Advances in the

Management of Non Small

Cell Lung Cancer
Presenter Disclosures
Personal financial relationships with commercial interests relevant to this
presentation during the past 12 months:

Research support: Eli Lilly, Genetech, OSI pharmaceuticals
Personal financial relationships with non-commercial interests (e.g.,
government or other nonprofit funding) relevant to this presentation,
within past 12 months:

Relevant institutional financial interests:

Personal financial relationships with tobacco industry entities within the
past 3 years:

No relationship to disclose


Jemal, CA Cancer J Clin 2008; 58: 71
Cancer Incidence Deaths

Colon 108,070 49,960
Breast 184,450 40,930
Prostate 186,320 28,660
Total 478,840 119,550
NSCLC Epidemiology
Lung 215,020
161,840
Statistics for 2008
NSCLC: Stage at Diagnosis
Stage IV 40%
Stage I 10%
Stage II 20%
Stage IIIA 15%
Stage IIIB 15%
Ettinger et al. Oncology. 1996;10:81-111.
Adapted with permission from Schiller JH et al. N Engl J Med. 2002
1 yr survival plateau at
about 35-40%
No clear efficacy benefit
for non-platinum
combinations or triplet
combinations
New paradigm is needed
Cisplatin/Paclitaxel
Cisplatin/Gemcitabine
Cisplatin/Docetaxel
Carboplatin/Paclitaxel
1.0
0.8
0.6
0.4
0.2
0.0
0 5 10 15 20 25 30
Months
Stage
IIIB/IV
Patient
Survival,
%
We had reached a Ceiling for Improved Benefit
of Cytotoxic Chemotherapy in Advanced NSCLC
ECOG 1594
Platinum Doublet Chemotherapy in
Advanced NSCLC
1

1. NCCN Non-small Cell Lung Cancer Clinical Practice Guideline, v.2.2008. Available at: http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf
2. Frasci et al. J Clin Oncol. 1999;17:2316-2325
3. Kelly et al. Clin Cancer Res. 2000;6:3474-3479.

Overall response 25%-35%
Time-to-progression
4-6 months
Median survival 8-12 months
1-year survival 30%-40%
2-yr survival 10%-15%
Failed Paradigms:
Triplet Cytotoxic
Chemotherapy
2,3

Non-Platinum Chemotherapy
Single Agent Chemotherapy

Strategies to improve treatment
effectiveness
Better Patient Selection:
What criteria?

Better Predictive Markers:
Which ones?

Better Treatments:
Less toxic
More specific

Cisplatin 75 mg/m
2
day 1 plus Gemcitabine 1250
mg/m
2
d 1 & 8
Randomization
Factors

Stage
PS
Gender
Histo vs cyto dx
Brain mets hx

R
Cisplatin 75 mg/m
2
day 1 plus Pemetrexed 500
mg/m
2
d 1

Vitamin B
12
, folate, and dexamethasone given in both arms

Role of Histology in Patient Selection:
JMDB Trial: Pemetrexed-Cisplation vs
Gemcitabine-Cisplatin in Adv NSCLC
Scagliotti & Gandara: JCO, 2008
1st-line NSCLC: Preplanned Analysis
Pemetrexed+cisplatin
Median OS: 12.6 mos
Gemcitabine+cisplatin
Median OS: 10.9 mos
HR=0.844
(95% CI: 0.710.98)
p=0.011
Pemetrexed+cisplatin
Median OS: 9.4 mos
Gemcitabine+cisplatin
Median OS: 10.9 mos
HR=1.229
(95% CI: 1.001.51)
p=0.051
Nonsquamous* (n=1252) Squamous (n=473)
Survival Time (months) Survival Time (months)
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* Non-squamous = adenocarcinoma, large cell carcinoma, and other/indeterminate NSCLC histology
Scagliotti, et al. J Clin Oncol 2008
JMDB Trial: Cisplatin-Pemetrexed (CP) vs. Cisplatin-Gemcitabine (CG) in
Adv NSCLC
No difference in overall
PFS or Survival between
study arms
CP improves Survival over CG
in Non-SCCA (HR 0.81, p=0.005)

CG improves Survival over CP
in SCCA (HR 1.23, p=0.05)

