LUNG CANCER

1

• LUNG CANCER
• MOLECULAR THERAPY
• Prof. Dr. Can ÖZTÜRK
• Gazi University School of
  Medicine
• Department of Pulmonology

2
Turkey - Male (All ages)
Crude Rate ASR (World)
Lung 37.3 47.7
Stomach 9.6 12.2
Bladder 8.6 11.0
Colorectal 7.4 9.1
Larinx 6.4 8.0
Prostate 6.1 8.0
Leukemia 5.1 5.8
Brain,CNS 3.9 4.5
NHL 3.3 3.8
Oral cavity 2.6 3.2
Total(except skin) 110.3 137.3
per 100.000
3
Turkey - Female (All Ages)
Crude Rate ASR (World)
Breast 19.9 22.0
Colorectal 7.6 8.5
Stomach 5.7 6.4
Ovarium 4.8 5.4
Lung 4.6 5.3
Leukemia 4.4 4.7
Corpus-Uterus 4.1 4.8
Cervix- Uterus 4.0 4.5
Brain, CNS 3.5 3.8
Non-Hodgkin lenfoma 2.9 3.1
Total(except skin) 82.0 91.2
per 100.000
4
UNTREATED NSCLC- PROGNOSIS
STAGE MS(Mts) 1yr. Sur.() 2yr. Sur.()
c I, II 13 56 8
c III 4-9 16-30 0-4
c IV 3 - -
5
UNTREATED SCLC- PROGNOSIS
STAGE MEDIAN SUR. 1 YR. SURVIVAL
LIMITED Supportive Care 12 weeks 18 weeks 7
EXTENSIVE Supportive Care 5 weeks 8 weeks
6
Treatment- Prognosis

• Status of treatment is dismal
• Five year survival approx. 15
• 61 for Colon
• 86 for Breast
• 96 for Prostate

7
NSCLC Survival based on stages
Greene et al, eds. AJCC Cancer Staging Manual.
6th ed. 2002.
8
5 year survival - TARGETS

• NSCLC CURRENT TARGET
• STAGE
• IA 70-85 85-95
• IB 60-70 70-85
• IIA 35-45 45-60
• IIB 25-35 35-45
• IIIA 5-20 20-30
• IIIB 3-7 10-20
• IV lt1 2-5

• SCLC CURRENT TARGET
• STAGE
• LTD 15-25 25-30
• EXT lt1 2-5

Langer CJ, Fox Chase Cancer Center-2006
9
NSCLC- Systemic Therapy

• Uptodate standart therapies
• Epidermal Growth Factor Receptor (EGFR)
  Inhibitors
• Gefitinib (Iressa)
• Erlotinib (Tarceva)
• Anti-EGFR Monoclonal antibodies
• Cetuximab (Erbitux)
• Anti-Vascular Endothelial Growth Factor (VEGF)
  Monoclonal antibody
• Bevacizumab (Avastin-Altuzan)

10
Systemic Therapy First Line

• 2-drug platinum-based combinations

2 drug platinum based regimens
Schiller JH. NEJM 2002 34692-98
11
Results- First Line
Survival
Medan survival 8 months
Response rate 19
TTP
MedianTTP 3.7 months
Schiller JH. NEJM 2002 34692-98
12
Second Line Therapies

• Docetaxel is superior than best supportive care
• Response rate 7
• Median survival 7.0 vs 4.6 months
• Median TTP 10.6 vs. 6.7 weeks
• Pemetrexed (Alimta) is effective as docetaxel,
  but less toxicity profile

Shepherd et al. JCO 2000182095-2103 Hanna et
al. JCO 2004 221589-97
13
Targeted Therapies in Lung Cancer
General Spesific
Cell Cycle cdks
Apoptosis Bcl-2 Survivin XIAP P53 clusterin
Others DNA MTase HDAC proteosom
Extracellular MMP
Receptors/ kinases C-kit PDGFR abl
General Spesific
Angiogenesis VEGF VEGFR FGF Integrin
EGFR family EGFR HER2
Signal Ras Raf kinaz MEK mTOR PKC
14
Targeted Therapies

• EGFR Inhibitors
• Gefitinib (Iressa)
• Erlotinib (Tarceva)
• Anti-EGFR Monoclonal antibody
• Cetuximab (Erbitux)
• Anti-VEGF Monoclonal antibody
• Bevacizumab (Avastin-Altuzan)

