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  1. new moves in breast cancer

  2. Welcome Richard BellAndrew Love Cancer Centre, Geelong, Australia

  3. Contributions of Roche Oncology • Substantial clinical trial programme across the spectrum of breast cancer: • paclitaxel ± Avastin as first-line treatment for MBC • Xeloda + docetaxel (XT) vs docetaxel for MBC • HERceptin Adjuvant trial (HERA) • Commitment to the continued development of existing products • Continued exploration of new treatments

  4. Current investigative programme • Different disease settings • neoadjuvant, adjuvant and metastatic • Combinations of chemotherapy with biologic agents • Combinations of biologic agents • Evaluating new treatment strategies

  5. new moves in breast cancer

  6. Integrating Avastin(bevacizumab) into currentand future practice Julie Gralow University of Washington School of Medicine, Seattle, USA David Miles Mount Vernon Hospital, Northwood, Middlesex, UK Kathy Miller Indiana Cancer Pavilion, Indianapolis, USA

  7. E2100: paclitaxel ± Avastin Treat to disease progressiona Paclitaxel (n=354) Previously untreated locally recurrent breast cancer or MBC (n=722) • Primary endpoint: PFS • Other endpoints: ORR, OS, QoL • Inclusion criteria • HER2 negative (HER2 positive only if pretreated with Herceptin [trastuzumab] or unsuitable) • adjuvant taxanes allowed if therapy completed >12 months prior to randomisation Randomised Treat to disease progressiona Paclitaxel + Avastin 10 mg/kg q2w (n=368) Paclitaxel: 90 mg/m2 for 3 weeks of a 4-week cycle aNo crossover permitted; HER2, human epidermal growth factor receptor 2;MBC, metastatic breast cancer; ORR, overall response rate; OS, overall survival;PFS, progression-free survival; QoL, quality of life; q2w, every 2 weeks Miller et al SABCS 2005

  8. The addition of Avastin doubles median PFS, the E2100 primary endpoint Avastin + paclitaxel (n=368): 13.3 months Paclitaxel (n=354): 6.7 months 99%increase in median PFS 1.0 PFS estimate HR=0.48 (95% CI 0.39, 0.59)Log-rank test: p<0.0001 15 10 5 0 0.8 Median PFS (months) 0.6 0.4 Paclitaxel Avastin +paclitaxel 0.2 0.0 6.7 13.3 0 10 20 30 40 Months CI, confidence interval; HR, hazard ratio Avastin Summary of Product Characteristics (SmPC)

  9. The MoA of Avastin suggeststhat it has utility in breast cancer Continued effects Early effects Regression Normalisation Inhibition Reduces tumour mass Enhances activity of concomitant therapies Prevents growth of micrometastases Efficacy in the metastatic, neoadjuvant and adjuvant settings MoA, mechanism of action

  10. Single-agent Avastin showsactivity in pretreated breast cancer 3 mg/kg(n=18) 0 / 5.6 11.0 22.0 6.0 0 6.0 10 mg/kg(n=41) 2.4 / 9.8 17.0 17.0 0 2.0 6.0 20 mg/kg(n=16) 0 / 6.3 19.0 19.0 6.0 6.0 19.0 (n=75) Activity CR/PR, % Clinical benefit at 22 weeks, % Grade 3/4 adverse events Hypertension, % Proteinuria, % CHF/cardiomyopathy, % Headache, % CHF, congestive heart failure;CR, complete response; PR, partial response Cobleigh et al Semin Oncol 2003

  11. Phase III Xeloda (capecitabine) ± Avastin Treat to disease progressiona Xeloda (n=230) • Primary endpoint: PFS • Other endpoints: ORR and OS • Prior anthracycline and taxane treatment • 1 or 2 prior chemotherapy regimens for MBC, overall response • relapse within 12 months of completing anthracycline- and taxane-containing adjuvant Previously treated MBC (n=462) Randomised Treat to disease progression Xeloda + Avastin 15 mg/kg q3w (n=232) Xeloda: 1250 mg/m2 orally bid for 2 weeks of a 3-week cycle aNo crossover permitted; q3w, every 3 weeks Miller et al J Clin Oncol 2005

