 37
8.4 vs 6.7
NR
1Mok
et al NEJM 2009, 2Lee et al WCLC 2009, 3Mitsudomi et al Lancet Oncol 2010, 4Maemondo NEJM 2010, 5Zhou et al
ESMO 2010, 6Rosell et al ASCO 2011; 7-Sequist LV, et al. J Clin Oncol. 2013

25. IPASS: PFS by EGFR Mutation Status
•
•
•
Randomized phase III trial; previously untreated pts with advanced NSCLC (N = 1217)
PFS: gefitinib superior to carboplatin/paclitaxel in ITT population
EGFR mutations strongly predicted PFS (and tumor response) to first-line gefitinib vs
carboplatin/paclitaxel
1.0
EGFR Mutation Negative
Gefitinib
Pac/carbo
0.8
HR: 0.48
(95% CI: 0.36-0.64; P < .001)
0.6
0.4
0.2
0
Probability of PFS
Probability of PFS
EGFR Mutation Positive
1.0
Gefitinib
Pac/carbo
0.8
HR: 2.85
(95% CI: 2.05-3.98; P < .001)
0.6
0.4
0.2
0
0
4
8
12
16 20 24
Mos Since Randomization
Mok TS, et al. N Engl J Med. 2009;361:947-957.
0
4
8
12
16 20 24
Mos Since Randomization

26. TKI en CNMP con mutación EGFR
Study
EGFR TKI
Sample
size
Response
rate (%)
Median PFS
(months)
HR
IPASS1
Gefitinib
261
71 vs 47
9.8 vs 6.4
0.48
First-SIGNAL2
Gefitinib
NR
85 vs 37
8.4 vs 6.7
NR
WJTOC34053
Gefitinib
177
62 vs 31
9.2 vs 6.3
0.49
NEJ0024
Gefitinib
198
74 vs 31
10.8 vs 5.4
0.30
OPTIMAL5
Erlotinib
154
83 vs 36
13.7 vs 4.6
0.16
1Mok
et al NEJM 2009, 2Lee et al WCLC 2009, 3Mitsudomi et al Lancet Oncol 2010, 4Maemondo NEJM 2010, 5Zhou et al
ESMO 2010, 6Rosell et al ASCO 2011; 7-Sequist LV, et al. J Clin Oncol. 2013

27. TKI en CNMP con mutación EGFR
Study
EGFR TKI
Sample
size
Response
rate (%)
Median PFS
(months)
HR
IPASS1
Gefitinib
261
71 vs 47
9.8 vs 6.4
0.48
First-SIGNAL2
Gefitinib
NR
85 vs 37
8.4 vs 6.7
NR
WJTOC34053
Gefitinib
177
62 vs 31
9.2 vs 6.3
0.49
NEJ0024
Gefitinib
198
74 vs 31
10.8 vs 5.4
0.30
OPTIMAL5
Erlotinib
154
83 vs 36
13.7 vs 4.6
0.16
EURTAC6
Erlotinib
174
58 vs 15
9.7 vs 5.2
0.37
Afatinib
(vs cis-pem)
345
56 vs 22
11,1 vs 6.9
0,001
LUX-Lung 37
1Mok
et al NEJM 2009, 2Lee et al WCLC 2009, 3Mitsudomi et al Lancet Oncol 2010, 4Maemondo NEJM 2010, 5Zhou et al
ESMO 2010, 6Rosell et al ASCO 2011; 7-Sequist LV, et al. J Clin Oncol. 2013

28. EURTAC
Erlotinib 150 mg/día
a. Sin quimioterapia previa
b. CPNM en estadio IIIB/IV
c.
Deleción de exón 19 EGFR o
mutación exón 21 L858R
d. ECOG PS 0–2
(n=174)
Objetivo principal
•
Supervivencia libre de progresión (SLP)
análisis intermedio planeado a los 88
eventos
1227 pts screened  224 mut + (17.6%)
R
Estratificación
 Tipo de mutación
 ECOG PS (0 vs. a 1 vs. 2)
Quimioterapia con doblete de
platino cada 3 semanas x 4 ciclos*
Objetivos secundarios
•
Tasa de repuesta objetiva (%)
•
Supervivencia global (SG)
•
Localización de la progresión
•
Seguridad
•
Análisis de la mutación del EGFR en suero
•
Calidad de vida
*Cisplatino 75 mg/m2 d1 / docetaxel 75 mg/m2 d1; cisplatino 75 mg/m2 d1 / gemcitabina 1250 mg/m2 d1,8;
carboplatino AUC6 d1 / docetaxel 75 mg/m2 d1; carboplatino AUC5 d1 / gemcitabina 1000 mg/m2 d1,8
Rosell, et al. Lancet Oncol. 2012

