Nick Thatcher Professor of Oncology at the University of Manchester, Christie Hospital NHS Trust and Wythenshawe Hospital, Manchester, UK Chairman of the Lung Cancer Disease Oriented Group Former Vice-Chairman of the United Kingdom Coordinating Committee on Cancer Research Member of the National Cancer Trials Network Lung Group Author or co-author of many articles in international peer- reviewed journals Main clinical interests: clinical trial research of lung cancer and the development of new treatments University of Manchester
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Nick Thatcher Professor of Oncology at the University of Manchester, Christie Hospital NHS Trust and Wythenshawe Hospital, Manchester, UK Chairman of the.
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Nick ThatcherProfessor of Oncology at the University of Manchester, Christie Hospital NHS Trust and Wythenshawe Hospital, Manchester, UK
Chairman of the Lung Cancer Disease Oriented Group
Former Vice-Chairman of the United Kingdom Coordinating Committee on Cancer Research
Member of the National Cancer Trials Network Lung Group
Author or co-author of many articles in international peer-reviewed journals
Main clinical interests: clinical trial research of lung cancer and the development of new treatments University of Manchester
1990s: survival expectations ofpatients with advanced NSCLC
Patient withPS 3–4
Elderlypatient with
PS 3–4
Patient withPS 0–2
BSC:2–5 months
Single-agent platinum:
6–8 months
Platinum-based
doublets:8–10
months
14
12
10
8
6
4
2
0
Med
ian
su
rviv
al (
mo
nth
s)
Vascular endothelial growth factor (VEGF),the key mediator of tumour angiogenesis,
is an ideal therapeutic target
1Ferrara N, et al. Nat Med 2003;9:669–76; 2Alon T, et al. Nat Med 1995;1:1024–83Folkman J. N Engl J Med 1971;285:1182–6; 4Netti P, et al. Proc Natl Acad Sci USA 1999;96:3137–42
5Dvorak H, et al. Am J Pathol 1995;146:1029–39
VEGF is overexpressed in a wide variety of tumours and
may be associated with reduced survival
Promotes survivalof vasculature
critical to tumour2
Increases intratumoural pressure, preventing
penetration of chemotherapeutic agents4,5
Stimulates new vasculature required for growth
and metastasis3
Has a limited role inhealthy adults1
Bevacizumab prevents angiogenesis through a novel mechanism of action
Bevacizumab is a recombinant humanised monoclonal anti-VEGF antibody that
– prevents the binding of VEGF to its receptors
– recognises all major isoforms of human VEGF
– P– P
P– P–
VEGF
X
Growth
Proliferation
Migration
Survival
X
Bevacizumab
Mechanism of action of bevacizumab
EARLY EFFECTS CONTINUED EFFECTS
Normalisation of remaining tumour vasculature5–8
1
2
Regression of existing tumour microvasculature1–7
Inhibition of new tumour vasculature1,2,9,10
3
1Baluk P, et al. Curr Opin Genet Dev 2005;15:102–11; 2Inai T, et al. Am J Pathol 2004;165:35–523Erber R, et al. FASEB J 2004; 4Tong R, et al. Cancer Res 2004;64:3731–6
5Jain R. Nat Med 2001;7:987–9; 6Jain R. Science 2005;307:58–62 7Lee C-G, et al. Cancer Res 2000;60:5565–70; 8Willett C, et al. Nat Med 2004;10:145–7
9Gerber H-P, et al. Cancer Res 2005;65:671–81; 10Warren R, et al. J Clin Invest 1995;95:1789–97
Phase II trial of bevacizumab in NSCLC (AVF0757g): trial design
Primary endpoints: time to progression and response rate
Secondary endpoints: overall survival and duration of response
Bevacizumab administered every 3 weeks until progression
Chemotherapy administration (maximum six cycles)– paclitaxel 200mg/m2 i.v. every 3 weeks– carboplatin i.v. to AUC 6 every 3 weeks following paclitaxel infusion
Previously untreated
stage IIIB/IV NSCLC
CP x 6 (n=32)
CP x 6 + bevacizumab (15mg/kg) every 3 weeks
(n=35)
CP x 6 + bevacizumab (7.5mg/kg) every 3 weeks
(n=32)
Bevacizumab(15mg/kg)
every 3 weeks
PD
PD
PD
PD = progressive disease; i.v. = intravenousAUC = area under the curve Johnson LD, et al. J Clin Oncol 2004;22:2184–91
Phase II trial of bevacizumab in NSCLC (AVF0757g): proof of principle
Bevacizumab + CP
CP(n=32)
Bevacizumab 7.5mg/kg (n=32)
Bevacizumab 15mg/kg(n=34)
Response rate, % (n)
Investigator
Independent review facility
18.8 (6)
31.3 (10)
28.1 (9)
21.9 (7)
31.5 (11)*
40.0 (14)*
Median time to progression (months)
Investigator
