1. University of Manchester
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

2. The new kid on the block: bevacizumab in first-line NSCLC
Nick Thatcher
Christie Hospital NHS Trust Manchester, UK

3. The therapeutic plateau
Modern platinum chemotherapy doublets achieve similar efficacy
1.0
0.8
0.6
0.4
0.2
Cisplatin/paclitaxel (CIP)
Cisplatin/gemcitabine (CG)
Cisplatin/docetaxel (CD)
Carboplatin/paclitaxel (CP)
Probability of survival
Months
Schiller JH, et al. N Engl J Med 2002;346:92–8

4. Median overall survival
Many targeted therapies have failed to show clinical benefit in first-line NSCLC
Trial
Regimen
Median overall survival
(months)
p value
Placebo
Agent
INTACT-1
CG ± gefitinib
10.9
9.9/9.9 NS
INTACT-2
CP ± gefitinib
9.9
9.8/8.7
TRIBUTE
CP ± erlotinib
10.5
10.6
TALENT
CG ± erlotinib
10.0
10.3
SPIRIT-1
VC ± bexarotene
8.7
SPIRIT-2
CP ± bexarotene
9.2
8.5
Paz-Ares et al.
CG ± aprinocarsen
10.4
ISIS-3521
CP ± aprinocarsen
9.7 AG
CG ± prinomastat
10.8
11.5
BR.18
CG ± BMS
8.6
NS = not significant; VC = vinorelbine/cisplatin

5. Treatment algorithm for NSCLC
Early stage
Locally advanced/metastatic
Surgery and radiotherapy
± adjuvant therapy
PS 3–4
PS 0–2
Best
supportive
care (BSC)
Platinum doublet
chemotherapy or third-generation non-platinum doublet
Single-agent chemotherapy (elderly)
2nd/3rd line
treatment
PS = performance status

6. 1990s: survival expectations of patients with advanced NSCLC14 12 10 8 6 4 2
Platinum-based doublets: 8–10
months
Median survival (months)
Single-agent platinum: 6–8 months
BSC:
2–5 months
Patient with
PS 3–4
Elderly
patient with
PS 3–4
Patient with
PS 0–2

7. Vascular endothelial growth factor (VEGF), the key mediator of tumour angiogenesis, is an ideal therapeutic target
VEGF is overexpressed in a wide variety of tumours and may be associated with reduced survival
Promotes survival of vasculature critical to tumour2
Has a limited role in healthy adults1
Stimulates new vasculature required for growth and metastasis3
Increases intratumoural pressure, preventing penetration of chemotherapeutic agents4,5
1Ferrara N, et al. Nat Med 2003;9:669–76; 2Alon T, et al. Nat Med 1995;1:1024–8 3Folkman 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 7

8. Bevacizumab prevents angiogenesis through a novel mechanism of action
VEGF
Bevacizumab
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 X P–
– P P–
– P X
Growth
Proliferation
Migration
Survival 8

9. Mechanism of action of bevacizumab
EARLY EFFECTS
CONTINUED EFFECTS
Regression of existing tumour microvasculature1–7
Inhibition of new tumour vasculature1,2,9,10 1 3 2
Normalisation of remaining tumour vasculature5–8
1Baluk P, et al. Curr Opin Genet Dev 2005;15:102–11; 2Inai T, et al. Am J Pathol 2004;165:35–52
3Erber 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

10. Phase II trial of bevacizumab in NSCLC (AVF0757g): trial design
(15mg/kg) every 3 weeks
CP x 6 (n=32) PD
Previously untreated stage IIIB/IV NSCLC
CP x 6 + bevacizumab (7.5mg/kg) every 3 weeks
(n=32) PD
CP x 6 + bevacizumab (15mg/kg) every 3 weeks
(n=35) PD
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
PD = progressive disease; i.v. = intravenous AUC = area under the curve
Johnson LD, et al. J Clin Oncol 2004;22:2184–91

11. 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)
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