29. Erlotinib en 1ª línea duplicó la SLP en comparación con
la quimioterapia
Erlotinib (n=86)
10·4
Chemotherapy
(n=87)
5·1
Patients at risk
Rosell et al. ESMO 2012

30. La tasa de respuesta con erlotinib fue más de tres veces mayor que la de la
quimioterapia
100
Erlotinib (n=69)
Deleción en el exón 19
Mutación en el exón 21
80
60
40
20
0
-20
-40
-60
-80
-100
Mejor cambio desde valores iniciales (%)
Mejor cambio en comparación con la
medida basal (%)
100
Quimioterapia (n=64)
Deleción en el exón 19
Mutación en el exón 21
80
60
40
20
0
-20
-40
-60
-80
-100
0
10
20
30
40
50
60
70
0
10
20
30
40
50
60
70
Tasa de repuesta global: 58% Erlotinib frente a 15% quimioterapia
de Marinis, et al. EMCC 2011

31. Protocolo 049/11
Gefitinib 250 mg/24 h
Objetivo
46 pacientes mut + (36 m, 10 h)
20 exon 19
4 exon 20
20 exón 21
Mediana edad: 67 años
93%: PS 0-1
Tasa de respuestas
57%
SLP
6 meses
SG
17 meses

32. Protocolo 049/11

33. Noviembre 2011: inicia erlotinib
Primera reevaluación: febrero de 2012
Progresión 2 años después

34. Efficacy, safety and tolerability results from a Phase
IV, open-label, single-arm, study of first-line gefitinib in
Caucasian patients with EGFR mutation-positive nonsmall-cell lung cancer
Jean-Yves Douillard,1 Gyula Ostoros,2 Manuel Cobo,3 Tudor Ciuleanu,4 Rose
McCormack,5 Alan Webster,5 Tsveta Milenkova5
1Institut
de Cancerologie, Centre René Gauducheau, Nantes, France; 2National
Koranyi Institute of Pulmonology, Budapest, Hungary;
3Hospital Regional Universitario, Malaga, Spain; 4Institutul Oncologic Ion Chiricuta
and UMF Iuliu Hatieganu, Cluj Napoca, Romania; 5AstraZeneca, Macclesfield, UK

35. Background
• Several Phase III studies have demonstrated prolonged PFS and improved
tolerability and QoL with the EGFR-TKI gefitinib compared with first-line
chemotherapy in advanced EGFR mutation-positive NSCLC1-4
• In 2009, the European Medicines Agency approved gefitinib for the
treatment of adult patients with locally advanced or metastatic NSCLC
with activating mutations of the EGFR TK5. As the first-line EGFR
mutation positive data at that time were mainly in Asian populations a
follow up study was required.
• Results from the prospective, Phase IV, open-label, single-arm study of
first-line gefitinib in Caucasian patients with EGFR mutation-positive
NSCLC are reported here
1Mok
TKI, tyrosine kinase inhibitor
et al. 2009; 2Han et al. 2012
3Maemondo et al. 2010
4Mitsudomi et al. 2010; 5EMA 2009

