Describes the evolving treatment paradigm in non-small cell lung cancer

1. +
EVOLVING STRATEGIES IN THE
PERSONALIZED TREATMENT OF NON-SMALL
CELL LUNG CANCER (NSCLC)
Best Supportive Care
Single-agent platinum
Doublets
Histology-
directed care
Biomarker-
directed
care?

2. +
Histological Sub-Types of Lung
Cancer
Lung Cancer
Small Cell Lung
Cancer
Non-Small Cell
Lung Cancer
(NSCLC)
Adenocarcinoma
Squamous Cell
Carcinoma
Large Cell
Carcinoma
40%
25-30%
10-15%
20%
Adenocarcinoma
Squamous cell carcinoma
Large cell carcinoma
Other
Sub-Types of Lung Cancer Sub-Types of NSCLC
American Cancer Society database.
http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer.
Accessed October 8, 2014.

3. +
Molecular Subsets of NSCLC
Defined by Driver Mutations
Driver Mutations in NSCLC
Oncogene Frequency (%)
AKT1 1
ALK 3-7
BRAF 1-3
EGFR 10-35
HER2 2-4
KRAS 15-25
MEK1 1
NRAS 1
PIK3CA 1-3
RET 1-2
ROS1 1
Lovly, C., L. Horn,W. Pao. 2014. Molecular Profiling of Lung Cancer. My Cancer Genome.
http://www.mycancergenome.org/content/disease/lung-cancer. Accessed October 6, 2014.
AKT1 ALK
BRAF
EGFR HER2
KRAS
MEK1
NRAS
PIK3CA
RET
ROS1
Unknown
AKT=AK strain transforming; ALK=The anaplastic lymphoma kinase; BRAF=B-rapidly
accelerated fibrosarcoma; EGFR=epidermal growth factor receptor; HER=human
epidermal growth factor receptor, KRAS,V-Ki-ras2 Kirsten rat sarcoma viral oncogene
homolog; MEK=mitogen-activated protein kinase kinase; NRAS=neuroblastomas RAS;
PIK3CA=phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha;
RET=rearranged during transfection; ROS=reactive oxygen species.

4. +
Mechanism of Action of EGFR
Tyrosine Kinase Inhibitors (TKIs)
Yuan Y et al. Onco Targets Ther. 2014;28:841-852.
Figure adapted from Araki T,Yashima H, Shimizu K, et al. Clin Med Insights Oncol.2012;6:407–421.
ATP=adenosine triphosphate; ERK=Extracellular signal-regulated kinases;
mTOR=mammalian target of rapamycin; MAPK=mitogen-activated protein kinase.

5. +
Transition from Empiric to Targeted
Therapy of NSCLC
“Activating Mutations in the Epidermal Growth Factor Receptor
Underlying Responsiveness of Non-Small-Cell Lung Cancer to
Gefitinib”1
“EGFR Mutations in Lung Cancer: Correlation with Clinical
Response to Gefitinib Therapy”2
“Mutations of the Epidermal Growth factor Receptor Gene Predict
Prolonged Survival After Gefitinib Treatment in Patients with Non-
Small-Cell Lung CancerWith Postoperative Recurrenc”3
1. Lynch et al. New Eng J Med.2004;350:2129- 2139.
2. Paez et al. Science. 2004;304:1497-1500.
3. Mitsudomi T et al. J Clin Oncol. 2005;2513-2520.

6. +
Gefitinib (IRESSA™)
 First approved in Japan in 2002
 In 2009, the European Commission granted
marketing authorisation for gefitinib for the
treatment of adults with locally advanced or
metastatic NSCLC with activating mutations of
EGFR-TK across all lines of therapy
 Gefitinib is currently approved for the
treatment of first-line EGFR mutation-positive
advanced NSCLC patients in 64 countries
(excluding US)
Yuan Y et al. Onco Targets Ther. 2014;28:841-852.

7. +
GEFITINIB CLINICAL TRIALS:
A Brief History

8. +
Second- or Third-Line Comparative
Studies of Gefitinib in NSCLC
2008
2010
2012
2006
2003
2005
Note: *Time to treatment failure.
ORR=overall response rate; PFS=progression-free survival; OS=overall survival; NA=not available; BSC=best supportive care;
IDEAL=Iressa Dose Evaluation in Advanced Lung Cancer;
ISEL=Iressa Survival Evaluation in Lung Cancer;
INTEREST=Iressa Non-small cell lung cancer Trial Evaluating Response and Survival against Taxotere;
ISTANA=Iressa as Second-line Therapy in Advanced NSCLC-KoreA.
Yuan Y et al. Onco Targets Ther. 2014;28:841-852.

9. +
First-line Large-Scale Comparative
Studies of Gefitinib in NSCLC
2010 201220082004 2009
Yuan Y et al. Onco Targets Ther. 2014;28:841-852.

