master template

1
Novelties in the treatment of NSCLC
Are there any???? Denis Soulières, MD,
MSc Hematologist and Medical Oncologist CHUM
2
Adjuvant therapy for NSCLC

• Choosing the adequate patient ?

3
Adjuvant chemotherapy studiesfrom ASCO 2003-2005
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ASCO 2004 HR 0,62 90CI 0,44-0,89 p0,01
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No recent clinical trial has shown a
statistically significant survival advantage from
platinum based adjuvant therapy for patients with
Stage 1B non-small cell lung cancer (NSCLC).
Meta-analyses suggest a trend toward a benefit,
but do not unambiguously confirm a benefit.
Based on the results in Stage 2 and 3A disease
and trends in some recent trials Adjuvant! uses
an estimate of a 20 proportional risk reduction
for platinum doublets such as cisplatin/vinorelbin
e, but this estimate is controversial and might
be too high.
16
Pt selection in adjuvant trials
17
Age as a selection criteria
18
Age and NSCLC

• Mean age of patients 69 ans
• Comorbidities
• Polypharmacopeia
• Biology of NSCLC related to age ?
• Elderly very poorly represented in adjuvant
  studies
• practically absent over 75 yrs.

19
Evaluation tools

• Comprehensive geriatric assessment (CGA)
•  gold standard 
• Simplified screening tools
•  Cardiovascular health study 
• Vulnerable elderly study 13
• EORTC-QLQ C30
• Biologic markers
• Albumine, Clairance créatinine, Hb

20
Pepe et al, ASCO 2006
21
Pepe et al, ASCO 2006
22
NCCN recommendations for geriatric assessment in
oncology

• Geriatric assessment warranted if gt 70 age
• ClCreat determination if gt 65 age
• G-CSF if NF risk CHOP (estimated gt 20)
• 7 for BR.10 12,5 for ANITA
• Try to maintain Hb 12 g/L
• Preferential selection of chemotherapy with low
  toxicity profile

23
Cell regulation complex molecular interactions
Anti-growth factors (e.g. TGF-b)
Tubulin
WNT
Disheveled
Frizzled
GSK-3b
TCF
APC
TGFbR
Cells
b-Catenin
b-CateninTCF
E-Cadherin
p16
CdC42
PI3K
Rac
ECM
Integrins
Cycl DCDK4
p15
Smads
Fak
Cas
Crk
Src
Rb
HPVE7
PLC
p27
Fyn
Growth factors (e.g. EGF, amphiregulin TGF-a)
Shc
E2Fs
Surface Ag
MKKs
JNKs
JUN
Cycl ECDK2
p21
NF1
PKC
Mos
DNA damage sensor
Grb2
Changes in gene expression
Ras
Ral
MEK
MAPK
MAPK
ELK
Fos
RTK
Cell proliferation (cell cycle)
SOS
MaxMax
p53
MEKK
MycMax
Hormones (e.g. bombesin)
Abl
CdC42
Rac
Rho
G-Prol
PKA
CREB
ARF
Ad Cycl
MDM2
7-TMR
Nuclear receptors (e.g. oestrogen)
Bax
NHR (e.g. ER)
PKC
NF-kB
NF-kB
Mitochondria
Stat 3.5
Survival factors (e.g. IGF1)
Cell death (Apoptosis)
Bcl 2
P13K
Akt
Akka
IKB
RTK
Caspase 8
FADD
Stat 3.5
PTEN
?
Caspase 9
FAP
Fas
Cytochrome C
Bcl XL
Stat 3.5
Bcl 2
Decoy R
Bid
Bad
Mitochondria
Jaks
Deathfactors (e.g. FasL)
Abnormality sensor
Bim, etc.
Cytokine R
Cytokines (e.g. ILs, IFNs)
24
JBR.10 ESMO 2004

• Mutation ras
• Survival   observation 6.54 yrs (CI
  3.97-infini), chemo 6.25 yrs (CI
  5.28-infini)
• HR 0.96, CI .53-1.74 P 0.44
• WT
• Survival  observation 6.17 yrs (CI
  3.79-infini), chemo not reached (CI
  6.09-infini)
• HR 0.74, CI .52-1.05 P 0.04