36. Study design
Conducted in: Hungary, Romania, Spain, Poland, Greece, UK, Portugal, Turkey, Italy, Bulgaria, France, Norway,
Switzerland
Enrollment period: September 2010-February 2012
Patients
Objectives
Caucasian
Age ≥18 years
WHO PS 0-2
Histologically confirmed
stage IIIA / B / IV EGFR
mutation-positive NSCLC
• Eligible for 1st-line
treatmenta
• Provision of matched
tumour samples for EGFR
mutation testing
• Provision of plasma
samples for EGFR mutation
testing
Primary
• Objective response rate (investigator
assessment)c
Secondary
• Disease control rate
• Progression-free survival
• Overall survival
• Safety and tolerability
• Correlation of clinical characteristics
with EGFR mutation status
Exploratory
• Comparison of EGFR mutation status
between matched tumour and plasma
(cfDNA) samples
•
•
•
•
aIncluded
Gefitinib 250 mg
once daily until
disease progressionb
patients who had received previous adjuvant chemotherapy or had completed prior surgery or radiotherapy >6 months
prior to the start of study treatment and patients who had received radiotherapy ≥4 weeks prior to the start of study treatment;
bassessed 6-weekly by RECIST 1.1; cORR was also analysed by a secondary, supportive central review; cfDNA, circulating free DNA

37. Sample size and EGFR mutation
testing methodology / eligibility
• Determination of sample size
–
–
It was estimated that 1250 Caucasian patients with advanced NSCLC would have to be screened to
obtain 100 patients with eligible EGFR mutation-positive tumours for treatment with gefitinib
A total of 100 patients with EGFR mutation-positive tumours would ensure precise estimation of
the ORR (primary endpoint), with the lower limit of the 95% CI (calculated using Wilson score
intervals) falling within 10% of the observed ORR
• EGFR mutation test method and eligibility regarding mutation subtype
–
–
–
Scorpion® ARMS®-based EGFR mutation detection kit (EGFR RGQ PCR kit, Qiagen, Crawley, UK).
29 mutations detectable by this method across Exons 18, 19, 20 and 21
Tumour
•
•
–
Patients whose tumours harboured Exon 19 deletions, L858R, L861Q and G719X (G719S/A/C) were
considered eligible
Patients whose tumours harboured T790M, Exon 20 insertions or S768I mutations either alone or in
combination with other mutations were considered ineligible
Plasma
•
Plasma samples were analysed for Exon 19 deletions, L858R and T790M
mutations only

38. Study flow diagram
Patients screened (N=1060)
Patients with EGFR mutation-positive
tumours (N=118)
Treatment started (N=107)a
Full Analysis Set (FAS; N=106)
Evaluable For Safety (EFS; N=107)a
Patients not eligible based on
their EGFR mutation status (n=942)
EGFR mutation-negative (n=732)
EGFR mutation-unknown (n=201)
EGFR mutation-positive
status ineligible (n=9)b
Treatment not started (n=12)
Eligibility criteria failed (n=5)
Death (n=3)
Patient decision (n=2)
Adverse event (n=1)
Severe non-compliance (n=1)c
Discontinued study (n=36; 33.6%)
Death (n=29)
Patient decision (n=3)
Lost to follow-up (n=2)
Other (n=2)
Status at Data Cut Off 15 August 2012
On gefitinib (n=49; 45.8%)
Off gefitinib (n=58; 54.2%)
aOne patient with a non-activating EGFR mutation-positive tumour (ineligible) was treated in error and included
bPatients with EGFR mutation-positive tumours who were ineligible for the study included those with any of the
in the EFS population
following mutations:
T790M, Exon 20 insertions or S768I mutations either alone or in combination with other mutations not listed
cOne patient was not treated due to severe protocol non-compliance (screening period far in excess of 28 day maximum)

39. Demographic characteristics (FAS)
Demographic characteristic
Median age, years (range)
Sex, %
Race, %
Disease stage at screening, %
Histology, %
WHO performance status, %
Smoking status, %
EGFR mutation subtype, %
Prior treatment, %
FAS, full analysis set
Patients (N=106)
Female
Male
Caucasian
IIIA, IIIB, IV
Adenocarcinoma (NOS)
Adenocarcinoma (bronchioloalveolar)
Adenosquamous carcinoma
Large cell carcinoma (NOS)
Adenocarcinoma tubulo-papillary
0, 1, 2
Never
Current
Former
Exon 19 deletions
L858R
L861Q
G719X (G719S / A / C)
Chemotherapy
Radiotherapy
65 (32-82)
70.8
29.2
100.0
1.9, 5.7, 92.5
86.8
9.4
1.9
0.9
0.9
45.3, 48.1, 6.6
64.2
5.7
30.2
65.1
31.1
1.9
1.9
9.4
13.2