Ligand: IGF-I, IGF-II. Local bioavailability subject to regulation by binding with IGF-BP
and release by IGF-BP protease
IGF-IR: binds to IGF-I, II
IGF-IR/IR-A: Hybrids with preferential binding to IGF-1 >> insulin.
IR exists in two isoforms:
IR-B: traditional insulin receptors.
IR-A: preferentially binds IGF-II (a fetal form; re-expressed in some tumors)
IGF-IIR: non-signaling receptor, acting as a sink for IGF-II.
Insulin/IGF Receptor System

Hybrid
Receptors
C
N N
IGF-IR
IGF-IIR
IGF
Binding
Proteins
(M6P-receptor)
C C C
IGF-I IGF-II
N N
IR-A IR-B
C C C C
N N N N
Insulin
RAS /MAPK mitogenesis
PI3K/AKT survival
4
0,1 1 10
Adjusted Relative Risk
Colorectal cancer Ma et al, 1999
Kaaks et al, 2001
Probst-Hensch et al, 2001
Giovannucci et al, 2000
Prostate cancer
Stattin et al, 2000 (<59yrs)
Stattin et al, 2000
Harman et al, 2000
Chan et al, 2002
Breast cancer
Toniolo et al, 2000 (premenopausal)
Toniolo et al, 2000
Hankinson et al, 1998
Hankinson et al, 1998 (<50yrs)
Lung cancer
London et al, 2002
Lukanova et al, 2000
Bladder cancer
Zhao et al, 2003
Ischemic Heart disease
IGT/NIDDM
Osteoporotic fractures
Juul et al, 2002
Sandhu et al, 2002
Garnero et al, 2000
IGF-I and risk of Cancers
prospective population-based case-control studies
2:1 randomization
N=150, 2 stages
of 73 and 77 pts
TC: paclitaxel 200 mg/m
2
,
carboplatin (AUC=6)
TCI: paclitaxel 200 mg/m
2
,
carboplatin (AUC=6),
Stage 1: CP-751,871 10 mg/kg
Stage 2: CP-751,871 20 mg/kg
TCI
n=97
n=53
CP-751,871
Single agent
Optional upon
progression
on TC alone
CP-751,871
Single agent
IGF1R Inhibitor Therapy: Randomized Phase II
Trial Paclitaxel/Carboplatin +/-CP-751,871 in
advanced NSCLC
Karp: ASCO 08
TCI: paclitaxel 200 mg/m
2
,
carboplatin (AUC=6)
CP-751,871 20 mg/kg
Stage 3: single-arm,
post-study extension
in SCC
n=30, 14 pts
evaluable
Response Rate by Dose and Histology
Histology
TaxCarbo
TaxCarbo +
CP (10mg/kg)
TaxCarbo +
CP (20mg/kg)
Squamous
(randomized)
6/13 (46%) 4/7 (57%) 7/9 (78%)

Squamous
(single arm)
11/14 (78%)
Adenoca 5/20 (25%) 8/21 (38%) 16/28 (57%)
NOS 8/15 (53%) 3/6 (50%) 9/18 (50%)
Karp: ASCO 08
-100.0
-80.0
-60.0
-40.0
-20.0
0.0
20.0
40.0
Major Responses of TCI in Bulky Squamous
RR 78% vs 57%
October 2005
February 2006
August 2007
October 2007 April 2008
November 2007
BEST RESPONSE IN
VISCERAL LESIONS > 5 cm
0 mg/kg
20 mg/kg
10 mg/kg
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Choice of treatment according to histology:
Adenocarcinoma: Pemetrexed based
Squamous cell carcinoma:
Gemcitabine based
Pac/carbo + IGF inhibitor CP 27181
1
6
?
Histology will ultimately prove to be Suboptimal for Selecting
Chemotherapy (or Targeted Therapy)
Histological sub typing groups tumors based on microscopic pattern
recognition by a pathologist (using 18
th
century technology)
At best, Histology is the phenotypic expression of complex genetic and
molecular interactions
21
st
century approach will refine choice at the molecular level