10. +
IMPROVED BIOMARKER ANALYSIS AND MOLECULAR
DIAGNOSTICS IN NSCLC
Data From Phase-IV, Open-label, Single-Arm Study of First-Line Gefitinib
in Caucasian EGFR Mutation-Positive Patients With NSCLC (NCT01203917)

11. +
First-Line Gefitinib in Caucasian EGFR
Mutation-Positive NSCLC
Gefitinib
250 mg/day
Patients
• Caucasian
patients with EGFR
mutation-positive,
locally advanced or
metastatic NSCLC
• Patients with EGFR
mutation conferring
resistance to TKIs
were excluded
from the study
Primary
• Objective Response Rate (ORR)
(investigator assessment)
Secondary
• Progression-free survival (PFS)
• Disease control rate (DCR)
• Overall Survival (OS)
• Safety and tolerability
• Correlation between clinical
characteristics and baseline
tumor EGFR mutation status
Exploratory
Biomarker Objective I
• Utility of surrogate samples
(plasma) using circulating-free
tumor DNA (cfDNA) for EGFR
mutation analysis
Endpoints

12. +
Patient Disposition
Screeneda
n=1060
Patients eligible for
treatment based on
EGFR mutation-
positive status
n=118
Treatment startedb
n=107
Eligible by EGFR
mutation status
n=106c (89.8%)d
Discontinued
treatment
n=58 (54.2%)e
Discontinued study
n=36 (33.6%)e
Status at data cutoff
On gefitinib n=49
(45.8%)e
Off gefitinib n=58
(54.2%)e
aAll screened patients. Used to calculate the correlation between clinical characteristics and tumor. EGFR mutation
status and the comparison of EGFR mutation status between tumor DNA and plasma-derived circulating free DNA.
bOne patient of EGFR mutation-positive-ineligible status was treated in error and included in the evaluable-for-
safety population. A total of 107 patients therefore started study treatment. cFull analysis set population. Used to
summarize efficacy data, and for the comparison of EGFR mutation status in plasma and tumor samples. dNumber of
patients with EGFR mutation-positive tumors (n=118) used as the denominator for the percentage calculation.
eNumber of patients started on treatment (n=107) used as the denominator for the percentage calculation
Patients ineligible for
treatment based on
EGFR mutation status
n=942
Exploratory biomarker analyses
Baseline tumour samples n = 1033 (97.5%)
EGFR mutation status determined n = 859 (81.0%)
EGFR mutation-positive n = 118 (11.1%)
Baseline plasma 1 samples n = 803 (75.8%)
EGFR mutation status determined n = 784 (74.0%)
EGFR mutation-positive n = 82 (7.7%)
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.

13. +
Key Patient Demographic and
Baseline Characteristics
Characteristic FAS (N=106)
Median age, years (range) 65 (35 – 82)
Age group, years, N (%)
≥ 18 to < 65
≥ 65 to < 75
≥ 75
52 (49.1)
28 (26.4)
26 (24.5)
Gender, n (%)
Male
Female
31 (29.2)
75 (70.8)
Race, n (%)
Caucasian
Black/ African-American
106 (100.0)
0 (0.0)
Histology, n (%)
Adenocarcinoma (NOS)
Adenocarcinoma bronchiolo-alveolar
Adenosquamous carcinoma
Large-cell carcinoma (NOS)
Other/missing
92 (86.8)
10 (9.4)
2 (1.9)
1 (0.9)
1 (0.9)
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.

14. +
Key Patient Demographic and
Baseline Characteristics (cont’d)
Characteristic FAS (N=106)
Performance status, n (%)
0
1
2
Other/Missing
48 (45.3)
51 (48.1)
7 (6.6)
0 (0.0)
Smoking status, n (%)
Never
Current
Former
Missing
68 (64.2)
6 (5.7)
32 (30.2)
0 (0.0)
Prior treatment, n (%)
Radiotherapy
Chemotherapy
14 (13.2)
10 (9.4)
EGFR mutation subtype, n (%)
Exon 19 deletions
L858R
L861Q
G719X (G719S/A/C)
69 (65.1)
33 (31.1)
2 (1.9)
2 (1.9)
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.

15. +
Primary End point: ORR
Category
FAS
(N=106) (n)
Objective
responders
(n)
ORR
(%)
95% Cl
Total
response
106 74 69.8 60.5 – 77.7
CR 2 - 1.9 -
PR 72 - 67.9 -
Age
≤ 65 years
> 65 years
55
51
36
38
65.5
74.5
52.3 – 76.7
61.1 – 84.5
Sex
Male
Female
31
75
22
52
71.0
69.3
53.4 – 83.9
58.2 – 78.6
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.