40. Objective response rate (primary endpoint) and disease
control rate (FAS)
Rate, % (N)
Objective response
ratea
Disease control rate
•
•
69.8
(74/106)
90.6
95% CI
60.5 – 77.7
83.5 – 94.8
ORR by secondary, supportive, central review: 50% (53/106)
ORR (post-hoc analysis) of patients assessed by central review
with measurable disease at baselineb: 60%
aInvestigator
assessment (primary endpoint)
patients with measurable disease by investigator assessment were assessed as having no measurable disease at baseline
by central review
ORR, percentage of patients in the FAS with a confirmed response of CR or PR (RECIST 1.1); DCR, percentage of patients (FAS)
with a best response of CR, PR or SD (SD required for ≥6 weeks)
b17

41. Objective response rate by subgroup (FAS)
Gefitinib (N=106)
Subgroup
Category
n
Objective
Responders
Objective
response rate, %
95% CI
Age group (years)
≤65 Years
55
36
65.5
( 52.3, 76.6)
>65 Years
51
38
74.5
( 61.1, 84.5)
Male
31
22
71.0
( 53.4, 83.9)
Female
75
52
69.3
( 58.2, 78.6)
0-1
99
69
69.7
( 60.0, 77.9)
≥2
7
5
71.4
( 29.0, 96.3)
Never
68
50
73.5
( 62.0, 82.6)
Ever
38
24
63.2
( 47.3, 76.6)
Exon 19 Deletions
69
50
72.5
( 61.0, 81.6)
L858R
L861Q
33
2
21
1
63.6
NC
( 46.6, 77.8)
( NC, NC)
G719X (G719S/A/C)
2
2
NC
( NC, NC)
103
3
72
2
69.9
NC
( 60.5, 77.9)
( NC, NC)
Sex
Performance status
Smoking status
EGFR mutation type
Histology
Adenocarcinoma
Non-adenocarcinoma
ORR was not calculated when <3 patients responded in a subgroup
NC: Not Calculated

42. Progression-free survival and overall survival (FAS)
Progression-free survival
Overall survival
No. events: 61 / 106 (57.5%)
Median PFS (95% CI): 9.7 months (8.5, 11.0)
12-month PFS (95% CI): 38.5% (27.5, 49.3)
No. events: 29 / 106 (27.4%)
Median OS (95% CI): 19.2 months (17.0, NC)
12-month OS (95% CI): 70.4% (58.4, 79.6)
1.0
0.8
0.8
Probability of OS
Probability of PFS
1.0
0.6
0.4
0.2
0.0
0.4
0.2
0.0
0 2 4 6 8 10 12 14 16 18 20 22
Time from first dose (months)
No. pts:
0.6
106 101 93 70 49 31 24 10
4
2
1
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time from first dose (months)
106 104 94 91 69 49 39 28 15
7
5
Dotted line represents 50% (median) PFS and OS; PFS, assessed in the FAS from the date of first dose until disease progression
(RECIST 1.1); OS, assessed in the FAS from the date of first dose until death from any cause; NC, not confirmed
0
0

43. Adverse events (MedDRA preferred term)
with frequency >5% (EFS)
Patients (N=107)
Adverse eventa
Total
Rash
Diarrhoea
Vomiting
Asthenia
Cough
Dry skin
Nausea
Decreased appetite
Alanine aminotransferase increased
Hypertension
Dermatitis acneiform
Urinary tract infection
Aspartate aminotransferase increased
aAdverse
All adverse events
(%)
93.5
44.9
30.8
13.1
11.2
11.2
11.2
10.3
9.3
8.4
7.5
6.5
6.5
5.6
Adverse events
CTC grade ≥3 (%)
15.0
0
3.7
0
0
0
0
0
0
0.9
0.9
0
0
0
events with frequency >5% presented. Includes adverse events with an onset date between the date
of first dose and 30 days following the date of last dose of study medication

44. Serious adverse events
(MedDRA preferred term) with frequency >1% (EFS)
Serious adverse eventa,b
%
Total
Patients (N=107)
%
18.7
Pneumonia
2.8
Vomiting
2.8
Cardiac failure
1.9
Diarrhoea
1.9
Hypertension
1.9
aIncludes
serious adverse events with an onset date between the date of first dose and 30 days following the date of last dose
of study medication
b2 patients (1.9%) experienced a serious adverse event that was considered by the investigator to be related to treatment
with gefitinib