Robert Hooke
Tissue Microarray
TS
SCLC High TS
Squamous High TS
Adeno Low TS
Thymidylate Synthtase Expression in Lung Cancer
Bhattacharjee PNAS 2001
Possible explanation to SQCCA sensitivity to CP 721871
De-regulation of the IGFR pathway seems a possibility in
squamous cell carcinoma:

ILGF binding protein 3 levels, which regulates activity
of IGF-1, are low in SQCCA

IGF-R appears to be expressed more in SQCCA

IGF-IIR gene which codes for a negative regulator of
the IGF-IR pathway is mutated in up to 60% of
SQCCA
Karp JCO 2009
Strategies to improve treatment
effectiveness
Better Patient Selection:
-What criteria?

Better Predictive markers:
-Which Ones?
Better Treatments:
-Less Toxic
-More Specific

PI3k P
P P
P
IGF-1R/
IR
HER C-MET
P
P P
P P
P P
P
EGFR HGF
IGF-1/
Insulin
Src Ras
Ras
Raf
MEK
Erk
PIP3
PTEN
PIP2
PDK-1
Akt
raptor
mTOR
rictor
mTOR
p70s6k
4EBP
Hif-1
Protein Translation
FoxO3a
Transcription
Angiogenesis
Cell Cycle Progression
Proliferation
Differentiation
BAD
Apoptosis
Anti-HER
Lapatinib
BMS599626
BMS690514
PF00299804
XL647
BIBH2992
ARRY334543
Anti-cMET
XL880
ARQ197
PF02341066
JNJ388
MGCD265
SU11274
PHA665752
HGF mAb
AMG102
OA5D5
IGF-1 mAb
CP721871
AMG479
IMC-A12
R1507
BIIB022
Anti-IGF-1R
XL228
OSI906
NDGA
Anti-Src
Bosutinib
XL999
AZD0530
KX010107
Anti-mTOR
Everolimus
Deforolimus
UCN01
Anti-Akt
Perifosine
GSK690693
Anti-PI3k
PI103
BGT226
BEZ235
XL765
XL147
Anti-Ras
Tipifarnib
Lonafarnib
BMS214662
Anti-Raf
Sorafenib
RAF265
XL281
PLX4032
Anti-MEK
AZD6244
RDEA119
XL518
IRS
Anti-DNMT
5-azacitadine
5-aza-2-deoxycitidine
Anti-HDAC
SNDX275
CI994
Apicidin
Desipeptide
Trapoxin
Depeudecin
SK7068
vorinostat
The trick is:
To pick right target
To have the right agent
To have the right pairing
Many Targeted Therapies Failed to Show Additional
Benefit when Combined with Platinum Based CT
Median Survival results in months Placebo Agent
INTACT-1

CG gefitinib 10.9 9.9/9.9 NS
INTACT-2

CP gefitinib 9.9 9.8/8.7 NS
TRIBUTE

CP erlotinib 10.5 10.6 NS
TALENT

CG erlotinib 10.0 10.3 NS
SPIRIT-1

VC bexarotene 9.9 8.7 NS
SPIRIT-2

CP bexarotene 9.2 8.5 NS
Paz-Ares et al.

CG aprinocarsen 10.4 10.0 NS
ISIS-3521

CP aprinocarsen 9.7 10.0 NS
AG-3340-017

CG prinomastat 10.8 11.5 NS
BR.18

CG BMS-275291 9.2 8.6 NS
Study 5404 CP panitumumab 8.0 8.5 NS
ESCAPE CbP sorafenib Phase III study stopped due to high mortality
BR.24 CbP cediranib
Will not proceed to Phase III because of
toxicity
Courtesy: E. Vokes

Bevacizumab Blocks Angiogenesis

Recombinant
humanized
monoclonal
antibody to
VEGF-A
E4599. Ph III RCT :Bevacizumab and
CP vs CP in non-squamous NSCLC
R
A
N
D
O
M
I
Z
E
Paclitaxel 200 mg/m
2
IV
Carboplatinum AUC 6 q 21d
X6 cycles
Paclitaxel 200 mg/m2 IV +
Carboplatinum AUC 6 q 21d
X6 cycles
Bevacizumab 15mg/kg q3 wk
til PD
Stratification by:
Stage (IIIB or IV)
Geographic region
Sandler. NEJM 2006; 355: 2542
IIIB and IV non-squamous
No brain mets
No hemoptysis
No prior chemotherapy