25
K-ras mutations

• 3 ras genes
• K-ras
• N-ras
• H-ras
• gt95 of mutations occur in K-ras
• 3 sites of mutation in K-ras
• Codon 12
• Codon 13
• Codon 62
• gt90 of mutations occur at locus codon 12

26
K-ras, PCR-RFLP
Codon 12 GGT/WT
Codon 12 TGT/Mut GTT/Mut GAT/Mut GCT/Mut CGT/Mut A
GT/Mut
27
Sensitivity of regular K-ras PCR assay for codon
12

• Can detect heterozygous K-ras mutations at a
  level of up to 0.01 in specialized laboratories
• Can be done on cytology
• Will not detect mutations caused by formalin
  fixation (which happens for sequencing)
• Can be applied in many laboratories

28
Conclusion

• Practically speaking
• Primary selection by the thoracic surgeon
• Medical oncology consultation for eligible
  patients
• Multidisciplinary tumor board for difficult cases
  
• Neoadjuvant therapy
• Combined modality therapy
• Patient selection
• Stage II
• Rarely stage IB or III (tumor board)
• Consideration K-RAS and ERCC1 (borderline pts)
• Preferred treatment
• Clinical trials
• Standard of care cisplatin-vinorelbine (4
  cycles)

29
NSCLC Optimizing combination therapies in the
first-line setting
New evidence
30
Therapeutic needs in NSCLC

• Primary
• prolonged survival time
• Secondary
• improved disease-related symptoms/QoL
• better-tolerated regimens
• regimens for patients not suitable for
  chemotherapy e.g. the elderly

31
The current treatment algorithm
32
ECOG 1594 First-Line Platinum-Based Combination
Chemotherapies for Advanced NSCLCSurvival
Median Survival (mo)
100
Paclitaxel/cisplatin 7.8 Gemcitabine/cisplatin
8.1 Docetaxel/cisplatin 7.4 Paclitaxel/carbopl
atin 8.1
80
60
Survival
40
20
0
0
5
10
15
20
25
30
Months
P not significant vs paclitaxel/cisplatin. Sch
iller et al. N Engl J Med. 200234692.
33
Recent results with chemotherapy strategies

• Highlights from recent phase III trials

34
Docetaxel vs vinorelbine in elderly patients

• Improvement in most QoL parameters was better
  with docetaxel compared with vinorelbine
• Docetaxel was associated with more toxicities
  than vinorelbine in this setting

Takeda K, et al. J Clin Oncol 200523(Suppl)623s
Abstr 7009
35
Triplets vs doublets

• Previous trials with triplets with cytotoxics
  have demonstrated an advantage on RR, but not for
  OS
• Cis/Gem vs Cis/Vino vs Cis/Gem/Vino
• Previous trials with doublet cytotoxic therapy
  biologic modifier have not reported an advantage
  in survival
• MMPIs
• EGFR inhibitors

36
Tarceva and gefitinib phase III combination
trials in advanced NSCLC
INTACT I gefitinib gemcitabine/cisplatin
No difference in OS vs chemotherapy
INTACT II gefitinib paclitaxel/carboplatin
Never-smokers OS, PFS increased (HR 0.39 0.195)
TALENT Tarceva gemcitabine/cisplatin
All patients no difference in OS vs chemotherapy
TRIBUTE Tarceva paclitaxel/carboplatin
Never-smokers OS Tarceva 22.5 months placebo
10.1 months p0.01
37
Angiogenesis is involved throughout tumour
formation, growth and metastasis
Premalignant stage
Malignant tumour
Tumourgrowth
Vascularinvasion
Dormantmicrometastasis
Overtmetastasis
(Avascular tumour)
(Angiogenicswitch)
(Vascularisedtumour)
(Tumour cellintravasation)
(Seeding indistant organs)
(Secondary angiogenesis)
Stages at which angiogenesis plays a role in
tumour progression
Adapted from Poon RT, et al. J Clin Oncol
200119120725
38
The Normal Angiogenic Process
Intravascular modulators of angiogenesis
Griffioen and Molema. Pharmacol Rev. 200052237.
39
Normal and Tumor Vasculature
Growth and survival factors (eg, VEGF) present
Highly permeable
Lowpermeability
Fewer pericytes
Pericytes present
Low integrinexpression
Upregulation of integrins
Blau and Banfi. Nat Med. 20017532.Jain. Nat
Med. 20017987.
40
Antiangiogenic Therapies May Normalize
Vasculature Structure and Function
Abnormal
Normalized
Normal
Antiangiogenictherapy
Tumorformation
Jain. Science. 200530758.
41
VEGF A Central Mediator of Angiogenesis
Environmental factors (hypoxia, low pH) Growth
factors Hormones (EGF, bFGF, PDGF, IGF-1,
IL-1a)
Tumor suppressor genes (p53) Oncogenes (src, ras)
Increased VEGF levels
Binding and activation of VEGFR
Endothelial cell activation
Proliferation
Survival
Migration/invasion
Permeability
ANGIOGENESIS
Dvorak. J Clin Oncol. 2002204368. Ebos et al.
Mol Cancer Res. 2002189. Ferrara et al. Nat
Med. 20039669.
42
Bevacizumab