45. Adverse events (MedDRA preferred term) leading to treatment
discontinuation (EFS)
Adverse eventa, %
Total
Patients (N=107), %
7.5
Cardiac failure
0.9
Pneumonia
0.9
Alanine aminotransferase increased
0.9
Aspartate aminotransferase increased
0.9
Cognitive disorder
0.9
Dementia Alzheimer’s type
0.9
Fine motor delay
0.9
Dyspnoea
0.9
Interstitial lung disease
0.9
Pneumonitis
0.9
Patients with multiple adverse events leading to discontinuation are counted once for each preferred term.
One patient = 0.9%.

46. Correlation between clinical characteristics
and tumour EGFR mutation status
Odds
Ratiob
pvalue
Histology (adeno vs non-adeno) n=609, n=228
6.78
<0.0001
Smoking status (never- vs ever-smoker) n=194,
n=643
5.48
<0.0001
Gender (female vs male) n=320, n=517
2.83
<0.0001
Age (≤65 vs >65 years) n=433, n=404
1.20
0.4226
WHO performance status (0-1 vs ≥2) n=755, n=82
0.80
0.5563
Clinical factor, na
aFrom
837 out of 850 screened patients with known (positive or negative) EGFR mutation status (data missing
for 13 patients)
bLogistic regression model

47. Comparison of EGFR mutation frequency
in evaluable tumour and evaluable plasma samples (FAS)
EGFR mutation-positive
Sample
N
%
Tumour
118 / 859
13.7
Plasma (cfDNA)
82 / 784
10.5
• Tumour and plasma EGFR mutation status results agreed in 615 out of
the 652 patients who were evaluable for both samples
• Concordance ratea: 94.3% (95% CI 92.3, 96.0)
aFor
patients who were evaluable for both tumour and plasma samples

48. Conclusions
• Gefitinib is effective as a first-line treatment in Caucasian patients with
activating, sensitising EGFR mutation-positive NSCLC, as assessed by ORR
(70%), DCR (91%), median PFS (9.7 months) and median OS (19 months)
• The ORR seen in this EGFR mutation-positive Caucasian population is
similar to that seen in the EGFR mutation-positive IPASS population1.
Gefitinib therefore appears to be consistent in efficacy in patients with
EGFR mutation-positive tumours, irrespective of their ethnicity
• Gefitinib has a well characterised tolerability and safety profile (consistent
with the mechanism of action of EGFR inhibition). Our study has
demonstrated a similar tolerability profile to previous gefitinib studies1-4
1Mok
3Kris
et al 2008; 2Kim et al 2008;
et al 2003; 4Fukuoka et al 2003

49. 2013: First-line Treatment of Advanced/Metastatic NSCLC
75%
25%
Non-SCCa
Other
mutations
5% to 10%
Mutational analysis
EGFR mutation
KRAS or no other “actionable” mutation: 80%
+15%
SCCa
EGFR-TKI
10%
EML4/ALK
ROS1
TKI
90%
Any hemoptysis
No hemoptysis
Platinum + pemetrexed
Carboplatin + paclitaxel
+ bevacizumab or
platinum + pemetrexed
Crizotinib
Platinum +
paclitaxel, docetaxel
gemcitabine or
vinorelbine
nab-paclitaxel
(? cetuximab)

50. 2013: First-line Treatment of Advanced/Metastatic NSCLC
75%
25%
Non-SCCa
Other
mutations
5% to 10%
Mutational analysis
EGFR mutation
+15%
KRAS or no other “actionable” mutation: 80%
SCCa
EGFR-TKI
10%
EML4/ALK
ROS1
TKI
90%
Any hemoptysis
No hemoptysis
Platinum + pemetrexed
Carboplatin + paclitaxel
+ bevacizumab or
platinum + pemetrexed
Gefitinib
Crizotinib
Erlotinib
afatinib
Platinum +
paclitaxel, docetaxel
gemcitabine or
vinorelbine
nab-paclitaxel
(? cetuximab)