HR: 0.79, 0.67-0.92
P = .003
Pac/carbo + bev, n=434 51% 23%
Pac/carbo, n=444 44% 15%
0.0
0.2
0.4
0.6
0.8
1.0
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0 6 42 48 18 30
12 mo 24 mo
12 24 36
Months
12.3
10.3
Sandler AB, et al. New Engl J Med. 2006;355:2542-2550.
~37% of patients with advanced NSCLC are eligible to receive bevacizumab, <20% if also exclude age 70 years

Phase III ECOG 4599 trial: Paclitaxel/Carboplatin
Bevacizumab
Non-Squamous histology, no hemoptysis, brain metastases
PC
n=427
PCB
n=420
Hemorrhage
Hemoptysis
0 5
GI Bleed
1 2
Neutropenic Fever
1 5
CNS
0 2*
Pulmonary Embolus
0 1
Total
2 15
ECOG Trial (E4599): Treatment Related
Deaths*
Sandler AB, et al. New Engl J Med. 2006;355:2542-2550.



Just when you think youve got it right..
2
8
AVAIL Study design
PD
PD
PD
Bevacizumab
Bevacizumab
2
2
1
1
Placebo 7.5 + CG
Bevacizumab
15mg/kg + CG
Bevacizumab
7.5mg/kg +
Cis/Gem (CG)
Placebo 15 + CG
Previously
untreated, stage
IIIb, IV or
recurrent
non-squamous
NSCLC
N=1050
R
A
N
D
O
M
I
Z
E
Manegold, et al. ASCO 2007, LBA 7514
Positive for primary endpoint: PFS
Negative for Overall Survival
AVAIL Efficacy
Placebo
CG
Bevacizumab
7.5 mg/kg
+CG
Bevacizumab
15 mg/kg
+CG
PFS
(mos)
6.2
6.8
HR 0.75 (0.64-0.87)
P= 0.0003
6.6
HR 0.85 (0.73-1.00)
P=0.0456
OS
(mos)
13.1
13.6
HR 0.93 (0.78-1.11)
P=0.42
13.4
HR 1.03 (0.86-1.23)
P=0.76
The 1
o
endpoint for the trial: PFS
So that this was reported as a positive trial
But is it really clinically significant?
Epidermal Growth Factor Receptor (EGFR) Inhibitors
in NSCLC: Status of Predictive Biomarkers
Signal
Transduction
Blocked
Signal
Transduction
Blocked
TKI MoAb
Ligand
K K
TKI
K K
Gefitinib
Erlotinib

Single Agent
EGFR mut=predictive
EGFR FISH=predictive
KRAS mut=predictive


TKIs + Chemo
are negative
(INTACT I/II
TRIBUTE, TALANT
all negative)
Cetuximab

Single Agent
Biomarkers Unclear




Cetux + Chemo

(FLEX=positive)

IgG1 monoclonal antibody
Binds to EGFR and competitively inhibits
ligand binding (e.g. EGF)
Mechanisms different from TKI:
Receptor Internalization
Antibody-Dependent Cellular Cytotoxicity
(ADCC)
Combinations with Radiation or Chemotherapy
effective in other tumor types
Radiation: H & N Cancer
Chemotherapy: Colon Cancer
Harari: Clin Cancer Res, 2004
Cetuximab
EGFR
ADCC IgG1 MAb
Cetuximab Mechanism of Action
Chemotherapy-
nave advanced
NSCLC
Vinorelbine 25 mg/m
2
d1,8
+ cisplatin 80 mg/m
2
d1, Q3W
FLEX: Pivotal Trial
Cetuximab + Chemotherapy in 1
st
-Line Advanced NSCLC
Primary endpoint: OS