  12. Avastin + Xeloda demonstrates clinical activity in a highly pretreated population Xeloda(n=230) Avastin + Xeloda(n=232) p value ORR, % Investigator IRF Median PFS, months Median OS, months 19.19.1 4.2 14.5 30.219.8 4.9 15.1 0.0060.001 NS NS According to an independent review, the addition of Avastin to Xeloda more than doubled the response rate Miller et al J Clin Oncol 2005 IRF, independent review facility; NS, not significant

  13. E2100: the addition of Avastin more than doubles ORR Complete response Partial response ORR % 40 36.2 30 19.8% p<0.0001 20 16.4 10 0 Paclitaxel(n=268) Avastin + paclitaxel(n=246) http://www.emea.europa.eu/humandocs/Humans/EPAR/avastin/avastin.htm

  14. E2100: the addition of Avastin doubles median PFS, the primary endpoint Avastin + paclitaxel (n=368): 13.3 months Paclitaxel (n=354): 6.7 months 99%increase in median PFS 1.0 PFS estimate HR=0.48 (95% CI 0.39, 0.59)Log-rank test: p<0.0001 15 10 5 0 0.8 Median PFS (months) 0.6 0.4 Paclitaxel Avastin +paclitaxel 0.2 0.0 6.7 13.3 0 10 20 30 40 Months Avastin SmPC

  15. E2100: a meaningful increase in PFS in prespecified patient subgroups Increase inmedian PFS (%) 12 months Median PFS Prior adjuvant hormonetherapy (n=341) 71 122 207 112 58 66 95 51 Prior adjuvantchemotherapy (n=469) Prior adjuvant taxanetherapy (n=140) Prior adjuvant anthracyclinetherapy (n=353) Prior metastatic hormonetherapy (n=264) ER-positive status (n=445) ≤24-month disease-free interval (n=296) ≥3 metastatic sites (n=208) 0 5 10 15 Months Paclitaxel Avastin + paclitaxel ER, oestrogen receptor http://www.emea.europa.eu/humandocs/Humans/EPAR/avastin/avastin.htm

  16. E2100: the addition of Avastin to paclitaxel leads to superior 1-year survival Avastin + paclitaxel (n=368): 25.7 months 1.0 OS estimate Paclitaxel (n=354): 23.8 months 82.3%; p=0.007a 0.8 73.8% 0.6 0.4 0.2 HR=0.82 Log-rank test: p=0.082 0.0 0 6 12 18 24 30 36 42 48 Months aExploratory analysis http://www.emea.europa.eu/humandocs/Humans/EPAR/avastin/avastin.htm

  17. new moves in breast cancer

  18. Grade 3/4 hypertension in Phase III trials of Avastin in MBC 40 Incidence (%) Paclitaxel (n=346) Avastina + paclitaxelb (n=362) Xeloda (n=215) Avastinc + Xeloda (n=229) 30 20 10 0 Grade 3 Grade 4 Grade 3 Grade 4 aAvastin given every 2 weeks; bIncludes NCI AdEERS mandatory collection in the Avastin + paclitaxel arm only, which does not allow a valid comparison between the 2 arms; cAvastin given every 3 weeks http://www.emea.europa.eu/humandocs/Humans/EPAR/avastin/avastin.htm;Miller et al J Clin Oncol 2005

  19. Grade 3/4 proteinuria in Phase III trials of Avastin in MBC 40 Incidence (%) Paclitaxel (n=346) Avastina + paclitaxelb (n=362) Xeloda (n=215) Avastinc + Xeloda (n=229) 30 20 10 0 Grade 3 Grade 4 Grade 3 Grade 4 aAvastin given every 2 weeks; bIncludes NCI AdEERS mandatory collection in the Avastin + paclitaxel arm only, which does not allow a valid comparison between the 2 arms; cAvastin given every 3 weeks http://www.emea.europa.eu/humandocs/Humans/EPAR/avastin/avastin.htm;Miller et al J Clin Oncol 2005

