Conclusions

1
Delivering the promise ofanti-EGFR therapy
inadvanced NSCLC
Enriqueta Felip Vall dHebron University
HospitalBarcelona, Spain
2
Major EGFR cellular signalling pathways
P
P
MAPK pathway
PI-3 kinase/AKT pathway
Proliferation
Cell survival
Ligand binding and receptor dimerisation
Activation of downstream signalling cascades
Autophosphorylation of intracellulartyrosine
residues
MAPK mitogen activated protein kinase AKT
protein kinase B EGFR epidermal growth factor
receptor
3
Tarceva a potent inhibitor of EGFR
Tarceva
NH
O
O
N
O
O
N
MW 428Da
IGF insulin-like growth factor HER2 human
epidermal growth factor receptor-2VEGFR
vascular endothelial growth factor receptor
Moyer, et al. Cancer Res 1997
4
Tarceva-mediated inhibition ofEGFR signalling
Tarceva
P
P
? REDUCTION IN PROLIFERATION ?
? INCREASE IN APOPTOSIS ?
Nucleus
5
Phase II pharmacodynamic study of Tarceva
(150mg/day) in previously treated NSCLC

• Serial tumour biopsies collected before and after
  6 weeks of Tarceva therapy

pEGFR
pMAPK
300 200 100 0
300 200 100 0
Staining H-score
Staining H-score
p0.002
p0.001
Pretreatment
After 6 weeks of therapy
Pretreatment
After 6 weeks of therapy
Ki-67
TUNEL
100 75 50 25 0
2.5 2.0 1.5 1.0 0.5 0 0.5
Ratio of changein apoptosis
Staining percentage
p0.025
p0.029
Pretreatment
Patientswithout clinical benefit
Patientswith clinical benefit
After 6 weeks of therapy
Felip, et al. CCR (in press)
6
Pivotal clinical trial NCIC-CTG BR.21
Tarceva 150mg/day (n488)
Previously treated (failure of 12 previous
chemotherapy regimens) stage IIIB/IV NSCLC with
PS 03 (n731)
Placebo (n243)
Primary endpoint overall survival (OS) Secondary
endpoints progression-free survival (PFS),
response rate, duration of response, safety,
quality of life (QoL)
NCIC-CTG National Cancer Institute of Canada -
Clinical Trials Group PS performance status
7
Phase III trial BR.21 demonstratedimprovement in
OS versus placebo
100 75 50 25 0

Tarceva

Placebo




(n488)

(n243)

HR0.73 (0.600.87), p0.001



27 reduction in risk of death with Tarceva
Survival probability ()
42.5 increase in median survival with Tarceva
0 5 10 15 20 25 30
Survival time (months)
Shepherd, et al. NEJM 2005Tarceva Summary
of Product Characteristics
Hazard ratio and p (log-rank test) adjusted for
stratification factors at randomisation and EGFR
status
8
TRUST phase IV trial of Tarceva inreal-life
clinical practice
Previously treated (failure on previous lines of
chemotherapy or radiotherapy) stage IIIB/IV
NSCLC (n7,000)
Tarceva 150mg/day

• Phase IV, open-label, non-randomised, multicentre
  study
• Tarceva administered until either disease
  progression or unacceptable levels of toxicity

9
TRUST confirmed improved PFS observed in the
BR.21 trial
1.00 0.75 0.50 0.25 0
BR.211
Median PFS Tarceva 9.7 weeks placebo 8 weeks
(plt0.001)
TRUST2
Median PFS 13 weeks
Tarceva (TRUST), n6,181
Survival distribution function
Tarceva (BR.21), n488 Placebo (BR.21), n243
0 5 10 15 20 25 30
PFS (months)
Note results cannot be directly compared
becauseof different study designs and populations
1Shepherd, et al. NEJM 2005 2Ardizzoni, et al. J
Thoracic Oncol 2007
10
TRUST higher disease control rate in real-life
clinical practice
80 60 40 20 0
Patients ()
CRPR SD DCR
CR complete responseDCR disease control
rate (CRPRSD) PR partial response SD
stable disease
Shepherd, et al. NEJM 2005Ardizzoni, et al. J
Thorac Oncol 2007
11
BR.21 demonstrated improvement in QoL with
Tarceva (EORTC QLQ-C30)
p0.01
Tarceva Placebo
p0.01
p0.01
Patients with improvement ()
Global Physical Role Cognitive
Emotional Social
Improvements seen in more Tarceva-treated
patients than placebo-treated patients for all
QoL domains (significant in three)
10 point change from baselineat any time
(clinically significant)
Bezjak, et al. JCO 2006
12
Tarceva achieves similar efficacy to chemotherapy
in second-line setting
Results cannot be compared directly due to
different patient populations
1Shepherd, et al. NEJM 2005 2OSI and Roche, data
on file3Shepherd, et al. JCO 2000 4Fossella, et
al. JCO 20005Hanna, et al. JCO 2004 6Cullen, et
al. JCO 2007
13
Further evidence for similar efficacy of
chemotherapy and EGFR TKIs
INTEREST phase III trial comparing gefitinib and
docetaxel in second or third-line setting (84
second-line)
1.0 0.8 0.6 0.4 0.2 0
Probability of survival
0 4 8 12 16 20 24 28 32 36 40 Months
Douillard, et al. J Thorac Oncol 2007 Thatcher,
et al. Lancet 2005
14
Some patient groups have better survival outcomes
regardless of treatment received
Gender
Ethnicity
1.0 0.8 0.6 0.4 0.2 0
1.0 0.8 0.6 0.4 0.2 0
Gefitinib
Gefitinib
Gefitinib
Gefitinib
Survival probability
Survival probability
Women
Asian
Non-Asian
Men
0 4 8 12 16 20 24 28 32 36
0 4 8 12 16 20 24 28 32 36
Time (months)
Time (months)
Histology
Smoking history
1.0 0.8 0.6 0.4 0.2 0
1.0 0.8 0.6 0.4 0.2 0
Gefitinib
Gefitinib
Gefitinib
Gefitinib
Survival probability
Survival probability
Never smoker
Adeno
Non-adeno
Smoker
0 4 8 12 16 20 24 28 32 36
0 4 8 12 16 20 24 28 32 36
Time (months)
Time (months)
Douillard, et al. J Thorac Oncol 2007
Results from INTEREST trial
15
Some patient groups have better survival outcomes
regardless of treatment received
Gender
Ethnicity
1.0 0.8 0.6 0.4 0.2 0
1.0 0.8 0.6 0.4 0.2 0
Gefitinib Docetaxel
Gefitinib Docetaxel
Survival probability
Survival probability
Women
Asian
Non-Asian
Men
0 4 8 12 16 20 24 28 32 36
0 4 8 12 16 20 24 28 32 36
Time (months)
Time (months)
Histology
Smoking history
1.0 0.8 0.6 0.4 0.2 0
1.0 0.8 0.6 0.4 0.2 0
Gefitinib Docetaxel
Gefitinib Docetaxel
Survival probability
Survival probability
Never smoker
Adeno
Non-adeno
Smoker
0 4 8 12 16 20 24 28 32 36
0 4 8 12 16 20 24 28 32 36
Time (months)
Time (months)
Douillard, et al. J Thorac Oncol 2007
Results from INTEREST trial
16
Tarceva has better tolerability than chemotherapy
Importantly, Tarceva does not produce
haematological toxicity
1Shepherd, et al. NEJM 20052Tarceva Summary of
Product Characteristics 3Ramalingam Sandler.
Oncologist 2006
17
Favourable safety profile observed in BR.21
confirmed in gt7,000 patients in TRUST
100 80 60 40 20 0