15
Epidermal Growth Factor Receptor (EGFR) Human
Cancer

• EGFR critically regulates tumor cell division,
  proliferation, repair
• EGFR may play a critical role in metastasis,
  angiogenesis, invasion
• Binding of specific ligands to EGFR (eg, EGF,
  TGF-a) activates the receptor and triggers signal
  transduction cascades that affect cell
  proliferation
• EGFR is expressed in a significant percentage of
  human tumors and is correlated with poor
  prognosis, decreased survival, and/or increased
  metastasis
• Inhibition of EGFR on tumor cells may inhibit the
  growth or progression of EGFR-expressing tumors

16
EGFR structure
Extracellular area
Transmembranous area
Intracellular area
17
(No Transcript)
18
(No Transcript)
19
(No Transcript)
20
EGFR expression in human tumors
Tumors showing high EGFR expression
High expression generallyassociated with

• Invasion
• Metastasis
• Late-stage disease
• Chemotherapy resistance
• Hormone-therapy resistance
• Poor outcome

• NSCLC 40-80
• Prostate 40-80
• Gastric 33-74
• Breast 14-91
• Colorectal 25-77
• Pancreatic 30-50
• Ovarian 35-70

21
NSCLC- EGFR HER2
Lung Cancer- EGFR expression
F. Hirsch et al. Semin Oncol, 2002
22
NSCLC- EGFR HER2Survival
J. Brabender et al. Clin Cancer Res, 2001
23
EGFR Targeted Therapies

• Inhibition of EGFR signalling with either the
  monoclonal Ab or the tyrosine kinase
  inhibitors(TKI) reduces proliferation in a
  variety of epithelial tumor cells and blocks cell
  cycle progression in the G1 phase
• Inhibition of cell cycle progression is an
  effective mechanism for modulating the growth of
  tumors
• EGFR inhibition, using TKI induce apoptosis (in
  human tumor cells and vascular endothelial cells)
• Ongoing trials are evaluating the clinical
  utility of EGFR inhibitors for the treatment of
  EGFR-expressing cancers

24
Acquired spesifications of Cancer Cells

• Spesifications
• Autocrine growth signal Yes
  Yes
• Insensitivity to anti-growth signals
  Yes Yes
• Awareness of cell death Yes
  Yes
• Uncontrolled proliferation Yes
  Yes
• Continious angiogenesis Yes
  Yes
• Tissue invasion and Metastasis Yes
  Yes

Increase by EGFR activation
Decrease by EGFR Inhibition
Hanahan ve Weinberg, Cell, 2000
25
TKI-Small molecules mechanism of action
TKI
Proliferation
Apoptosis
Invasion
Sensitivity to chemotherapy
Metastasis
Adhesion
Angiogenesis
Etessami A, et al. Drugs Fut 2000258959 Moyer
J, et al. Cancer Res 199757483848Harari PM,
et al. Semin Radiat Oncol 200212(Suppl. 2)216
26
Growth Factors Cell Cycle
Receptors
27
Targeted Therapies

• EGFR Inhibitors
• Gefitinib (Iressa)
• Erlotinib (Tarceva)
• Anti-EGFR Monoclonal antibody
• Cetuximab (Erbitux)
• Anti-VEGF Monoclonal antibody
• Bevacizumab (Avastin-Altuzan)

28
Gefitinib- with ChemotherapyFirst Line-Phase III
INTACT 1 2
Untreated advanced NSCLC Stratification Weigh
t loss in last 6 months(?5 vs gt5) PS 0 - 1
vs 2
Chemo x 6 cycles
250 mg gefitinib
Gefitinib / Placebo until progression
Chemo x 6 cycles
Randomise
500 mg gefitinib
Chemoi x 6 cycles
Placebo
Evre IIIB/IV KHDAKINTACT IRESSA NSCLC Trial
Assessing Combination Therapy INTACT 1 (N1093)
gemcitabin (1250 mg/m2)/cisplatin (80 mg/m2)
INTACT 2 (N1037) paclitaxel (225
mg/m2)/carboplatin (AUC6).
29
Gefitinib- with ChemotherapyFirst Line-Phase III
Med. survival
10 months
10 months
30
Gefitinib Second Third Line-Phase II
(250mg vs. 500mg)
Patient no. Response Rate () Median survival (Mts)
IDEAL-1 Japan, Europe, Australia, S. Africa 208 18.4 (total) 27.5 (Japan) 10.4 (Non-Japan) 7.6
IDEAL-2 United States 216 12 7