Independent review facility
4.2
5.9
4.3
4.1
7.4
7.0
Median survival (months) 14.9 11.6 17.7
*n=35 Johnson LD, et al. J Clin Oncol 2004;22:2184–91
Phase III trial of bevacizumab plus CP in NSCLC (E4599): trial design
Previously untreated stage IIIB/IV
non-squamous NSCLC(n=878)
CP (n=444)
Bevacizumab (15mg/kg) every
3 weeks + CP (n=434)
Primary endpoint: overall survival
Bevacizumab 15mg/kg i.v. administered every 3 weeks
Carboplatin i.v. to AUC 6 and paclitaxel 200mg/m2 i.v. every 3 weeks
PD*
PD
Bevacizumab (15mg/kg) every
3 weeks until progression
Sandler A, et al. N Engl J Med 2006;355:2542–50
*No crossover permitted
E4599: bevacizumab-based therapy was the first regimen to extend overall survival beyond 1 year
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42 48
Months
Pro
bab
ilit
y o
f su
rviv
al
10.3 12.3
Sandler A, et al. N Engl J Med 2006;355:2542–50HR = hazard ratio
Bevacizumab + CPCP
HR=0.79 (0.67–0.92); p=0.003
Med
ian
ove
rall
su
rviv
al (
mo
nth
s)
15
10
5
0 Bevacizumab+ CP
CP
Median overall survival>12 months
10.3
12.3
2006: survival expectations ofpatients with advanced NSCLC
E4599: breaking through the therapeutic plateau
Patientwith
PS 3–4
Elderly patient
withPS 3–4
Patientwith
PS 0–2
Med
ian
su
rviv
al (
mo
nth
s)
BSC:2–5
months
Single-agent
platinum:6–8
months
Platinum-based
doublets:8–10
months
Therapeutic plateau14
12
10
8
6
4
2
0
Bevacizu-mab +
platinum-based
doublet: 12.3
months
Bevacizumab-eligiblepatient
Phase III trial of bevacizumab plus CG in NSCLC (AVAiL): trial design
Primary endpoint: PFS
Initiated to evaluate bevacizumab in combination with a platinum-based chemotherapy regimen commonly used in Europe and other regions of the world
Manegold C, et al. Eur J Cancer Suppl 2007;5:9 (Abstract 1B)
PD
PD
PD
Bevacizumab
Bevacizumab
Placebo + CG(n=347)
Bevacizumab15mg/kg + CG
(n=351)
Bevacizumab7.5mg/kg + CG
(n=345)Previously untreated,
stage IIIB, IV or recurrent non-
squamous NSCLC
(n=1,043)
RANDOMISE
Placebo
(no crossoverallowed)
PFS = progression-free survival
AVAiL: significant improvement in PFS with both doses of bevacizumab
Placebo+ CG
Bevacizumab 7.5mg/kg
+ CG
Bevacizumab 15mg/kg
+ CG
HR95% CI
0.750.62–0.91
0.82 0.68–0.98
p value 0.0026 0.0301
Median PFS (months) 6.1 6.7 6.5
1.0
0.8
0.6
0.4
0.2
0
Po
ssib
ility
of
PF
S
Time (months)0 3 6 9 12 15 18
Manegold C, et al. Eur J Cancer Suppl 2007;5:9 (Abstract 1B)CI = confidence interval
Value of PFS to the patient
PFS is an increasingly important endpoint in oncologic drug development
– risk of confounding overall survival due to ever more effective second- and third-line cancer treatments and thegrowing use of ‘crossover’ trial designs in oncology
– use of PFS rather than overall survival can expedite the availability of novel therapeutic options to patients
PFS is relevant to clinical practice
– in a systematic review of adjuvant colon cancer studies, disease-free survival was considered to be the most informative endpoint for assessing the effect of treatment1
1Punt C, et al. J Natl Cancer Inst 2007;99:998–1003
AVAiL and E4599have comparable PFS benefit
PR
OG
RE
SS
ION
OR
DE
AT
H
AVAiL primary PFS analysis
E4599 PFS analysis andAVAiL censored analysis
Bevacizumab or placebo
+ chemotherapy
Second-line
antineoplastictherapy
With non-protocol therapy censoringE45991 AVAiL2
Bevacizumab15mg/kg + CP
(n=434)
Bevacizumab 7.5mg/kg + CG
(n=345)
Bevacizumab 15mg/kg + CG
(n=351)HR95% CI
p value
0.660.57–0.77
0.001
0.68 0.56–0.83
0.0001
0.74 0.60–0.90
0.00211Sandler A, et al. N Engl J Med 2006;355:2542–50
2Manegold C, et al. Eur J Cancer Suppl 2007;5:9 (Abstract 1B)
Positive trial results led to US and EU approval of bevacizumab plus chemotherapy
24 August 2007The EU approved the use of bevacizumab at a dose of
7.5mg/kg or 15mg/kg, in combination with platinum-based chemotherapy, for the first-line treatment of patients with unresectable advanced, metastatic or recurrent NSCLC
other than predominantly squamous cell histology
11 October 2006The Food and Drug Administration approved the use of bevacizumab at a dose of 15mg/kg, in combination with
carboplatin/paclitaxel, for the first-line treatment of patients with unresectable, locally advanced, metastatic or recurrent
non-squamous NSCLC