  20. Avastin + paclitaxel: generally well tolerated with no unexpected adverse events Paclitaxel(n=346), % Avastin + paclitaxel (n=362), % Selected grade 3/4 adverse eventsa Grade 3 Grade 4 Grade 3 Grade 4 Sensory neuropathy Fatigue Neutropenia Hypertension Arterial thromboembolic eventsb,c Venous thromboembolic events Bleeding Proteinuria Left ventricular dysfunctionb 15.9 4.6 1.2 1.4 0 1.4 0 0 0 0.6 0.3 0.3 0 0 1.7 0 0 0 22.9 8.8 2.8 15.2 1.1 2.5 1.4 1.7 1.1 0.6 0.3 0.3 0.3 1.4 0.3 0.6 1.4 0.3 aIncludes additional NCI-AdEERS mandatory collection in the Avastin + paclitaxel arm only, therefore does not allow a valid comparison between study arms;bEvents double-counted where applicable; cAn additional patient died from myocardial infarction in the Avastin + paclitaxel arm http://www.emea.europa.eu/humandocs/Humans/EPAR/avastin/avastin.htm

  21. AVADO final PFS data expected in 2008 Treat to disease progression Docetaxel 100 mg/m2 + placebo q3w • Recruitment commenced March 2006 and completed in March 2007 • target exceeded (736 patients enrolled) • Primary endpoint: PFS • Secondary endpoints: ORR, OS, safety, QoL Previously untreated HER2-negative locally recurrent breast cancer or MBC (n=705) Treat to disease progression Docetaxel + Avastin 7.5 mg/kg q3w Randomised Treat to disease progression Docetaxel + Avastin 15 mg/kg q3w PI: David Miles

  22. RIBBON-1 expands the use of Avastin with SOC chemotherapy in 1st-line MBC • Recruitment expected to finish end October 2007 • Primary endpoint: PFS • Secondary endpoints: chemotherapy-specific PFS, objective response rate, OS, safety Taxane- or anthracycline-based chemotherapy or Xeloda + Avastin 15 mg/kg q3w Treat to disease progressiona Previously untreated MBC (n=1200) Randomised Taxane- or anthracycline-based chemotherapy or Xeloda + placebo Treat to disease progressiona PI: Joyce O’Shaughnessy aContinuation or crossover to Avastin is allowed at the discretion of the investigator; SOC, standard of care

  23. new moves in breast cancer

  24. Avastin Phase III studies in the neoadjuvant and adjuvant settings in breast cancer Neoadjuvant HER2 negative E2104 / E5103Doxorubicin +cyclophosphamide paclitaxel Triple negative NSABP-B40 Docetaxel + Xeloda or gemcitabine  doxorubicin + cyclophosphamide BEATRICEMultiplechemotherapyregimens HER2 positive BETHAdjuvantchemotherapy+ Herceptin Adjuvant Avastin

  25. Doubles median PFS Superior 1-year survival More than doubles ORR Generally well tolerated Higher QoL scores Avastin establishes the anti-angiogenesis era in MBC Targeting VEGF with Avastin improves clinical outcomes The unique MoA of Avastin supports use until disease progression Avastin has the potential to be used with all standard regimens VEGF, vascular endothelial growth factor

  26. new moves in breast cancer

  27. Xeloda at the X-roadsof therapy decisions Martin Stockler Sydney Cancer Centre, Sydney, Australia Julie Gralow University of Washington, Seattle, USA Chris Twelves University of Leeds, Yorkshire, UK