• Recombinant humanized monoclonal IgG1 antibody1
• Recognizes all isoforms of VEGF-A2
• Estimated half-life is approximately 20 days
  (range, 11-50)1

1. Avastin (bevacizumab) PI. 2. Presta et al.
Cancer Res. 1997574593.
43
Bevacizumab, Carboplatin, and Paclitaxel Phase II
First-Line Trial in NSCLC (AVF0757s) Design
CP 6

• Previously untreated stage IIIB/IV NSCLC
• N99

CP 6 low-dose bevacizumab (7.5 mg/kg q3w ?
18 or to PD)
RANDOMIZATION
CP 6 high-dose bevacizumab (15 mg/kg q3w ?
18 or to PD)

• End points include TTP, DOR, and survival
• Chemotherapy administration
• Paclitaxel 200 mg/m2 IV q3w
• Carboplatin AUC 6 q3w following paclitaxel
  infusion

111 randomization. Permitted to receive
bevacizumab (15 mg/kg) upon disease
progression. Johnson et al. J Clin Oncol.
2004222184.
44
Bevacizumab, Carboplatin, and Paclitaxel Phase II
First-Line Trial in NSCLC (AVF0757s) Efficacy
P0.02 vs control. Johnson et al. J Clin Oncol.
2004222184.
45
Bevacizumab adverse events

• Six life-threatening haemorrhages
• all had central lesions (gt3cm)
• five occurred in low-dose bevacizumab group
• four were fatal
• three occurred late (gt200 days)
• Haemorrhages in squamous cell gt adenocarcinoma
• incidence in squamous cell 4/13 (31)
• incidence in adenocarcinoma 2/54 (4)

Johnson DH, et al. J Clin Oncol 200422218491
46
Bevacizumab, Carboplatin, and Paclitaxel Phase II
First-Line Trial in NSCLC (AVF0757s) Conclusions

• Safety
• 6 life-threatening hemorrhages (4 were fatal)
• Overall incidence 9 (6/66)
• 5 occurred at bevacizumab 7.5 mg/kg
• Apparent risk factors
• Baseline hemoptysis
• Squamous cell histology (risk factor 31 vs 4
  in nonsquamous histology)
• Similar bleeds not seen in other solid tumor
  trials
• Efficacy
• Bevacizumab 15 mg/kg selected as optimal dose to
  use in phase III trials

Johnson et al. J Clin Oncol. 2004222184.
47
Carbo/Taxol rhuMAb-VEGF in NSCLCSubset
Analysis of Non-SqC Ca Pts.
48
Phase III trial of Avastin in NSCLC(ECOG 4599)
study design
CP ? 6 (n444)
PD
Previously untreated stage IIIb/IV non-squamous
NSCLC (n878)
Avastin (15mg/kg) every 3 weeks CP ? 6 (n434)
Avastin every 3 weeks until progression
PD

• Primary objective to assess overall survival in
  patients with advanced non-squamous NSCLC treated
  with CP versus CP Avastin
• Secondary objective to assess response rates,
  time to progression and toxicity