• 250mg ve 500mg doses- no difference in efficacy
• Adverse effects- acceptable (rash and diarrhea)
  more frequent in 500 mg group
• IDEAL-1 M. Fukuoka et al. JCO
  2003 212237-2246
• IDEAL-2 MG Kris et al. JAMA
  2003 2149-2158

31
Gefitinib Second Third Line-Phase III ISEL
Iressa Survival Evaluation in Lung Cancer
R A N D O M I Z E
Gefitinib 250 mg/gün

• Inclusion Criteria
• Stage IIIB veya IV NSCLC
• Treated with platinum based CT( 1 or 2 times)
• PS 0-3

N1692
Placebo
Thatcher et al. Lancet 2005
32
Gefitinib Second Third Line-Phase III ISEL -
Survival
Placebo
Gefitinib
(n1129)
(n563)
1.0
Median survival (mts)
5.6
5.1
0.8
1-year survival ()
27
22
0.6
HR0.89 (95 CI, 0.78-1.03) Plt0.11
Probability
0.4
Gefitinib
0.2
Placebo
0.0
0
16
2
14
4
10
12
8
6
Months
Thatcher et al. Lancet 2005
33
Targeted Therapies

• EGFR Inhibitors
• Gefitinib (Iressa)
• Erlotinib (Tarceva)
• Anti-EGFR Monoclonal antibody
• Cetuximab (Erbitux)
• Anti-VEGF Monoclonal antibody
• Bevacizumab (Avastin-Altuzan)

34
Erlotinib-With Chemotherapy-First Line - Phase
III

• TALENT study - Cisplatin/gemcitabine (tarceva
  or placebo)
• 1172 pts, chemo-naive

Tarceva Placebo
Med. survival (days) 301 309
TTP (days) 167 179
Gatzemeier U. ASCO 2004 Abstract
35
Erlotinib-with chemotherapy-First Line-Phase III

• TRIBUTE study - Carboplatin/paclitaxel (tarceva
  or placebo)
• 1059 pts, chemo-naive

Tarceva Placebo
Med. survival (mts) 10.8 10.6
RR () 21.5 19.3
TTP (mts) 5.1 4.9
Herbst R. J Clin Oncol 2005
36
Erlotinib-with chemotherapy-First Line-Phase III

• TRIBUTE study Subgroup analysis
• Nonsmokers
• tarceva vs placebo
• Median survival 23 mts vs. 10 mts

Miller VA et al. ASCO 2004 Abstract
37
Why are TALENT and TRIBUTE negative studies?
Possible explanations

• Concurrent use may be antagonistic
• in vitro evidence of antagonism with combination
  chemotherapy regimens
• Remarkable benefit in the non-smoker subset
• smoking potentially reduces exposure to Tarceva
  via induction of metabolising enzymes1
• Triplets are redundant doublets Tarceva kills
  the same tumour cell population?

1Hamilton M, et al. Proc Am Assoc Cancer Res
200543 (Abs. 6165)
38
Erlotinib Second or Third Line
BR.21 Phase III
39
Erlotinib Second or Third LineBR.21 Phase III
40
Erlotinib Second or Third LineBR.21 Phase III

Tarceva (n488) Placebo (n243)
RR () 8.9 lt1
Median survival 6.7 mts 4.7 mts
PFS 2.2 mts 1.8 mts
En sik yan etki kizariklik, diyare
Shepherd FA et al. NEJM 2005
41
BR.21 Study-Survival
100
Median Survival (mts)
1-year Survival ()
80
Erlotinib Placebo
6.7
31.2
4.7
21.5
60
Survival
HR0.73, Plt0.001
40
20
0
0 5 10 15 20 25 30
Months
42
BR.21 Toxicity
Patients Patients Patients Patients Patients Patients
Erlotinib(n485) Erlotinib(n485) Erlotinib(n485) Placebo(n242) Placebo(n242) Placebo(n242)
Total Grade 3 Grade 4 Total Grade 3 Grade 4
Rash 75 8 lt1 17 0 0
Diarrhea 54 6 lt1 18 lt1 0
Anoreksia 52 8 1 38 5 lt1
Fatigue 52 14 4 45 16 4
Dyspne 41 17 11 35 15 11
Cough 33 4 0 29 2 0
Emesis 33 3 0 24 2 0
Infection 24 4 0 15 2 0
Vomitting 23 2 lt1 19 2 0
Tarceva? (erlotinib) PI.
43
BR.21 Summary