16. +
Primary End point: ORR (cont’d)
Category
FAS
(N=106)
(n)
Objective
responders (n)
ORR (%) 95% Cl
Performance status
0-1
≥ 2
99
7
69
5
69.7
71.4
60.0 – 77.9
29.0 – 96.3
Smoking status
Never
Ever
68
38
50
24
73.5
63.2
62.0 – 82.6
47.3 – 76.6
EGFR mutation type
Exon 19 deletion
L858R
L861Q
G719X (G719S/A/C)
69
33
2
2
50
21
1
2
72.5
63.6
NC
NC
61.0 – 81.6
46.6 – 77.8
NC – NC
NC - NC
Histology
Adenocarcinoma
Non-adencocarcinoma
103
3
72
2
69.9
NC
60.5 – 77.9
NC - NC
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.

17. +
Secondary End Points: PFS & OS
Progression-Free Survival (PFS) Overall Survival (OS)
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.

18. +
Exploratory Biomarker Objective I Data
Tumor and plasma 1 – screened patients evaluable for both samples (N=652)
Plasma 1 EGFR mutation status (n)
Positive Negative Total
Adjusted baseline tumor EGFR mutation status, n
Positive
Negative
Total
69
1
70
36
546
582
105
547
652
Exon 19
deletions
L858R
L858R and
T790M
Negative Total
Exon 19
deletions
48 0 0 23 71
L858R 0 21 0 12 33
L858R and
T790M
0 0 0 1 1
Negative 0 1 0 546 547
Total 48 22 0 582 652
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.

19. +
Conclusions From the Phase IV Study
 Gefitinib is effective as a first-line therapy
in patients with EGFR mutation-positive
NSCLC, irrespective of ethnicity or clinical
characteristics
 Plasma is a suitable substitute for mutation
analysis when tumor tissue is unavailable as
EGFR mutation status can be accurately
assessed using cfDNA
Douillard J-Y et al. Br J Cancer. 2014;110:55–62.

20. +
ACQUIRED RESISTANCE TO EGFR TKIS
Approaches to Management

21. +
Acquired Resistance to
EGFR TKIs
16%
63%
5%
3%
13%
Others EGFR T790M
MET Amplification SCLC Transformation
HER2 Amplification
EGFR T790M point mutation in
exon 20 is the most frequent
mechanism of acquired
resistance1
Progressive Disease Sub-Type
Influences Clinical Practice
1. Yu HA et al. Clin Cancer Res.2013;19:2240–2247.
2. Gandara DR, et al. Clin Lung Cancer. 2014;15:1-6.
CNS=central nervous system; PD= progressive disease.

22. +
Switch Therapy
(Chemotherapy or
second-generation TKI)
Systemic-PD
Approaches to Manage Acquired
Resistance to TKIs
Add Therapy to TKI
 Chemotherapy ?
 Another targeted agent?
Continue Same TKI Alone
(Post PD to “slow progression”)
Re-biopsy
RECIST
Response
Subsequent
systemic PD
Advanced
NSCLC With
Oncogene-Driven
Cancer
Targeted
TKI
 EGFR mutation
 ALK fusion
RemissionBaseline Multiple PD Lesions
Gandara DR, et al. Clin Lung Cancer. 2014;15:1-6.
RECIST=Response Evaluation Criteria In Solid Tumors.

23. +
Approaches to Manage Acquired
Resistance to TKIs (cont’d)
Oligo-PD
RemissionBaseline Solitary New
Lesion
RemissionBaseline Brain-Only PD
CNS-PD
(Sanctuary)

24. +
Treatment of Brain MetastasisWith
Gefitinib
Study Treatment ORR Median PFS OS
Ma et al1
(N=21)
40 Gy/20 fractions/
4 weeks whole-brain
radiotherapy and
gefitinib 250 mg once
daily
81%
(95% CI;
58%–95%)
10.0 mos
(95% CI;
7.5–12.5)
13.0 mos
(95% CI;
8.2–17.8)
Park et al2
(N=28)
Erlotinib or gefitinib
after systemic
treatment
NA NA
15.9 mos
(95% CI;
7.2–24.6)
Fan et al3
(N=210)
Chemotherapy +
Localized Treatment
NA NA
9 mos
(P=0.002)
EGFR TKI +
localized treatment
NA NA
12 mos
(P=0.002)
Luchi et al4
(N=41)
Gefitinib alone without
radiation
87.8% 14.5 mos
21.9
months
1. Ma S et al. Lung Cancer.2009;65:198–203.
2. Park SJ et al. Lung Cancer.2012;77:556–560.
3. Fan Y et al. Onco Targets Ther.2013;6:1789–1803.
4. Luchi T et al.Lung Cancer.2013;82: 282–287.

25. +
Summary
 Gefitinib is effective as a first-line therapy in patients with
EGFR mutation-positive NSCLC
 Results from clinical trials are awaited for the use of gefitinib
in combination with chemotherapy in patients with NSCLC
who have acquired resistance to gefitinib
 While gefitinib has demonstrated efficacy in brain
metastases, large-scale randomized clinical trials are
needed to confirm its efficacy
 Improved tumor molecular characterizations on small
amounts of tumor material or using CfDNA will allow
personalized and evidence-based treatment for advanced
NSCLC