No cross over will be permitted
Sandler A, et al. J Clin Oncol 200523(June 1
Suppl.)2s (Abstract LBA4)
49
Bevacizumab, Carboplatin, and Paclitaxel Phase
III First-Line Trial in NSCLC (E4599) Key
Inclusion Criteria

• Chemotherapy-naive stage IIIB (pleural or
  pericardial effusion only) or stage IV
  nonsquamous NSCLC
• Measurable or nonmeasurable disease
• ECOG PS 0-1

Based on the apparent risk factor for hemorrhage
noted in the phase II trial of CP bevacizumab
(AVF0757s), the E4599 trial involved only
patients with nonsquamous NSCLC as the
predominant cell type. Sandler et al. ASCO,
2005. Abstract LBA4 and oral presentation.
50
Bevacizumab, Carboplatin, and Paclitaxel Phase
III First-Line Trial in NSCLC (E4599) Key
Exclusion Criteria

• Squamous NSCLC
• INR ?1.5 and a PTT greater than upper limits of
  normal within 1 week prior to randomization
• History of thrombotic or hemorrhagic disorders
• History of hypertension
• Gross hemoptysis
• Brain metastases
• Therapeutic anticoagulant

Defined as bright red blood of a ½ teaspoon or
more. Sandler et al. ASCO, 2005. Abstract LBA4
and oral presentation.
51
Bevacizumab, Carboplatin, and Paclitaxel Phase
III First-Line Trial in NSCLC (E4599) Patient
Characteristics
Sandler et al. ASCO, 2005. Abstract LBA4 and oral
presentation.
52
Phase III trial of Avastin in NSCLC (E4599)
efficacy
Sandler A, et al. J Clin Oncol 200523(June 1
Suppl.)2s (Abstract LBA4)
53
Bevacizumab, Carboplatin, and Paclitaxel Phase
III First-Line Trial in NSCLC (E4599) PFS
6 mo 12 mo 32.6 6.4 55.0 14.6
CP
BCP
HR 0.62 (0.53, 0.72) Plt0.0001
Medians 4.5, 6.4
0
6
12
18
24
30
36
Months
Sandler et al. ASCO, 2005. Abstract LBA4 and oral
presentation.
54
Bevacizumab, Carboplatin, and Paclitaxel Phase
III First-Line Trial in NSCLC (E4599) OS
12 mo 24 mo 43.7 16.9 51.9 22.1
CP
BCP
HR 0.77 (0.65, 0.93) P0.007
Medians 10.2, 12.5
0
6
12
18
24
30
36
Months
Sandler et al. ASCO, 2005. Abstract LBA4 and oral
presentation.
55
Bevacizumab, Carboplatin, and Paclitaxel Phase
III First-Line Trial in NSCLC (E4599)
Hematologic Toxicity
Includes 1 death on each arm due to neutropenic
fever. Sandler et al. ASCO, 2005. Abstract LBA4
and oral presentation.
56
Bevacizumab, Carboplatin, and Paclitaxel Phase
III First-Line Trial in NSCLC (E4599)
Nonhematologic Toxicity
Sandler et al. ASCO, 2005. Abstract LBA4 and oral
presentation.
57
Bevacizumab, Carboplatin, and Paclitaxel Phase
III First-Line Trial in NSCLC (E4599)
Treatment-Related Deaths
No. of Pts

• CP BCP (n427) (n420)
• Hemorrhage 1 7
• Hemoptysis 0 5
• GI bleed 1 2
• Neutropenic fever 1 1
• Total 2 8

Sandler et al. ASCO, 2005. Abstract LBA4 and oral
presentation.
58
Bevacizumab, Carboplatin, and Paclitaxel Phase
III First-Line Trial in NSCLC (E4599) Conclusions

• Bevacizumab improves survival whenadded to CP
  chemotherapy in patients with nonsquamous NSCLC
• Bevacizumab also improves response rate and PFS
• Bevacizumab is associated with a significant
  increase in serious bleeding (from 0.7 to 4.5
  Plt0.001), including hemoptysis (from 0.2 to
  1.9 P0.04)