• Erlotinib has confered a survival advantage in
  previously treated and relapsed NSCLC patients
• Erlotinib is effective in both subgroups
• Therapy is well tolerated
• Most frequent toxicity is rash and diarrhea
• Pulmonary toxicity is rare, but 30 fetal

44
BR.21 ISEL
No. of patients 731 1692
Response rate Overall survival 1 year survival HR P value 8.9 Tarceva 6.7 mts Plasebo 4.7 mts 31 vs. 21 0.73 lt0.001 8 Iressa 5.6 mts Plasebo 5.1 mts 27 vs. 22 0.89 0.11
45
Response to TKI- Important factors
Group Response rate () p
Male vs. Female 19 vs. 3 0.001
Asian vs. Non-Asian 27.5 vs. 10.4 0.0023
Adeno. vs. others 13 vs. 4 0.046
BAC vs. adeno 38 vs 14 lt0.001
Nonsmoker vs. smoker 36 vs. 8 lt0.001
Fukuoka JCO 2003212237-46. Kris JAMA
20032902149-58. Miller JCO 2004221103-09.
46
Erlotinib - Faz II Survival Grade of Rash
1.00
Grade 2/3 (n17)
0.75
Survival
0.50
Grade 1 (n26)
Yok (n14)
0.25
0.00
Perez-Soler R, et al. Am Soc Clin Oncol Mol Ther
Symp. 2002
47

NSCLC EGFR Mutations
48
Gefitinib-EGFR mutation and amplification

• EGFR EGFR
  amplification mutation
  - -
• 33 67 17 83
• Obj. response() 36 3
  (lt.001) 53 5 (lt.001)
• Med. Survival (ay) 18.7 7.0
  (.03) 20.8 8.4 (.09)
• 1 year survival () 57 33
  (.03) 57 38 (.22)

Cappuzzo JNCI 97643,2005
49
Targeted Therapies

• EGFR Inhibitors
• Gefitinib (Iressa)
• Erlotinib (Tarceva)
• Anti-EGFR Monoclonal antibody
• Cetuximab (Erbitux)
• Anti-VEGF Monoclonal antibody
• Bevacizumab (Avastin-Altuzan)

50
Single agent Cetuximab

• Phase II study
• (n60, 1 chemo)
• Response rate 3.3
• Median TTP 2.3 ay
• Median survival 8.1 mo.
• Well tolerated (Most frequent adverse effect
  rash)

Lilenbaum ASCO 2005
51
Cetuximab-with chemotherapy
Docetaxel 75 mg/m2 Every 3
weeks Cetuximab 400 mg/m2 every week then, 250
mg/m2 every week

• Patients (no.47)
• Stage IIIB/IV
• 1 previous CT
• Median KPS 80
• Faz II study

• RR 28,SD 17
• TTP 3 mts
• Well tolerated
• (rash, neutropenia)

Kim ES. 2005 ASCO
52
Cetuximab- With chemotherapy
Cisplatin 80 mg/m2 Day 1 Vinorelbin 25
mg/m2 Day 1,8. Every 3 weeks Cetuximab
400 mg/m2 week 1, then 200 mg/m2
week 2 and 3
RANDOMISATION

• Patients (No.86)
• Stage IV (92)
• Chemo-naive
• Median KPS 90
• Faz II study

Cisplatin 80 mg/m2 Day 1 Vinorelbin 25
mg/m2 Day 1,8 Every 3 weeks
Rosell 2004 ASCO
53
Cetuximab- With chemotherapy
RR () (GA) Median survival (mts) Median TTP (mts)
Cisplatin/Vinor. 20 (7.6-32.4) 7.0 4.2
Cisplatin/Vinor. Cetuximab 32 (17.5-46.0) 8.3 4.7
Rosell 2004 ASCO
54
Targeted Therapies

