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

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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 Thatcher

Christie Hospital NHS Trust Manchester, UK

The therapeutic plateau



Modern platinum chemotherapy doublets achieve similar efficacy 1.0

0.8

0.6

Cisplatin/paclitaxel (CIP) Cisplatin/gemcitabine (CG) Cisplatin/docetaxel (CD) Carboplatin/paclitaxel (CP) 0.4

0.2

0 0 5 10 15 Months 20 25 30 Schiller JH, et al. N Engl J Med 2002;346:92 –8

Many targeted therapies have failed to show clinical benefit in first-line NSCLC

Trial INTACT-1 INTACT-2 TRIBUTE TALENT SPIRIT-1 SPIRIT-2 Paz-Ares et al.

ISIS-3521 AG-3340-017 BR.18

Regimen CG ± gefitinib CP ± gefitinib CP ± erlotinib CG ± erlotinib VC ± bexarotene CP ± bexarotene CG ± aprinocarsen CP ± aprinocarsen CG ± prinomastat CG ± BMS-275291 NS = not significant; VC = vinorelbine/cisplatin Median overall survival (months) Placebo 10.9

Agent 9.9/9.9

9.9

10.5

10.0

9.9

9.2

10.4

9.7

10.8

9.2

9.8/8.7

10.6

10.3

8.7

8.5

10.0

10.0

11.5

8.6

p value NS NS NS NS NS NS NS NS NS NS

Treatment algorithm for NSCLC

NSCLC Early stage Surgery and radiotherapy ± adjuvant therapy Locally advanced/metastatic 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

1990s: survival expectations of patients with advanced NSCLC

14 12 10 8 6 4 2 0 BSC: 2 –5 months Patient with PS 3 –4 Single-agent platinum: 6 –8 months Elderly patient with PS 3 –4 Platinum based doublets: 8 –10 months Patient with PS 0 –2

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 Has a limited role in healthy adults 1 Promotes survival of vasculature critical to tumour 2 Stimulates new vasculature required for growth and metastasis 3 Increases intratumoural pressure, preventing penetration of chemotherapeutic agents 4,5 1 Ferrara N, et al. Nat Med 2003;9:669 –76; 2 Alon T, et al. Nat Med 1995;1:1024 –8 3 Folkman J. N Engl J Med 1971;285:1182 –6; 4 Netti P, et al. Proc Natl Acad Sci USA 1999;96:3137 –42 5 Dvorak H, et al. Am J Pathol 1995;146:1029 –39

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 Bevacizumab P – P – X X – P – P Growth Proliferation Migration Survival VEGF

Mechanism of action of bevacizumab

EARLY EFFECTS CONTINUED EFFECTS 1 2 Regression of existing tumour microvasculature 1 –7 Normalisation of remaining tumour vasculature 5 –8 3 Inhibition of new tumour vasculature 1,2,9,10 1 Baluk P, et al. Curr Opin Genet Dev 2005;15:102 –11; 2 Inai T, et al. Am J Pathol 2004;165:35 –52 3 Erber R, et al. FASEB J 2004; 4 Tong R, et al. Cancer Res 2004;64:3731 –6 5 Jain R. Nat Med 2001;7:987 –9; 6 Jain R. Science 2005;307:58 –62 7 Lee C-G, et al. Cancer Res 2000;60:5565 –70; 8 Willett C, et al. Nat Med 2004;10:145 –7 9 Gerber H-P, et al. Cancer Res 2005;65:671 –81; 10 Warren R, et al. J Clin Invest 1995;95:1789 –97

Phase II trial of bevacizumab in NSCLC (AVF0757g): trial design

CP x 6 (n=32) PD Bevacizumab (15mg/kg) every 3 weeks 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/m 2 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

Phase II trial of bevacizumab in NSCLC (AVF0757g): proof of principle

CP (n=32) Bevacizumab + CP Bevacizumab 7.5mg/kg (n=32) Bevacizumab 15mg/kg (n=34) Response rate, % (n) Investigator Independent review facility Median time to progression (months) Investigator Independent review facility Median survival (months) *n=35 18.8 (6) 31.3 (10) 4.2

5.9

14.9

28.1 (9) 21.9 (7) 4.3

4.1

11.6

31.5 (11)* 40.0 (14)* 7.4

7.0

17.7

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) PD* *No crossover permitted Bevacizumab (15mg/kg) every 3 weeks until progression PD