12. Phase III trial of bevacizumab plus CP in NSCLC (E4599): trial design
CP (n=444)
PD*
Previously untreated stage IIIB/IV
non-squamous NSCLC
(n=878)
*No crossover permitted
Bevacizumab (15mg/kg) every 3 weeks + CP (n=434)
Bevacizumab (15mg/kg) every
3 weeks until progression PD
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
Sandler A, et al. N Engl J Med 2006;355:2542–50

13. E4599: bevacizumab-based therapy was the first regimen to extend overall survival beyond 1 year
Bevacizumab + CP CP
Median overall survival
>12 months
HR=0.79 (0.67–0.92); p=0.003
1.0
0.8
0.6
0.4
0.2 15 10 5
12.3
10.3
Median overall survival (months)
Probability of survival CP
Bevacizumab
+ CP
10.3
12.3
Months
HR = hazard ratio
Sandler A, et al. N Engl J Med 2006;355:2542–50

14. 2006: survival expectations of patients with advanced NSCLC
E4599: breaking through the therapeutic plateau 14 12 10 8 6 4 2
Therapeutic plateau
Bevacizu-mab + platinum-based doublet: months
Platinum-based doublets: 8–10 months
Median survival (months)
Single-agent platinum: 6–8 months
BSC:
2–5 months
Patient
with
PS 3–4
Elderly patient
with
PS 3–4
Patient
with
PS 0–2
Bevacizumab-eligible
patient

15. Phase III trial of bevacizumab plus CG in NSCLC (AVAiL): trial design
7.5mg/kg + CG
(n=345) R A N D O M I S E
Bevacizumab PD
Previously untreated, stage IIIB, IV or recurrent non-squamous NSCLC
(n=1,043)
Placebo + CG
(n=347)
Placebo
(no crossover
allowed) PD
Bevacizumab
15mg/kg + CG
(n=351)
Bevacizumab PD
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
PFS = progression-free survival
Manegold C, et al. Eur J Cancer Suppl 2007;5:9 (Abstract 1B)

16. AVAiL: significant improvement in PFS with both doses of bevacizumab
Placebo + CG
Bevacizumab 7.5mg/kg + CG
Bevacizumab 15mg/kg + CG
HR 95% CI
–0.91
–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
Possibility of PFS
Time (months)
CI = confidence interval
Manegold C, et al. Eur J Cancer Suppl 2007;5:9 (Abstract 1B)

17. 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 the growing 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

18. AVAiL and E4599 have comparable PFS benefit
AVAiL primary PFS analysis
PROGRESSION
OR DEATH
Bevacizumab or placebo
+ chemotherapy
Second-line
antineoplastic
therapy
E4599 PFS analysis and
AVAiL censored analysis
With non-protocol therapy censoring
E45991
AVAiL2
Bevacizumab 15mg/kg + CP (n=434)
Bevacizumab 7.5mg/kg + CG (n=345)
Bevacizumab 15mg/kg + CG (n=351)
HR 95% CI
p value
–0.77
0.001
–0.83
0.0001
–0.90
0.0021
1Sandler A, et al. N Engl J Med 2006;355:2542–50 2Manegold C, et al. Eur J Cancer Suppl 2007;5:9 (Abstract 1B)

19. Positive trial results led to US and EU approval of bevacizumab plus chemotherapy
11 October 2006
The 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
24 August 2007
The 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

20. Efficacy of other agents in first-line NSCLC

21. Phase III trial of cetuximab plus cisplatin/vinorelbine in first-line NSCLC (FLEX)
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)
Patients with EGFR- expressing NSCLC (n=1,100)
1:1 randomisation
Cisplatin (80mg/m2 day 1 every 3 weeks)
Vinorelbine (30mg/m2 day 1 and 8 every 3 weeks)
Increase median survival from 8 to 10 months
Met primary overall survival endpoint 11/09/2007
EGFR = epidermal growth factor receptor

22. Time from randomisation (months)
Phase III trial of cetuximab plus taxane/carboplatin versus taxane/carboplatin (TC) in first-line NSCLC
PFS (per Independent Radiologic Review Committee)
1.0
0.8
0.6
0.4
0.2
HR=0.802 (95% CI: 0.761–1.089), p=0.2358
4.40 months
Probability of PFS
Cetuximab + TC (n=338, events=284)
TC (n=338, events=263)
4.24 months
Time from randomisation (months)
Lynch LT, et al. J Thorac Oncol 2007;2(Suppl. 4)S296 (Abstract Y1-03)