• Grade 12 rash remains the most commonly reported
  adverse event
• Most of these cases are manageable with topical
  emollients
• Higher grades of rash can still be managed, but
  may require dose reduction and/or interruption

Grade 12
Grade 3
Incidence of rash ()
BR.211(n727)
TRUST2(n6,153)
1Tarceva Summary of Product Characteristics 2Ardiz
zoni, et al. J Thorac Oncol 2007
18
Tarceva has demonstrated survival benefit
irrespective of patient characteristics
Tarcevaplacebo PS 01 0.73 (0.60.9) PS 23
0.77 (0.61.0) Male 0.76 (0.60.9) Female
0.80 (0.61.1) lt65 years 0.75 (0.60.9) ?65
years 0.79 (0.61.0) Adenocarcinoma 0.71
(0.60.9) Squamous-cell carcinoma 0.67
(0.50.9) Other histology 1.04 (0.71.5) Prior
weight loss lt5 0.77 (0.60.9) Prior weight
loss 510 0.63 (0.41.0) Prior weight loss
gt10 0.70 (0.41.1) Never-smoker 0.42
(0.30.6) Current/ex-smoker 0.87 (0.71.1) 1
prior regimen 0.76 (0.61.0) 2 prior regimens
0.75 (0.61.0)
All patient subgroups in BR.21 derived clinical
benefit from Tarceva
Factors
0 1 2
HR
Shepherd, et al. NEJM 2005Tarceva Summary of
Product Characteristics
HR lt1 improved survival with Tarceva
19
Tarceva has demonstrated survival benefit
irrespective of EGFR biomarker status
0.47
0.25
0.12
p-value for subgroup compared with
placebo p-value for interaction CI confidence
interval FISH fluorescent in-situ
hybridisation IHC immunohistochemistry
Tsao, et al. NEJM 2005 Shepherd, et al. JCO 2007
20
MERIT multicentre phase II trial to identify
genes predicting for clinical benefit with Tarceva

• 264 patients
• Bronchoscopy before starting Tarceva
• 3 genes expressed at higher levels in the
  responding group (PSPH, RAPGEF5 and EGFR)
• Higher response rate in EGFR FISH (11) vs FISH
  (0), but no significant difference in PFS
• KRAS mutations observed in 10 patients
• 4 SD (2 gt12 weeks) / 5 PD / 1 NE
• 1 PR observed among 20 patients with KRAS
  mutations in BR.21 study (Shepherd et al. 2007)

Reck, et al. Eur J Cancer Suppl 2007 Roche, data
on fileShepherd, et al. JCO 2007
NE non-evaluable PD progression of
disease PR partial response SD stable disease
21
Challenges in identifying and implementing a
biomarker for Tarceva

• Validation of potential biomarkers
• Differentiation between prognostic andpredictive
  value
• this can only be confirmed in large prospective,
  randomised trials
• Standardisation of assays
• Obtaining adequate quality samples

22
Identifying a biomarker for Tarceva extensive
trial programme
RADIANTn945
EGFR IHC/FISH-positive patients
Adjuvant
EURTAC(monotherapy) n146
EGFR mutation-positive patients
Stratified by EGFR IHC status plus other
biomarker analyses
SATURN(maintenance) n1,700
First-line
FAST-ACT(intercalated)n154
EGFR IHC/FISH, MAPK/pAKT IHC, EGFR and KRAS
mutations
23
Conclusions

• Tarceva in second-line NSCLC
• is the only anti-EGFR agent with proven survival
  and symptom benefit versus placebo
• has similar efficacy to chemotherapy and
  isbetter tolerated
• All patient subgroups appear to derive
  benefitfrom Tarceva
• all patients can therefore be considered
  forTarceva therapy
• extensive ongoing clinical trial programme to
  identify biomarkers and further define role of
  Tarceva in NSCLC