Sandler et al. ASCO, 2005. Abstract LBA4 and oral
presentation.
59
Bevacizumab, Carboplatin, and Paclitaxel Phase
III First-Line Trial in NSCLC (E4599)
Conclusions (contd)

• BCP is now the ECOG reference standard for the
  first-line treatment of advancednonsquamous cell
  NSCLC
• Future plans include
• Combination with chemotherapy and radiotherapy
• Combination with other targeted agents
• Neoadjuvant and adjuvant settings

Sandler et al. ASCO, 2005. Abstract LBA4 and oral
presentation.
60
Bevacizumab in Combination with Chemotherapy

• Unanswered Questions
• Is Bevacizumab effective in combination with
  other regimens?
• Duration of therapy with Bevacizumab ? Role of
  maintenance
• Should it be administered with second-line
  therapies ? Do tumors become resistant?
• Should it be restricted to non-squamous patients
  without brain metastasis?
• Is the efficacy same in males and females?
• Is there enough information to declare it the new
  standard for nonsquamous patients?

61
Planned phase III trial of Avastin in NSCLC
(BO17704)
No Avastin after progression
PD
CG ? 6 placebo
Previously untreated, stage IIIb, IV or recurrent
NSCLC (n830)
CG ? 6 Avastin 7.5mg/kg every 3 weeks
PD
CG ? 6 Avastin 15mg/kg every 3 weeks
PD

• Two-stage design
• initially, 210 patients will be randomised to one
  of the three arms (111)
• following assessment, randomisation will continue
  to the CG plus placebo arm and one of the Avastin
  dose arms (11)
• no cross over allowed
• Cisplatin 80mg/m2 i.v. every 3 weeks gemcitabine
  1,250mg/m2 on days 1 and 8 of each 3-week cycle
• Primary endpoint overall survival
• Secondary endpoints include progression-free
  survival and response rate

CG cisplatin/gemcitabine
62
The current treatment algorithm
63
A new era in targeted therapy for NSCLC Who can
benefit?

• Biomarkers Should we use them?

64
Clonal events associatedwith NSCLC

• Clonality
• recurring cytogenetic anomaly
• Under-documented
• multiple cytogenetic anomalies
• primary or secondary?
• most associated with deletion of suppressor genes
  and/or LOH
• 9p deletion more frequently encountered
• less than 10 of cases
• not associated with different response to therapy
• not associated with specific histology

65
Cancer cellsDysregulation of many molecules
Antigrowth factors (e.g. TGF-b)
Tubulin
WNT
Dishevelled
Frizzled
GSK-3b
Clonal events necessary for proliferation?
TCF
APC
TGF bR
Cells
b-Catenin
b-CateninTCF
E-Cadherin
p16
CdC42
PI3K
Rac
ECM
Integrins
Cycl DCDK4
p15
Smads
Fak
Cas
Crk
Src
Rb
HPVE7
PLC
p27
Fyn
Growth factors (e.g. EGF, amphiregulin TGF-a)
Shc
E2Fs
Surface Ag
MKKs
JNKs
JUN
Cycl ECDK2
p21
NF1
PKC
Mos
DNA damage sensor
Grb2
Changes in gene expression
Ras
Ral
MEK
MAPK
MAPK
ELK
Fos
RTK
Cell proliferation (cell cycle)
SOS
MaxMax
p53
MEKK
MycMax
Hormones (e.g. bombesin)
Abl
CdC42
Rac
Rho
G-Prol
PKA
CREB
ARF
Ad Cycl
MDM2
7-TMR
Nuclear receptors (e.g. oestrogen)
Bax
NHR (e.g. ER)
PKC
NF-kB
NF-kB
Mitochondria
Stat 3.5
Survival factors (e.g. IGF1)
Cell death (apoptosis)
Bcl 2
P13K
Akt
Akka
IKB
RTK
Caspase 8
FADD
Stat 3.5
PTEN
?
Caspase 9
FAP
Fas
Cytochrome C
Bcl XL
Stat 3.5
Bcl 2
Decoy R
Bid
Bad
Mitochondria
Clonal events create oncogene addiction?
Jaks
Deathfactors (e.g. FasL)
Abnormality sensor
Bim, etc.
Cytokine R
Cytokines (e.g. ILs, IFNs)
66
Impact of increased TK activity
Exponential
Scale free

• Imbalance in equilibrium between the different
  cellular-activation pathways
• Identification of TK or other molecules playing
  a central role in cellular proliferation
• Clonality
• Oncogene addiction?