Efficacy of other agentsin first-line NSCLC
Increase median survival from 8 to 10 months
Met primary overall survival endpoint 11/09/2007
Phase III trial of cetuximab plus cisplatin/vinorelbine in first-line NSCLC (FLEX)
Patients with EGFR-
expressing NSCLC
(n=1,100)
1:1 randomisation
Cetuximab (initial 400mg/m2 2-hour infusion then 250mg/m2 1-hour
infusion weekly)
Cisplatin (80mg/m2 day 1 every 3 weeks)
Vinorelbine (30mg/m2 day 1 and 8 every 3 weeks)
Cisplatin (80mg/m2 day 1 every 3 weeks)
Vinorelbine (30mg/m2 day 1 and 8 every 3 weeks)
EGFR = epidermal growth factor receptor
Phase III trial of cetuximab plus taxane/carboplatin versus taxane/carboplatin
– no unexpected toxicities seen with bevacizumab plus platinum-based chemotherapy1–3
– events with higher incidence in bevacizumab-treated patients mainly include those already recognised in other bevacizumab trials, such as• bleeding• arterial and venous thromboembolic events• hypertension• proteinuria
– these events are generally easily managed
1Johnson D, et al. J Clin Oncol 2004;22:2184–912Sandler A, et al. N Engl J Med 2006;355:2542–50
SAiL interim safety results:serious adverse events of special interest
Grade 3–5 adverse events of special interest reported to date for the intent-to-treat population (n=513)
– hypertension (2.1%)
– arterial and venous thromboembolic events (1.4%)
– proteinuria (0.2%)
– gastrointestinal perforation (0.2%)
– congestive heart failure (0.2%)
– wound-healing complications (0%)
– haemoptysis (0%)
– CNS bleeding (0%)
– other haemorrhages (0.4%)
Crino L, et al. Eur J Cancer Suppl 2007;5:364 (Abstract 6522)
Case study of first-line bevacizumab:case history and treatment choice
38-year-old nurse presented with thoracic pain and prolonged bronchial infection
Stage IV adenocarcinoma (T2N2M1) diagnosedNovember 2006
– tumour in upper right lobe and lower left lobe
Patient enrolled into the SAiL trial
– received bevacizumab and chemotherapy on a 3-week cycle for six cycles
• day 1: bevacizumab (15mg/kg), cisplatin (75mg/m2), gemcitabine (1,250mg/m2)
• day 8: gemcitabine (1,250mg/m2)
Eric Dansin, CRLCC Oscar Lambret, Lille, France
Case study of first-line bevacizumab:management of treatment-associated
adverse events
Adverse events were mild and easily managed
– epistaxis: grade 1, successfully managed by standard first-aid techniques
– thrombocytopenia: successfully managed by platelet transfusion
– nausea: managed by anti-emetics
No proteinuria or hypertension observed
Eric Dansin, CRLCC Oscar Lambret, Lille, France
Case study of first-line bevacizumab:clinical course and outcome
Beforetreatment
After 6 cycles ofbevacizumab pluscisplatin/gemcitabine
Eric Dansin, CRLCC Oscar Lambret, Lille, France
Case study of first-line bevacizumab:clinical course and outcome
Partial response after two cycles; confirmed after cycles 4 and 6
– upper right lobe tumour reduced from 5cm to a residual lesion
– probable mediastinal downstaging (PET criteria)
Sufficient response to warrant surgical intervention
– bevacizumab discontinued to prepare for surgery
– however, following suspension of bevacizumab, disease progression occurred; surgery was cancelled
– bevacizumab reinitiated to counter further progression
This case supports the use of bevacizumab until disease progression
Eric Dansin, CRLCC Oscar Lambret, Lille, FrancePET = positron emission tomography
Bevacizumab consistently improves outcomes in advanced NSCLC
Bevacizumab administered until disease progression with platinum-based chemotherapy
– extends overall survival beyond 12 months
– significantly delays disease progression
– has a well-characterised safety profile
Based on E4599 and AVAiL, bevacizumab plus platinum-based chemotherapy represents the standard of care for bevacizumab-eligible patients with advanced NSCLC
Early stage
PS 0–2 PS 3–4
NSCLC
Locally advanced/metastatic
Surgery and radiotherapy ± adjuvant therapy
2nd/3rd linetreatment
Bestsupportive
care
Platinum doublet chemotherapy or third-generation
non-platinum doublet (PS 2)
Platinum doublet chemotherapy +bevacizumab*
(PS 0–1)
Single-agent chemotherapy
(elderly)
Bevacizumab is changing the therapeutic landscape for advanced NSCLC
*NCCN Clinical Practice Guidelines in OncologyNon-small cell lung cancer v.2.2008