• EGFR Inhibitors
• Gefitinib (Iressa)
• Erlotinib (Tarceva)
• Anti-EGFR Monoclonal antibody
• Cetuximab (Erbitux)
• Anti-VEGF Monoclonal antibody
• Bevacizumab (Avastin-Altuzan)

55
What is VEGF?

• Key driver of angiogenesis
• Stimulates angiogenic remodelling and sprouting
• Stimulates growth of endothelial cells, promotes
  endothelial cell survival (i.e prevents
  endothelial cell apoptosis and vessel regression)
• Also known as VEGF-A
• Related molecules are VEGF-B, C and D, placental
  growth factor (PlGF)
• When angiogenesis is stimulated , a region of the
  mature vessel becomes destabilized and undergoes
  angiogenic sprouting if VEGF is present
• Binds VEGF receptor-2

56
VEGF Receptors

• The biological effects of VEGF appear to be
  exerted through binding to VEGF receptor-2, which
  is expressed predominantly on vascular
  endothelial cells
• VEGF-2 receptor consists of 7 extracellular Ig
  like domains, a transmembrane region and an
  intracellular domain having tyrosine kinase
  activity

57
VEGF

• This binding to trans-membrane receptors
  activates
• Proliferation of vascular endothelial cells
• Migration of vascular endothelial cells
• Survival of immature endothelial cells
• Increased vascular permeability

58
Angiogenesis

• The primary factor controlling vessel formation
  is lack of oxygen
• This triggers the secretion of pro-angiogenic
  factors, principally vacular endothelial growth
  factor (VEGF)
• TGF alfa/beta, fibroblast growth factor(FGF) are
  other two pro-angiogenic growth factors

59
Angiogenesis

• Tumor angiogenesis can be considered to
  involve two phases
• Avascular phase lesions remain dormant and are
  not more than 1-2 mm diameter, proliferation and
  apoptosis are balanced
• Vascularization phase new vessels continue to
  form as long the tumor grows

60
Why inhibit angiogenesis in NSCLC?

• Angiogenesis plays a role at several stages in
  the growth and progression of all types of solid
  tumour
• tumours are incapable of growth beyond 12mm in
  the absence of vasculature1
• Expression of high levels of VEGF, the key
  mediator of angiogenesis, is associated with poor
  prognosis in NSCLC24
• Novel combinations of existing chemotherapy
  agents are not predicted to provide increased
  survival benefit in advanced NSCLC, suggesting
  that new therapeutic strategies are required5

1Folkman J. J Natl Cancer Inst 19908246 2Volm
M, et al. Int J Cancer 199774648 3OByrne KJ,
et al. Br J Cancer 200082142732 4Fontanini G,
et al. Br J Cancer 20028655863 5Socinski MA.
Respir Care Clin N Am 2003920736
61
Why inhibit angiogenesis in NSCLC?

• Inhibition of angiogenesis, using antiangiogenic
  agents has shown to be effective in preventing
  tumor growth
• In some cases tumor regression has also been
  shown
• Many antiangiogenic agents are currently in
  devolopment, targeting various factors and stages
  in the regulation of angiogenesis

62
Anti-angiogenic agents in clinical development
for NSCLC
Drug Mechanism of action Molecular target(s) Stage of development
Bevacizumab Anti-VEGF antibody VEGF Phase III
Sorafenib (BAY43-9006) TKI Raf-1, VEGFR-2, -3, PDGFR-?, Flt-3, c-Kit Phase III
Sunitinib (SU11248) TKI VEGFR-1, -2, -3, Flt-3, PDGFR-?, -?, c-Kit Phase II
Vatalanib (PTK787) TKI VEGFR-1, -2, -3, PDGFR-?, c-Kit, c-Fms Phase II
CP-547,632 TKI VEGFR-2 Phase II
ZD6474 TKI VEGFR-2, -3, EGFR Phase II
AG-013736 TKI VEGFR-1, -2, -3 Phase II
63
Different mechanisms of anti-angiogenesis VEGF
versus VEGF receptor
Monoclonal antibodies against VEGF Inhibitors of VEGF receptor tyrosine kinases
Directly block interaction between VEGF and its receptors Block signalling by activated VEGF receptors
Prevent activation of downstream signals Down-regulate signalling pathways which are already activated
Bind specifically to VEGF Interact with other receptor tyrosine kinases effects are not all specific to angiogenesis inhibition
Specific action on VEGF minimal effects on normal physiology Non-specific action could produce unexpected side effects
Inhibit all functions of VEGF May not inhibit all functions of VEGF
64
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
65
Effects of VEGF inhibitionregression of
microvasculature