TK tyrosine kinase
67
Effects of HER1/EGFR activation
Extracellular
Intracellular
Transactivation
P
P
Src PLCg GAP Grb2 Shc Nck Vav Grb7 Crk
PKC
Ras
Abl
JNK
PI3K Akt
MAPK
Proliferation, invasion, metastasis,
angiogenesis, and inhibition of apoptosis
Woodburn J. Pharmacol Ther 19998224150 Lynch
TJ, et al. N Engl J Med 2004350212939Knowlden
JM, et al. Endocrinology 20031441032 44
Chakravarti A, et al. Cancer Res 200262430715
68
A Randomized Placebo Controlled Study of
Erlotinib (OSI-774, Tarceva?) versus Placebo in
Patients with Incurable Non-Small Cell Lung
Cancer Who Have Failed Standard Therapy for
Advanced or Metastatic DiseaseNational Cancer
Institute of Canada Trial BR.21 Clinical
Predictors of Response and Prognostic Markers of
Survival

FA Shepherd, MD FRCPC
Scott Taylor Chair in Lung Cancer
Research Princess Margaret Hospital,
Professor of Medicine,
University of Toronto
69
BR.21 Study Design - 2
Erlotinib 150 mg daily
RANDOM I ZE
Stratified by Centre PS, 0/1 vs 2/3 Response to
prior Rx (CR/PRSDPD) Prior regimens, (1
vs 2) Prior platinum, (Yes vs no)
Placebo 150 mg daily
21 Randomization
70
BR.21 Study Endpoints

• Primary
• Overall survival
• Secondary
• Time to deterioration of cough, dyspnea and pain
  (QoL, QLQC30 QLQCLC13)
• Progression-free survival
• Response rate duration of response
• Toxicity tolerability

71
BR.21 Patient Characteristics
72
BR.21 Patient Characteristics
73
BR.21 Progression Free Survival
___ Erlotinib, _____ Placebo 2.2
mos 1.8 mos

HR 0.61, p lt0.0001
Months
Adjusted for stratification factors (except
centre) AND EGFR status
74
BR.21 Overall Survival
___ Erlotinib, _____ Placebo 6.7
mos 4.7 mos

HR 0.71, p lt0.0001
31
21
Adjusted for stratification factors (except
centre) AND EGFR status
Months
75
BR.21 adverse events ()
76
Trial 709Clinical Trial Design
1692 patients in 210 centers across 28
countries Stratified for histology, gender,
intolerant/refractoryand smoking history
IRESSA (250 mg) BSC
Primary endpoint SURVIVAL
Randomization
21 ratio
Placebo BSC
77
Endpoints and Methods

• Primary endpoint overall survival
• Stratified log-rank test
• Cox regression supportive
• Overall and adenocarcinoma populations co-primary
• At least 900 deaths for 90 power
• Secondary endpoints time to treatment failure,
  objective response, QoL, symptoms, and safety
• Several pre-planned subgroup analyses
• Outcomes in relation to clinical and biologic
  factors

78
Phase III studies of Tarceva and Iressa study
design
1Shepherd FA, et al. N Engl J Med 200535312332
2Thatcher N, et al. Lancet 2005366152737
79
Comparison of patient characteristics between
ISEL and BR.21
80
Overall PopulationSurvival
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
Patients surviving ()
IRESSA ------ Placebo
Month 0 2 4 6 8 10 12 14 At risk 1692 1348 876
484 252 103 31
81
Is there any biomarker for EGFR-TKIs ?
82
Gene overexpression

• Decreased mRNA degradation?
• Increased mRNA
• Gene amplification and transcription
• Protein modification and escape from
  ubiquitination

83
Gene overexpression

• Decreased mRNA degradation?
• Increased mRNA
• Gene amplification and transcription
• Protein modification and escape from
  ubiquitination