Secondary endpoints: PFS, ORR, DCR, QoL, Safety, PK
n=557
n=568
Cetuximab 400 mg/m
2
d1 wk1, then 250 mg/m
2
, QW
+ Vinorelbine 25 mg/m
2
d1,8
+ cisplatin 80 mg/m
2
d1, Q3W
R
A
N
D
O
M
I
Z
E
Up to 6 cycles of chemotherapy; patients not
progressing continue on cetuximab maintenance
Stratified by
IIIB or IV
ECOG PS 0,1
or 2
All histologic subtypes included
ECOG PS 02
No known brain metastases
EGFR expression by IHC (1 positive tumor cells)
Pirker R, et al. Lancet 373(9674): 1525 1531, 2009.
FLEX: Results
CV + Cetuximab CV P
RR 36% 29% 0.012
PFS 4.8 mos 4.8 mos NS
TTF 4.2 mos 3.7 mos 0.015
NS=not significant; TTF=time to treatment failure.
Months
O
S

(
%
)

Median OS 1-Yr Surv.
CV + Cetuximab 11.3 mos 47%
CV 10.1 mos 42%
HR: 0.871; P=0.044
Pirker R, et al. Lancet 373(9674): 1525 1531, 2009.
FLEX: Differences in Ethnicity
Caucasian
(N=946)
Asian
(N=121)
Prognostic Factors
Adenocarcinoma 44% 72%
Female 27% 46%
Never smoker

17% 52%
ECOG PS 0/1 81% 94%
Poststudy Treatment
EGFR TKIs 17% 61%
Median OS 9.6 mos
19.5 mos
[95% CI] [9.010.4] [16.423.3]
Pirker R, et al. Lancet 373(9674): 1525 1531, 2009.
FLEX: Asian Subgroup (N=121)
CV + Cetuximab
(N=62)
CV
(N=59)
P Value
Baseline Prognostic Factors
Adenocarcinoma 65% 80%
Post-Study Treatment
EGFR TKIs 50% 73%
OS 17.6 mos 20.4 mos NS
RR 50% 44% NS
Cannot draw definitive conclusions because of small sample size (10% of total),
differences in histology and differences in post-study EGFR TKI treatment
Pirker R, et al. Lancet 373(9674): 1525 1531, 2009.
Median OS
1-Year
Survival
CV + Cetuximab
(N=466)
10.5 mos 45%
CV
(N=480)
9.1 mos 37%
HR=0.803; P=0.003
FLEX: OS Caucasians (N=946)
Prespecified Analysis
Months
P value: stratified log-rank test (2-sided)
O
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(
%
)

Median OS CV + Cetuximab CV HR
Caucasians (N=946) 10.5 mos 9.1 mos 0.803
Adenocarcinoma (N=413) 12.0 mos 10.3 mos 0.815
Squamous Cell (N=347) 10.2 mos 8.9 mos 0.794
Other (N=185) 9.0 mos 8.2 mos 0.807
CV=cisplatin/vinorelbine.
Pirker R, et al. Lancet 373(9674): 1525 1531, 2009.
CV + Cetuximab Any grade Grade 0
OS 15.0 mos 8.8 mos
RR 44% 28%
PFS 5.4 mos 4.3 mos
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(
%
)

Months
Any grade: CT + Cetuximab
(N=290)
Grade 0: CT + Cetuximab
(N=228)
HR=0.631 (95% CI: 0.515-0.774)*
P<0.001
Patients at Risk
Grade 0 228 145 88 54 15 0
Any Grade 290 238 163 101 38 3
*Landmark analysis.
FLEX: OS Early Acne-Like Rash
Pre-Planned Analysis
Gatzemeier et al, JTO 2008, Vol 3, No. 11, S4 (abstract 8)
Cetuximab + Platinum-Based Chemotherapy in
1st line NSCLC: Consistent Efficacy
*Randomized to concurrent vs sequential cetuximab;

Randomized to pac/carbo q3w vs pac qw/carbo q4w

Pac qw/carbo q4w

* *Press release Aug 2008
Reference Phase Regimen N ORR, % TTP/PFS, m OS, m
Thienelt et al, 2005 I/II Cet + pac/carbo 31 26 5 11
Robert et al, 2005 I/II Cet + gem/carbo 35 28.6 5.5 10.3
Herbst et al, 2007 II Cet + pac/carbo 204 34/31* 4/4 11/11
Socinski et al, 2009 II Cet + pac/carbo 168 29.6/25

