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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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Presentation on theme: "Nick Thatcher Professor of Oncology at the University of Manchester, Christie Hospital NHS Trust and Wythenshawe Hospital, Manchester, UK Chairman of the."— Presentation transcript:

1 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 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 Probability of survival

4 Many targeted therapies have failed to show clinical benefit in first-line NSCLC TrialRegimen Median overall survival (months) p value Placebo Agent INTACT-1CG ± gefitinib /9.9NS INTACT-2CP ± gefitinib /8.7NS TRIBUTECP ± erlotinib NS TALENTCG ± erlotinib NS SPIRIT-1VC ± bexarotene NS SPIRIT-2CP ± bexarotene NS Paz-Ares et al.CG ± aprinocarsen NS ISIS-3521CP ± aprinocarsen NS AG CG ± prinomastat NS BR.18CG ± BMS NS NS = not significant; VC = vinorelbine/cisplatin

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

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

7 Vascular endothelial growth factor (VEGF), the key mediator of tumour angiogenesis, is an ideal therapeutic target 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 VEGF is overexpressed in a wide variety of tumours and may be associated with reduced survival Promotes survival of vasculature critical to tumour 2 Increases intratumoural pressure, preventing penetration of chemotherapeutic agents 4,5 Stimulates new vasculature required for growth and metastasis 3 Has a limited role in healthy adults 1

8 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– VEGF X Growth Proliferation Migration Survival X Bevacizumab

9 Mechanism of action of bevacizumab EARLY EFFECTSCONTINUED EFFECTS Normalisation of remaining tumour vasculature 5–8 1 2 Regression of existing tumour microvasculature 1–7 Inhibition of new tumour vasculature 1,2,9, 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

10 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/m 2 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 = 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) Investigator Independent review facility Median survival (months) *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 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/m 2 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

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

14 2006: survival expectations of patients with advanced NSCLC E4599: breaking through the therapeutic plateau Patient with PS 3–4 Elderly patient with PS 3–4 Patient with PS 0–2 Median survival (months) BSC: 2–5 months Single- agent platinum: 6–8 months Platinum- based doublets: 8–10 months Therapeutic plateau Bevacizu- mab + platinum- based doublet: 12.3 months Bevacizumab- eligible patient

15 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 Bevacizumab Placebo + CG (n=347) Bevacizumab 15mg/kg + CG (n=351) Bevacizumab 7.5mg/kg + CG (n=345) Previously untreated, stage IIIB, IV or recurrent non- squamous NSCLC (n=1,043) RANDOMISERANDOMISE Placebo (no crossover allowed) PFS = progression-free survival

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 – –0.98 p value Median PFS (months) Possibility of PFS Time (months) Manegold C, et al. Eur J Cancer Suppl 2007;5:9 (Abstract 1B) CI = confidence interval

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

18 AVAiL and E4599 have comparable PFS benefit PROGRESSION OR DEATH AVAiL primary PFS analysis E4599 PFS analysis and AVAiL censored analysis Bevacizumab or placebo + chemotherapy Second-line antineoplastic therapy With non-protocol therapy censoring E AVAiL 2 Bevacizumab 15mg/kg + CP (n=434) Bevacizumab 7.5mg/kg + CG (n=345) Bevacizumab 15mg/kg + CG (n=351) HR 95% CI p value – – – 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)

19 Positive trial results led to US and EU approval of bevacizumab plus chemotherapy 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 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

20 Efficacy of other agents in first-line NSCLC

21 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/m 2 2-hour infusion then 250mg/m 2 1-hour infusion weekly) Cisplatin (80mg/m 2 day 1 every 3 weeks) Vinorelbine (30mg/m 2 day 1 and 8 every 3 weeks) Cisplatin (80mg/m 2 day 1 every 3 weeks) Vinorelbine (30mg/m 2 day 1 and 8 every 3 weeks) EGFR = epidermal growth factor receptor

22 Phase III trial of cetuximab plus taxane/carboplatin versus taxane/carboplatin (TC) in first-line NSCLC PFS (per Independent Radiologic Review Committee) Cetuximab + TC (n=338, events=284) TC (n=338, events=263) HR=0.802 (95% CI: 0.761–1.089), p= 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) Probability of PFS

23 RANDOMISEDRANDOMISED 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/m 2 day 1 and day 8 Carboplatin AUC = 5 (Calvert)day 1 every 3 weeks 4 cycles or PD or intolerable toxicity Pemetrexed/carboplatin (n=219) Pemetrexed 500mg/m 2 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)

24 Median OS (months)95% CIp value Pemetrexed/carboplatin7.36.1–8.6 Gemcitabine/carboplatin7.05.8– Phase III trial of pemetrexed/carboplatin versus gemcitabine/carboplatin in first-line NSCLC Days since randomisation Survival (%) 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 OS (months) by histology Pemetrexed/ cisplatin Gemcitabine/ cisplatinHR (CI) Adenocarcinoma (n=847) (0.71–0.98) Large cell (n=153) (0.48–0.97) Squamous cell (n=473) (0.99–1.50) n=1,725 Pemetrexed/ cisplatin Gemcitabine/ cisplatin Overall survival (months)10.3 PFS (months) year survival (%) year survival (%) 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 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)

28 AVAiL had slightly more stringent exclusion criteria than E4599 Exclusion criteria E4599Exclusion criteria AVAiL History of gross haemoptysis (bright red blood  ½ teaspoon) History of grade  2 haemoptysis CNS metastasesBrain 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 AVAiLE4599 Grade  3 adverse events (%) Bevacizumab 7.5mg/kg + CG (n=330) Bevacizumab 15mg/kg + CG (n=329) Bevacizumab 15mg/kg + CP (n=427) Hypertension 697 Neutropenia* Febrile neutropenia* Thrombocytopenia* Venous thrombosis773.8 Arterial thrombosis231.9 Proteinuria Bleeding Epistaxis Haemoptysis 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) *E4599 reports only grade 4/5 haematological events

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 risk Grade  3 pulmonary haemorrhage Percentage 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;22:2184–91 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 Restricting eligibility to patients with non- squamous histology and minimal baseline haemoptysis Additional exclusion of tumours abutting or invading major blood vessels

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 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 ACE inhibitor Beta- blocker Calcium channel blocker DiureticOther Patients (%) 1 Avastin Summary of Product Characteristics ACE = angiotensin converting enzyme

34 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 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 Locally advanced, metastatic or recurrent non- squamous NSCLC (n=2,000) PD Bevacizumab 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

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/m 2 ), gemcitabine (1,250mg/m 2 ) day 8: gemcitabine (1,250mg/m 2 ) 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 Eric Dansin, CRLCC Oscar Lambret, Lille, FrancePET = positron emission tomography

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 Early stage PS 0–2PS 3–4 NSCLC Locally advanced/metastatic Surgery and radiotherapy ± adjuvant therapy 2nd/3rd line treatment Best supportive 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 Oncology Non-small cell lung cancer v


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