• Reduction in tumour blood flow after 1 day of
  anti-VEGF therapy

Inai T, et al. Am J Pathol 20041653552
66
Effects of VEGF inhibitionnormalisation of
existing vasculature

• Abnormal vasculature is normalised following
  VEGF inhibition

Inai T, et al. Am J Pathol 20041653552
67
Summary mechanism of action of anti-VEGF therapy
EARLY BENEFIT
CONTINUED BENEFIT
Regression of existing microvasculature
Inhibition of vessel regrowth and
neovascularisation
Normalisation of surviving microvasculature

• Inhibition of VEGF may act against tumours in
  three ways
• regression of existing microvasculature
• normalisation of mature vasculature
• inhibition of production of new vasculature

68
Bevacizumab
Anti-VEGF antibody (Bevacizumab)
VEGF
VEGFR-1
VEGFR-2
Endothel
Presta et al. Cancer Res. 1997574593.
69
Phase II trial of bevacizumab in NSCLC summary

• Addition of bevacizumab to carboplatin and
  paclitaxel improved response rate, time to
  progression and overall survival in patients with
  advanced NSCLC
• Patients with non-squamous cell histology appear
  to be a subpopulation with improved outcome and
  acceptable safety risks
• Recommended dose of bevacizumab for further
  evaluation is 15mg/kg every 3 weeks
• The promising benefit of bevacizumab with
  chemotherapy in this trial warrants further
  investigation

70
Phase III trial of bevacizumab in NSCLC(ECOG
4599) study design
Previously untreated stage IIIB/IV non-squamous
NSCLC (n878)
CP ? 6 (n444)
PD
Bevacizumab (15mg/kg) every 3 weeks CP ? 6
(n434)
Bevacizumab every 3 weeks until progression
PD

• Primary objective to assess overall survival in
  patients with advanced non-squamous NSCLC treated
  with CP (carboplatin/paclitaxel) versus CP
  bevacizumab
• Secondary objective to assess response rates,
  time to progression and toxicity

Sandler A, et al. J Clin Oncol 200523(Suppl 16
Pt I)2s (Abs. 4)
No cross over will be permitted
71
Phase III trial of bevacizumab in NSCLC(ECOG
4599) key eligibility criteria

• Chemotherapy-naïve stage IIIB (pleural or
  pericardial effusion only) or stage IV
  non-squamous NSCLC
• Measurable or non-measurable disease
• ECOG PS 01
• INR lt1.5 and a PTT no greater than upper limits
  of normal within 1 week prior to randomisation
• No history of thrombotic or haemorrhagic
  disorders
• No gross haemoptysis (defined as bright red blood
  of a 1/2 teaspoon or more)
• Brain metastases were not allowed

Sandler A, et al. J Clin Oncol 200523(Suppl. 16
Pt I)2s (Abs. LBA4)
72
Phase III trial of bevacizumab in NSCLC(ECOG
4599) patient population
CP bevacizumab n424 ()
CPn431 ()
 
13
14
Stage IIIB
91
91
Measurable disease
28
28
Prior weight loss ?5
43
44
Age ?65 years
40
38
ECOG PS 0
50
58
Male
90
91
Caucasian
Sandler A, et al. J Clin Oncol 200523(Suppl. 16
Pt I)2s (Abs. LBA4)
73
Phase III trial of bevacizumab in NSCLC (E4599)
efficacy
CP CP bevacizumab p value (HR)
Complete response, n () 0 (0) 5 (1.4)
Partial response, n () 35 (10) 92 (25.8)
Overall response rate, n () 35 (10) 97 (27.2) lt0.0001
Median OS (months) 10.2 12.5 0.007 (0.77)
Median PFS (months) 4.5 6.4 lt0.0001 (0.62)
Sandler A, et al. J Clin Oncol 200523(Suppl. 16
Pt I)2s (Abs. 4)
74
ECOG 4599 - Survival
75
ECOG 4599 - PFS
76
Phase III trial of bevacizumab in NSCLC(ECOG
4599) haematological toxicity
CP(n427)Grade 4 CP bevacizumab(n420)Grade 4 p value
Neutropenia () 16.4 24 0.006
Thrombocytopenia () 0 1.4 0.01
Anaemia () 0.7 0 NS
Febrile neutropenia () 1.9 3.3 NS
Includes one death on each arm due to
neutropenic fever
Sandler A, et al. J Clin Oncol 200523(Suppl. 16
Pt I)2s (Abs. LBA4)
77
Phase III trial of bevacizumab in NSCLC(ECOG
4599) non-haematological toxicity