4.7/4.3 11.4/9.8
Langer et al, 2007 II Cet + pac/carbo

53 57 5.5 13.8
Belani et al, 2007 II Cet + doc/carbo 76 14.5 4.7 11
Rosell et al, 2008 II Cet + vin/cis 43 35 5.0 8.3
Kim et al, 2008 II Cet+ bev/pac/carb 99 53 7 14.0
Butts et al, 2007 II Cet + gem/pla 65 27.7 5.1 12.0
Lynch et al, 2007 III Cet + tax/carbo 338 25.7 4.4 9.7**

Pirker et al, 2009 III Cet + vin/cis 1125 36 4.8 11.3
Structure of the EGFR-ATP Binding Site
Red: deletions
Light blue: missense mutations
Dark blue: gefitinib
From: Lynch TJ et al. N Engl J Med. 2004;350:2129-2139.
Exons 18, 19, 20
and 21- Tyrosine
kinase domain


In frame deletions
and missense
mutations

Individualizing Anti-EGFR Therapy: Methodology
EGFR mutation status by
gene sequencing
EGFR gene copy number by
fluorescence in situ hybridization
(FISH)
EGFR protein expression by
immunohistochemistry (IHC)
Serum Proteomics by MALDI MS
GGCGGGCCAAACTGCTGGGTGCG
NCIC-C BR.21 TRIAL
NSCLC
1 prior
combination
regimen (no more
than 2)
Elderly may have
had single-agent
No requirement
for PD
R
A
N
D
O
M
I
Z
E
Erlotinib
150 mg daily
n=488
Placebo
n=243
Shepherd et al.NEJM, 2005
*HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status.
BR-21 Overall survival: all patients
42.5% improvement in median survival
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f
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Survival time (months)
Tarceva
TM
Placebo

HR=0.73, P<0.001
Tarceva
TM

(n=488)
Placebo
(n=243)
Mediansurvival (months) 6.7 4.7
1-yearsurvival (%) 31 21

1.00
0.75
0.50
0.25
0
0 5 10 15 20 25 30
31%
21%
Log-rank: p=0.13
HR=0.73 (0.49, 1.10)
BR.21 Survival According to EGFR Mutation
p value for interaction = 0.97
No mutation
100
80
60
40
20
0
P
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c
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n
t
a
g
e

0 6 12 18 24 30
Months
Erlotinib
Placebo
+ EGFR mutation
100
80
60
40
20
0
P
e
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c
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n
t
a
g
e

Months
Erlotinib
Placebo
Log-rank: p=0.45
HR=0.77 (0.40, 1.50)
0 6 12 18 24 30
EGFR Mutation is NOT a Prognostic Marker
BR.21: EGFR FISH predicts Survival
Log-rank: p=0.008
HR=0.44 (0.23, 0.82)
Log-rank: p=0.59
HR=0.85 (0.48, 1.51)
BR21 FISH +
BR21 FISH -
Time (months)
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 30 24
Erlotinib
Placebo
Time (months)
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 30 24
Erlotinib
Placebo
Tsao: NEJM, 2005
FISH positivity is a prognostic marker
Biomarkers for EGFR-directed Therapy:
Summary of Current Status
EGFR TKIs
EGFR protein (IHC) equivocal for predictive value
EGFR mutation predicts response
EGFR FISH predicts survival (BR.21)
KRAS mutation predicts lack of activity
Cetuximab
EGFR protein (IHC): selection factor for FLEX
EGFR mutation: not predictive (preclinical)
EGFR FISH: conflicting data (S0342, BMS-099)
KRAS mutation: not predictive (S0342, BMS-099)
N0723: Predictive Marker Study Design
2
nd
line
NSCLC
with
specimen
Initial
Registration
FISH
Testing
EGFR FISH +
(~ 30%)
EGFR FISH
(~ 70%)
Erlotinib
Pemetrexed
Erlotinib
Pemetrexed
Strata Randomize
Outcome
1 PFS
2 OS,
ORR