23. Phase III trial of pemetrexed/carboplatin versus gemcitabine/carboplatin in first-line NSCLC
Pemetrexed/carboplatin (n=219)
Pemetrexed 500mg/m2 day 1
Carboplatin AUC = 5 (Calvert) day 1 every 3 weeks
4 cycles or PD or intolerable toxicity
Gemcitabine/carboplatin (n=218)
Gemcitabine 1,000mg/m2 day 1 and day 8
Carboplatin AUC = 5 (Calvert) day 1 every 3 weeks
4 cycles or PD or intolerable toxicity
All patients were supplemented with vitamins
Patients 75 years received 75% dose
Grønberg BH, et al. J Clin Oncol 2007;25(Suppl. 18 Pt I):S18 (Abstract 7517)

24. Days since randomisation
Phase III trial of pemetrexed/carboplatin versus gemcitabine/carboplatin in first-line NSCLC
Median OS (months)
95% CI
p value
Pemetrexed/carboplatin
7.3
6.1–8.6
Gemcitabine/carboplatin
7.0
5.8–8.2
0.60
1.0
0.8
0.6
0.4
0.2
Survival (%)
Days since randomisation
Grønberg BH, et al. J Clin Oncol 2007;25(Suppl. 18 Pt I):S18 (Abstract 7517)

25. Pemetrexed plus cisplatin versus gemcitabine/cisplatin in first-line NSCLC
Overall survival (months)
10.3
PFS (months)
4.8
5.1
1-year survival (%)
43.5
41.9
2-year survival (%)
18.9
14.0
OS (months) by histology
Pemetrexed/
cisplatin
Gemcitabine/
HR (CI)
Adenocarcinoma (n=847)
12.6
10.9
0.84 (0.71–0.98)
Large cell (n=153)
10.4
6.7
0.68 (0.48–0.97)
Squamous cell (n=473)
9.4
10.8
1.22 (0.99–1.50)
Scagliotti GV, et al. J Thorac Oncol 2007;2:107 (Abstract E09-03)

26. Patient management

27. Management of bevacizumab-associated adverse events
In patients with NSCLC
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;22:2184–91
2Sandler A, et al. N Engl J Med 2006;355:2542–50
3Manegold C, et al. J Clin Oncol 2007;25(Suppl. 18 Pt I):S18 (Abstract LBA7514)

28. AVAiL had slightly more stringent exclusion criteria than E4599
Exclusion criteria E4599
Exclusion criteria AVAiL
History of gross haemoptysis (bright red blood ½ teaspoon)
History of grade 2 haemoptysis
CNS metastases
Brain metastases or spinal cord compression
Symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia
Clinically significant cardiovascular disease
Evidence of tumour invading or abutting major blood vessels
Malignancies other than NSCLC within 5 years prior to randomisation
CNS = central nervous system

29. Bevacizumab has a well-characterised safety profile: similar profile was observed in E4599 and AVAiL
Grade 3 adverse events (%)
Bevacizumab 7.5mg/kg + CG (n=330)
Bevacizumab 15mg/kg + CG (n=329)
Bevacizumab 15mg/kg + CP (n=427)
Hypertension 6 9 7
Neutropenia* Febrile neutropenia*
40 2
36 2
Thrombocytopenia* 27 23
1.6
Venous thrombosis
3.8
Arterial thrombosis 2 3
1.9
Proteinuria
0.3 1
3.1
Bleeding Epistaxis Haemoptysis
*E4599 reports only grade 4/5 haematological events
Sandler A, et al. N Engl J Med 2006;355:2542–50
Manegold C, et al. Eur J Cancer Suppl 2007;5:9 (Abstract 1B)

