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

The new kid on the block: bevacizumab in first-line NSCLC

Nick ThatcherChristie Hospital NHS Trust

Manchester, UK

The therapeutic plateau Modern platinum chemotherapy doublets achieve similar efficacy

Schiller JH, et al. N Engl J Med 2002;346:92–8

Cisplatin/paclitaxel (CIP)Cisplatin/gemcitabine (CG)Cisplatin/docetaxel (CD)Carboplatin/paclitaxel (CP)

Months

1.0

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0.6

0.4

0.2

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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 NS

TRIBUTE CP ± erlotinib 10.5 10.6 NS

TALENT CG ± erlotinib 10.0 10.3 NS

SPIRIT-1 VC ± bexarotene 9.9 8.7 NS

SPIRIT-2 CP ± bexarotene 9.2 8.5 NS

Paz-Ares et al. CG ± aprinocarsen 10.4 10.0 NS

ISIS-3521 CP ± aprinocarsen 9.7 10.0 NS

AG-3340-017 CG ± prinomastat 10.8 11.5 NS

BR.18 CG ± BMS-275291 9.2 8.6 NSNS = not significant; VC = vinorelbine/cisplatin

Early stage

PS 0–2 PS 3–4

NSCLC

Locally advanced/metastatic

Surgery and radiotherapy ± adjuvant therapy

2nd/3rd linetreatment

Bestsupportivecare (BSC)

Platinum doublet chemotherapy or third-generation

non-platinum doublet

Single-agent chemotherapy

(elderly)

Treatment algorithm for NSCLC

PS = performance status

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

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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

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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

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mo

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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

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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

(TC) in first-line NSCLC

PFS (per Independent Radiologic Review Committee)

0 2 4 6 8 10 12 14 16 18 20 22 24

Cetuximab + TC (n=338, events=284)

TC (n=338, events=263)

HR=0.802 (95% CI: 0.761–1.089), p=0.2358

Time from randomisation (months)

4.40 months

4.24 months

Lynch LT, et al. J Thorac Oncol 2007;2(Suppl. 4)S296 (Abstract Y1-03)

1.0

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0.4

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RANDOMISED

All patients were supplemented with vitamins

Patients 75 years received 75% dose

Phase III trial of pemetrexed/carboplatin versus gemcitabine/carboplatin in first-line NSCLC

Gemcitabine/carboplatin (n=218)

Gemcitabine 1,000mg/m2 day 1 and day 8Carboplatin AUC = 5 (Calvert) day 1 every 3 weeks

4 cycles or PD or intolerable toxicity

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

Grønberg BH, et al. J Clin Oncol 2007;25(Suppl. 18 Pt I):S18 (Abstract 7517)

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

Phase III trial of pemetrexed/carboplatin versus gemcitabine/carboplatin in first-line NSCLC

0 200 400 600 800

Days since randomisation

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al (

%)

Grønberg BH, et al. J Clin Oncol 2007;25(Suppl. 18 Pt I):S18 (Abstract 7517)

Pemetrexed plus cisplatin versus gemcitabine/cisplatin in first-line NSCLC

OS (months) by histology Pemetrexed/

cisplatinGemcitabine/

cisplatin 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)

n=1,725Pemetrexed/

cisplatinGemcitabine/

cisplatin

Overall survival (months) 10.3 10.3

PFS (months) 4.8 5.1

1-year survival (%) 43.5 41.9

2-year survival (%) 18.9 14.0

Scagliotti GV, et al. J Thorac Oncol 2007;2:107 (Abstract E09-03)

Patient management

Management ofbevacizumab-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;22:2184–912Sandler 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)

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

Bevacizumab has a well-characterised safety profile: similar profile was observed in E4599 and AVAiL

AVAiL E4599

Grade 3 adverse events (%)

Bevacizumab7.5mg/kg + CG

(n=330)

Bevacizumab 15mg/kg + CG

(n=329)

Bevacizumab 15mg/kg + CP

(n=427)

Hypertension 6 9 7

Neutropenia* Febrile neutropenia*

402

362

25.55.2

Thrombocytopenia* 27 23 1.6

Venous thrombosis 7 7 3.8Arterial thrombosis 2 3 1.9Proteinuria 0.3 1 3.1

Bleeding Epistaxis Haemoptysis

42

1.5

43

0.9

4.40.71.9

Sandler A, et al. N Engl J Med 2006;355:2542–50Manegold C, et al. Eur J Cancer Suppl 2007;5:9 (Abstract 1B)

*E4599 reports only grade 4/5haematological events

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 eventscan be easily managed using standard first-aid

techniques

9.1

1.91.5

0.9

Appropriate patient selectionreduces bleeding risk

Grade 3 pulmonary haemorrhage

Per

cen

tag

e

10

8

6

4

2

0

AVF0757g Bevacizumab 7.5 or 15mg/kg + CP*

E4599 Bevacizumab 15mg/kg + CP

AVAiL Bevacizumab 7.5mg/kg + CG

AVAiL Bevacizumab 15mg/kg + CG

Johnson D, et al. J Clin Oncol 2004;22:2184–91Sandler 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 patientswith squamous cell histology

Restricting eligibility to

patients with non-

squamous histology and

minimal baseline

haemoptysis

Additional exclusion of

tumours abutting or invading major blood

vessels

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 pressureshould be

actively managed

Discontinuationof bevacizumab

is rarely required

Management of hypertension: ACEinhibitors, diuretics and calcium channelblockers all used successfully in AVAiL

Use of diuretics to manage hypertension is not advised in patients who receive cisplatin-based chemotherapy1

27.6

11.1

32.7

19.9

8.7

ACEinhibitor

Beta-blocker

Calciumchannelblocker

Diuretic Other

40

30

20

10

0

Pat

ien

ts (

%)

1Avastin Summary ofProduct CharacteristicsACE = angiotensin converting enzyme

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

Discontinuationof bevacizumab

is rarely required

Safety of Avastin® in Lung (SAiL) trial will provide further safety information

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 willbe recruited

Locally advanced, metastatic or

recurrent non-squamous NSCLC

(n=2,000)

PDBevacizumab

maintenance therapy

Chemotherapy* + bevacizumab

7.5mg/kg or 15mg/kg every 3 weeks

(up to 6 cycles)

*Standard-of-care first-line NSCLC chemotherapy regimen

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