Power: validation of EGFR FISH as predictive biomarker
90% to detect 50% PFS improvement favoring erlotinib in FISH+
90% to detect 30% PFS improvement favoring pemetrexed in FISH
> 90% to detect interaction
SWOG: Tumor repository & EGFR pathway analysis
NCCTG (Study Chair: Alex Adjei) + CALGB, ECOG, SWOG, NCIC
Others: C-Path & industry partners, Pharma
957 patients
4 years accrual, 1196 patients
1-2 years
minimum
additional
follow-up
Possible Selection Factors for
Individualizing Therapy of NSCLC
Characteristic Drug Class Population
Clinical Factors
EGFR TKIs
Bevacizumab
Female, Never-
smoker, Asian
No Hemoptysis
Tumor Histology EGFR TKIs
Bevacizumab
Pemetrexed
IGF1R Inhibitors
Adenoca
No SCCA b/o risk
Non-SCCA
SCCA (?)
Molecular Factors EGFR TKIs
Cetuximab
ERCC1/RRM1
TS
Anti-Angiogenics
EGFR Mut/FISH
EGFR IHC/FISH (?)
Platinum Chemo
Pemetrexed
(?)
from Gandara: CLC, 2008
Iressa Pan Asian Study (IPASS) Phase III Trial: Gefitinib
vs Carboplatin/Paclitaxel in Selected Patients With
Advanced NSCLC
Never or light
ex-smoker* with
adenocarcinoma
histology

PS 0-2

Stage IIIB or IV
chemotherapy-nave
NSCLC
N=1217

R
A
N
D
O
M
I
Z
E

Gefitinib (250 mg/day)

Offered carboplatin/paclitaxel
on progression
Carboplatin (AUC 5 or 6)
+
Paclitaxel (200 mg/m
2
)
3 times weekly up to 6 cycles

Primary endpoint: PFS (noninferiority)
Secondary endpoints: ORR, OS, QOL, disease-related symptoms, safety, and tolerability
Exploratory: biomarkers EGFR mutation, gene copy number, and protein expression
Mok. ESMO. 2008 (abstr LBA2).
*Never smoker=smoked <100 cigarettes in lifetime; light ex-smoker=stopped 15 years ago and
smoked 10 pack-years.
Progression-Free Survival in ITT
Population
609
453 (74.4%)
608
497 (81.7%)
N
Events
HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001
Gefitinib

Gefitinib demonstrated superiority relative to
carboplatin / paclitaxel in terms of PFS
Primary Cox analysis with covariates
HR <1 implies a lower risk of progression on gefitinib
Carboplatin /
paclitaxel
Carboplatin /
paclitaxel
Gefitinib
Median PFS (months)
4 months progression-free
6 months progression-free
12 months progression-free
5.7
61%
48%
25%
5.8
74%
48%
7%
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
1.0 Probability
of PFS
At risk :
Progression-Free Survival in EGFR Mutation
Positive and Negative Patients
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
No. events gefitinib, 97 (73.5%)
No. events C / P, 111 (86.0%)
Gefitinib (n=132)
Carboplatin / paclitaxel (n=129)

ITT population Mutation rate ~60%
Cox analysis with covariates

HR (95% CI) = 2.85 (2.05, 3.98)
p<0.0001
No. events gefitinib , 88 (96.7%)
No. events C / P, 70 (82.4%)

132 71 31 11 3 0
129 37 7 2 1 0
108
103
0 4 8 12 16 20 24
Gefitinib
C / P
0.0
0.2
0.4
0.6
0.8
1.0
P
r
o
b
a
b
i
l
i
t
y

o
f

p
r
o
g
r
e
s
s
i
o
n
-
f
r
e
e

s
u
r
v
i
v
a
l

At risk :
91 4 2 1 0 0
85 14 1 0 0 0
21
58
0 4 8 12 16 20 24
0.0
0.2
0.4
0.6
0.8
1.0
P
r
o
b
a
b
i
l
i
t
y

o
f

p
r
o
g
r
e
s
s
i
o
n
-
f
r
e
e

s
u
r
v
i
v
a
l

Gefitinib (n=91)
Carboplatin / paclitaxel (n=85)

Months Months
CONCLUSIONS
Treatment paradigm are evolving due to:

Molecular characterizations of disease and
agents to pick best fit

Realization that all populations with this
disease are not the same

Realization that lung cancer is quite
heterogeneous