84
HER1/EGFR IHC tumours showing membranous
staining in ?10 of tumour cells
Incomplete membrane and cytoplasmic staining
Complete membrane staining
Of any intensity
Tsao M-S, et al. N Engl J Med 200535313344
85
EGFR IHC status in BR.21 and ISEL
Cut-off of 10 cells positive for membranous
staining Cut-off score200 (intensity
multiplied by fraction of positive cells)
Hirsch FR, et al. Proc AACR-NCI-EORTC Int Conf
Mol Targets Cancer Ther 2005124 Abs. A268Tsao
M-S, et al. N Engl J Med 200535313344
86
BR.21 and ISEL survival according to EGFR IHC
status
87
Gene overexpression

• Decreased mRNA degradation?
• Increased mRNA
• Gene amplification and transcription
• Protein modification and escape from
  ubiquitination

88
EGFR FISH scoring categories(Cappuzzo et al.)
Cappuzzo F, et al. J Natl Cancer InstI
20059764355
89
EGFR gene copy number in BR.21 and ISEL
FISH -
FISH
Hirsch FR, et al. Proc AACR-NCI-EORTC Int Conf
Mol Targets Cancer Ther 2005124 Abs. A268Tsao
M-S, et al. N Engl J Med 200535313344
90
BR.21 and ISEL survival according to EGFR FISH
status
91
Gene overexpression

• Decreased mRNA degradation?
• Increased mRNA
• Gene amplification and transcription
• Protein modification and escape from
  ubiquitination

92
HER1/EGFR gene

• Genomic context chromosome 7, band p12
• Length 188329bp
• Exons 28
• kinase domain exons 1824
• Transcript length 5599bp
• Translation length 1,210 residues

93
HER1/EGFR mutations map
Leu858 (Paez)
Thr766 (Blencke)
gefitinib, TarcevaTM
Gly719 (Lynch)
E746-I757 deleted region (Lynch)
In red, ATP binding site
Blencke S, et al. J Biol Chem 20031543540
Lynch TJ, et al. N Engl J Med 2004350212939
Paez JG, et al. Science 20043041497500
94
Known HER1/EGFR activating mutations underlying
NSCLC sensitivity to gefitinib or TarcevaTM
Sensitive to gefitinib Sensitive to
TarcevaTM Never treated with TKI
Pao W, et al. Proc Natl Acad Sci USA
20041011330611
95
Autophosphorylation sites and major signal
transduction pathways
Sordella R, et al. Science 200430511637
96
(No Transcript)
97
Updated BR.21 mutation survival results
Exon 19 deletions and L858R mutations
Wild-type EGFR and indeterminate variants
100 80 60 40 20 0
100 80 60 40 20 0
Tarceva Placebo
Tarceva Placebo
Log-rank p0.16HR0.52 (95CI 0.211.31)
Log-rank p0.11HR0.75 (95CI 0.531.07)
Survival ()
Survival ()
0 6 12 18 24
0 6 12 18 24
Months
Months
At riskTarcevaPlacebo
10 6 5 1 0 14 7 5 1 0
120 69 38 9 0 57 24 12 6 0
p value for interaction 0.45
Tsao M-S, et al. N Engl J Med 20063545278
98
Frequency of deaths in ISEL according to mutation
status and treatment arm
99
Survival benefit with Tarceva according to EGFR
biomarker status
0.45
0.25
0.10
p value for subgroup compared with placebo p
value for interaction includes indeterminate
variants exon 19 deletions and L858R
Tsao M-S, et al. N Engl J Med 200535313344 Tsao
M-S, et al. N Engl J Med 20063545278
100
Survival benefit with gefitinib according to EGFR
biomarker status
-
0.05
0.04
p value for subgroup compared with placebo p
value for interaction
101
The current treatment algorithm
102
Conclusion

• Adjuvant therapy
• Selection of patient
• Cis/Vinorelbine a standard
• First-line chemo for stage IV
• Elderly Consider Docetaxel
• Addition of bevacizumab?
• Secondline therapy for stage IV
• No recognized marker of increased benefit
• Erlotinib (Tarceva) only drug approved in Canada

103
The End !!