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Primary endpoint: overall survival



Bevacizumab 15mg/kg i.v. administered every 3 weeks



Carboplatin i.v. to AUC 6 and paclitaxel 200mg/m 2 i.v. every 3 weeks Sandler A, et al. N Engl J Med 2006;355:2542 –50

E4599: bevacizumab-based therapy was the first regimen to extend overall survival beyond 1 year 1.0

0.8

Bevacizumab + CP CP HR=0.79 (0.67

–0.92); p=0.003

Median overall survival >12 months 15 12.3

10.3

10 0.6

5 0.4

0 0.2

0 0 6 10.3

12 12.3

18 24 Months HR = hazard ratio 30 36 42 CP 48 Bevacizumab + CP Sandler A, et al. N Engl J Med 2006;355:2542 –50

2006: survival expectations of patients with advanced NSCLC

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E4599: breaking through the therapeutic plateau 14 Therapeutic plateau 12 10 8 6 4 2 0 BSC: 2 –5 months Single agent platinum: 6 –8 months Platinum based doublets: 8 –10 months Bevacizu mab + platinum based doublet: 12.3 months Patient with PS 3 –4 Elderly patient with PS 3 –4 Patient with PS 0 –2 Bevacizumab eligible patient

Phase III trial of bevacizumab plus CG in NSCLC (AVAiL): trial design

Previously untreated, stage IIIB, IV or recurrent non squamous NSCLC (n=1,043) R A N D O M I S E Bevacizumab 7.5mg/kg + CG (n=345) Placebo + CG (n=347) Bevacizumab Placebo (no crossover allowed) PD 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)

AVAiL: significant improvement in PFS with both doses of bevacizumab

1.0

0.8

HR 95% CI p value Median PFS (months) Placebo + CG 6.1

Bevacizumab 7.5mg/kg + CG 0.75

0.62

–0.91

0.0026

6.7

Bevacizumab 15mg/kg + CG 0.82 0.68

–0.98

0.0301

6.5

0.6

0.4

0.2

0 0 3 CI = confidence interval 6 9 Time (months) 12 15 18 Manegold C, et al. Eur J Cancer Suppl 2007;5:9 (Abstract 1B)

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

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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 treatment 1 1 Punt C, et al. J Natl Cancer Inst 2007;99:998 –1003

AVAiL and E4599 have comparable PFS benefit

HR 95% CI p value AVAiL primary PFS analysis Bevacizumab or placebo + chemotherapy Second-line antineoplastic therapy E4599 PFS analysis and AVAiL censored analysis E4599 1 With non-protocol therapy censoring AVAiL 2 Bevacizumab 15mg/kg + CP (n=434) Bevacizumab 7.5mg/kg + CG (n=345) Bevacizumab 15mg/kg + CG (n=351) 0.66

0.57

–0.77

0.68 0.56

–0.83

0.74 0.60

–0.90

0.001

0.0001

0.0021

1 Sandler A, et al. N Engl J Med 2006;355:2542 –50 2 Manegold 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 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

Efficacy of other agents in first-line NSCLC

Phase III trial of cetuximab plus cisplatin/vinorelbine in first-line NSCLC (FLEX) Cetuximab (initial 400mg/m 2 infusion then 250mg/m 2 2-hour 1-hour infusion weekly) Cisplatin (80mg/m 2 day 1 every 3 weeks) Vinorelbine (30mg/m 2 day 1 and 8 every 3 weeks) Patients with EGFR expressing NSCLC (n=1,100) 1:1 randomisation Cisplatin (80mg/m 2 day 1 every 3 weeks) Vinorelbine (30mg/m 2 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

Phase III trial of cetuximab plus taxane/carboplatin versus taxane/carboplatin (TC) in first-line NSCLC

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PFS (per Independent Radiologic Review Committee) 1.0

HR=0.802 (95% CI: 0.761

–1.089), p=0.2358

0.8

0.6

0.4

4.24 months 0.2

4.40 months Cetuximab + TC (n=338, events=284) TC (n=338, events=263) 0 0 2 4 6 8 10 12 14 16 18 Time from randomisation (months) 20 22 24 Lynch LT, et al. J Thorac Oncol 2007;2(Suppl. 4)S296 (Abstract Y1-03)