CP

CP bevacizumab

n ()

n ()

gtGrade 3

gtGrade 3

p
value

Haemorrhage

3 (0.7)
19 (4.5)
lt0.00
1
Haemoptysis

1 (0.2)
8 (1.9)
0.04
CNS

0
4 (1.0)
0.03
GI

2 (0.5)
5 (1.2)
NS
Other

1 (0.2)
4 (1.0)
NS
Hypertension

3 (0.7)
25 (6.0)
lt0.001
Ve
nous thrombosis

13 (3.0)
16 (3.8)
NS
Arterial thrombosis

4 (1.0)
8 (1.9)
NS
Sandler A, et al. J Clin Oncol 200523(Suppl. 16
Pt I)2s (Abs. LBA4)
78
Phase III trial of bevacizumab in NSCLC(ECOG
4599) treatment-related deaths
CP

CP bevacizumab

(n427)

(n420)




Haemorrhage

Haemoptysis
0
5

GI bleed
1
2

Neutropenic fever
1
1

Total
2
8
Sandler A, et al. J Clin Oncol 200523(Suppl. 16
Pt I)2s (Abs. LBA4)
79
Phase III trial of bevacizumab in NSCLC(ECOG
4599) conclusions

• The addition of bevacizumab (15mg/kg every 3
  weeks) to CP improves OS, RR and PFS in patients
  with NSCLC
• In certain patients, bevacizumab plus CP is
  associated with life-threatening and fatal
  haemorrhage
• event is associated with squamous cell histology
• patients with squamous cell NSCLC excluded from
  ongoing trials

80
Bevacizumab in first-line advanced NSCLC

• Bevacizumab is the first novel agent combined
  with standard chemotherapy to significantly
  improve overall survival in unselected patients
  with advanced NSCLC in the first-line setting
• Bevacizumab plus CP is now the ECOG reference
  standard for the first-line treatment of advanced
  non-squamous NSCLC

81
Bevacizumab ErlotinibPhase II study

• Patients (No.40)
• Stage IIIB/IV
• Nonsquamous type
• Previously treated with chemo
• Median KPS 80

Erlotinib 150 mg/day Bevacizumab 15mg/kg every 3
weeks

• RR 20
• Med. survival 12.6 mts
• TTP 6.2 mts
• Well tolerated

Herbst RS. JCO 2005 232544-55.
82
Recurrent NSCLC Erlotinib ? Bevacizumab
83
Results

• Gefitinib does not prolong survival
• Erlotinib prolongs survival
• There is no advantage when added to standard
  chemo
• Efficacy is better in nonsmokers, asians,
  adenocarcinomas, females
• Response rates are higher in patients who have
  Exon 19 - 21 mutations and gene amplification
• If there is K-ras mutation response rates are
  lower

84
Results

• There is no advantage to add cetuximab to
  standard chemo
• Bevacizumab chemotherapy combination is an
  effective option
• Bevacizumab Erlotinib combination may have
  sinergic effect

85
Future

• Molecular biology of lung cancer has many unknown
  aspects
• New agents acting on different signal
  transduction pathways
• Important and significant predictive factors
  must be defined
• Chemotherapy Targeted therapies
• To understand which patients will benefit the
  most from targeted therapies
• Targeted therapies in the early stages of the
  disese

86
(No Transcript)
87
Future plans for bevacizumab and Erlotinib in
NSCLC

• Planned and ongoing trials of bevacizumab in
  NSCLC include
• combination with chemotherapy and radiotherapy
• combination with other novel agents
• neo-adjuvant and adjuvant settings
• SAiL (Safety of bevacizumab in Lung) in 2006
• Planned and ongoing trials of erlotinib in NSCLC
  include
• sequencing with chemotherapy
• monotherapy trials