30. Bleeding events for lung cancer patients are generally minor and easily managed
The majority of bleeding events are minor and mucocutaneous and do not require medical intervention
Most nosebleeds begin on the septum, an area lined with fragile blood vessels
Minor bleeding events can be easily managed using standard first-aid techniques

31. Appropriate patient selection reduces bleeding risk10 8 6 4 2
AVF0757g Bevacizumab 7.5 or 15mg/kg + CP*
E4599 Bevacizumab 15mg/kg + CP
AVAiL Bevacizumab 7.5mg/kg + CG
AVAiL Bevacizumab 15mg/kg + CG
Restricting eligibility to patients with non-squamous histology and minimal baseline haemoptysis
Additional exclusion of tumours abutting or invading major blood vessels
Percentage
Grade 3 pulmonary haemorrhage
Johnson D, et al. J Clin Oncol 2004;22:2184–91
Sandler A, et al. N Engl J Med 2006;355:2542–50
Manegold C, et al. Eur J Cancer Suppl 2007;5:9 (Abstract 1B)
*Phase II trial including patients with squamous cell histology

32. Hypertension is generally easily managed using standard antihypertensive treatment
Grade 1
continue treatment with bevacizumab
Grade 2
start antihypertensive therapy, once blood pressure (BP) is <150/100mmHg continue treatment with bevacizumab
Grade 3
start antihypertensive therapy with two or more drugs, hold bevacizumab for persistent or symptomatic therapy
Blood pressure
should be
actively managed
Discontinuation
of bevacizumab
is rarely required

33. Calcium channel blocker
Management of hypertension: ACE inhibitors, diuretics and calcium channel blockers all used successfully in AVAiL
Use of diuretics to manage hypertension is not advised in patients who receive cisplatin-based chemotherapy1 40 30 20 10
32.7
27.6
19.9
Patients (%)
11.1
8.7
ACE
inhibitor
Beta- blocker
Calcium channel blocker
Diuretic
Other
1Avastin Summary of
Product Characteristics
ACE = angiotensin converting enzyme

34. Proteinuria can be easily monitored
Proteinuria should be actively managed during treatment with bevacizumab
Monitoring for proteinuria is recommended prior to and during treatment with bevacizumab
If reading is 2+ or greater (3+ on second and subsequent occurrences), 24-hour urine collection should be used
Trial practice
interrupt bevacizumab if urine protein levels (UPL) 2g/24 hours, restart once UPL <1g/24 hours
Proteinuria can be easily monitored
Discontinuation
of bevacizumab
is rarely required

35. Safety of Avastin® in Lung (SAiL) trial will provide further safety information
Locally advanced, metastatic or recurrent non-squamous NSCLC
(n=2,000)
Chemotherapy* + bevacizumab 7.5mg/kg or 15mg/kg every 3 weeks
(up to 6 cycles)
Bevacizumab
maintenance therapy PD
Primary endpoint: safety profile of bevacizumab when combined with chemotherapy
Secondary endpoints: time to disease progression, overall survival, safety of bevacizumab in patients who develop CNS metastases
Approximately 2,000 patients from 400 centres worldwide will be recruited
*Standard-of-care first-line NSCLC chemotherapy regimen 35

36. 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)

37. 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) diagnosed November 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

38. 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

39. Case study of first-line bevacizumab: clinical course and outcome
Before
treatment
After 6 cycles of
bevacizumab plus
cisplatin/
gemcitabine
Eric Dansin, CRLCC Oscar Lambret, Lille, France

40. 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
PET = positron emission tomography
Eric Dansin, CRLCC Oscar Lambret, Lille, France

41. 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

42. Bevacizumab is changing the therapeutic landscape for advanced NSCLC
Early stage
Locally advanced/metastatic
Surgery and radiotherapy
± adjuvant therapy
PS 3–4
PS 0–2
Best
supportive
care
Platinum doublet
chemotherapy +
bevacizumab* (PS 0–1)
Platinum doublet
chemotherapy or third-generation non-platinum doublet (PS 2)
Single-agent chemotherapy (elderly)
2nd/3rd line
treatment
*NCCN Clinical Practice Guidelines in Oncology
Non-small cell lung cancer v