Phase III trial of pemetrexed/carboplatin versus gemcitabine/carboplatin in first-line NSCLC R A N D O M I S E D Pemetrexed/carboplatin (n=219) Pemetrexed 500mg/m 2 Carboplatin AUC = 5 (Calvert) day 1 day 1 every 3 weeks 4 cycles or PD or intolerable toxicity Gemcitabine/carboplatin (n=218) Gemcitabine 1,000mg/m 2 Carboplatin AUC = 5 (Calvert) day 1 and day 8 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)

Phase III trial of pemetrexed/carboplatin versus gemcitabine/carboplatin in first-line NSCLC 1.0

0.8

Pemetrexed/carboplatin Gemcitabine/carboplatin Median OS (months) 95% CI p value 7.3

7.0

6.1

–8.6

5.8

–8.2

0.60

0.6

0.4

0.2

0 0 200 400 Days since randomisation 600 800 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

n=1,725 Overall survival (months) PFS (months) 1-year survival (%) 2-year survival (%) Pemetrexed/ cisplatin 10.3

4.8

43.5

18.9

Gemcitabine/ cisplatin 10.3

5.1

41.9

14.0

OS (months) by histology Adenocarcinoma (n=847) Large cell (n=153) Squamous cell (n=473) Pemetrexed/ cisplatin 12.6

10.4

9.4

Gemcitabine/ cisplatin 10.9

6.7

10.8

HR (CI) 0.84 (0.71

–0.98) 0.68 (0.48

–0.97) 1.22 (0.99

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

Patient management

Management of bevacizumab-associated adverse events



In patients with NSCLC

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no unexpected toxicities seen with bevacizumab plus platinum-based chemotherapy 1 –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 1 Johnson D, et al. J Clin Oncol 2004;22:2184 –91 2 Sandler A, et al. N Engl J Med 2006;355:2542 –50 3 Manegold 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 History of gross haemoptysis (bright red blood



½ teaspoon) CNS metastases Exclusion criteria AVAiL History of grade



2 haemoptysis 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 Grade



3 adverse events (%) Hypertension Neutropenia* Febrile neutropenia* Thrombocytopenia* Venous thrombosis Arterial thrombosis Proteinuria Bleeding Epistaxis Haemoptysis *E4599 reports only grade 4/5 haematological events AVAiL Bevacizumab 7.5mg/kg + CG (n=330) Bevacizumab 15mg/kg + CG (n=329) 6 40 2 9 36 2 27 7 2 0.3

4 2 1.5

23 7 3 1 4 3 0.9

E4599 Bevacizumab 15mg/kg + CP (n=427) 7 25.5

5.2

1.6

3.8

1.9

3.1

4.4

0.7

1.9

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)

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

10 8 6 4 2

Appropriate patient selection reduces bleeding risk

9.1

Restricting eligibility to patients with non squamous histology and minimal baseline haemoptysis 1.9

AVF0757g Bevacizumab 7.5 or 15mg/kg + CP* E4599 Bevacizumab 15mg/kg + CP AVAiL Bevacizumab 7.5mg/kg + CG AVAiL Bevacizumab 15mg/kg + CG Additional exclusion of tumours abutting or invading major blood vessels 1.5

0.9

0 Grade



3 pulmonary haemorrhage *Phase II trial including patients with squamous cell histology 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)

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 Blood pressure should be actively managed



Grade 3

–

start antihypertensive therapy with two or more drugs, hold bevacizumab for persistent or symptomatic therapy Discontinuation of bevacizumab is rarely required

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 chemotherapy 1 40 32.7

30 27.6

19.9

20 11.1

8.7

10 0 ACE inhibitor Beta blocker ACE = angiotensin converting enzyme Calcium channel blocker Diuretic Other 1 Avastin Summary of Product Characteristics

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

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

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) 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/m gemcitabine (1,250mg/m 2 ) 2 ),

•

day 8: gemcitabine (1,250mg/m 2 ) 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

Before treatment After 6 cycles of bevacizumab plus cisplatin/ 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 PET = positron emission tomography Eric Dansin, CRLCC Oscar Lambret, Lille, France

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

Bevacizumab is changing the therapeutic landscape for advanced NSCLC

NSCLC Early stage Surgery and radiotherapy ± adjuvant therapy Best supportive care Locally advanced/metastatic PS 3 –4 PS 0 –2 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.2.2008