  28. Phase III trial: first-line Xeloda vs CMF Primary endpoints: PFS (efficacy), quality-adjusted PFS (effectiveness) Secondary endpoints:RR, health-related QoL, OS and safety RANDO MIS ATION Intermittent Xeloda1,000 mg/m2 bid d1–14 q3w (increased to 1,250 mg/m2 if no toxicity in cycles 1 and 2) MBC patients unsuitable for intensive chemotherapy Stratified for institution, PS, liver or brain mets, planned use of bisphosphonates/ prednisone Continuous Xeloda650 mg/m2 bid d1–21 q3w Classical CMFOral cyclophosphamide 100 mg/m2 d1–14i.v. methotrexate 40 mg/m2 d1,8 i.v. 5-FU 600 mg/m2 d1,8 q4w Stockler MR et al ASCO 2007, poster 1031

  29. Xeloda vs CMF baseline characteristics:a relatively young, fit population Stockler MR et al ASCO 2007, poster 1031

  30. Xeloda vs CMF: similar response rates Stockler MR et al ASCO 2007, poster 1031

  31. Xeloda vs CMF: similar PFS 1.0 0.8 0.6 0.4 0.2 0 Median (months) Xeloda (int + cont) 6 CMF 7 HR 0.86 (95% CI: 0.67–1.10) Log-rank p=0.2 Proportion progression-free 0 6 12 18 24 30 36 42 48 Months Stockler MR et al ASCO 2007, poster 1031

  32. Xeloda vs CMF: significant survivalbenefit with Xeloda 1.0 0.8 0.6 0.4 0.2 0 Median (months) Xeloda (int + cont) 22 CMF 18 HR 0.72 (95% CI: 0.55–0.94) Log-rank p=0.02 Proportion alive 0 6 12 18 24 30 36 42 48 Months Stockler MR et al ASCO 2007, poster 1031

  33. Xeloda vs CMF: longer treatment duration with Xeloda Stockler MR et al ASCO 2007, poster 1031

  34. Xeloda vs CMF: significant survivalbenefit with Xeloda 1.0 0.8 0.6 0.4 0.2 0 Median (months) Xeloda (int + cont) 22 CMF 18 HR 0.72 (95% CI: 0.55–0.94) Log-rank p=0.02 Proportion alive 0 6 12 18 24 30 36 42 48 Months Stockler MR et al ASCO 2007, poster 1031

  35. Xeloda vs CMF: post-study therapydoes not explain the survival difference Stockler MR et al ASCO 2007, poster 1031

  36. First-line Xelodamonotherapy: summary of Phase II efficacy 1O’Shaughnessy J et al Ann Oncol 2001 2Bajetta E et al J Clin Oncol 2005

  37. Global QoL measures were similar. . . Favours CMF Favours Xeloda Mood Physical well-being Overall QoL Spitzer’s QoL index Health status –2 –1 0 1 2 3

  38. . . . but many specific aspects werebetter with Xeloda than CMF Favours CMF Favours Xeloda Loss of hair Uncertainty about the future Inability to concentrate Thought of chemo Feeling anxious or worried Difficulty sleeping Shortness of breath Dissatisfaction with weight or appetite Constipation Loss of self confidence Lack of energy Anger or resentment Feeling sad or depressed Diarrhoea Loneliness Feeling dependent on others Numbness or pins and needles Feeling sick (nausea/vomiting) Loss of appetite Aches and pains –2 –1 0 1 2 3

  39. . . . but many specific aspects werebetter with Xeloda than CMF Favours CMF Favours Xeloda Sore or watery eyes Sore mouth Altered taste Problems with needles or injections Problems with family and friends Coping with treatment Inconvenience Nausea Problems doing what I want Problems taking tablets Problems looking after myself Vomiting Difficulty walking Skin rash Sore hands or feet –2 –1 0 1 2 3

  40. Grade 3/4 adverse events (%) Stockler MR et al ASCO 2007, poster 1031

  41. new moves in breast cancer

  42. CIBOMA Phase III adjuvant trial: Xelodavs observation after standard chemotherapy RANDO MISATION Xeloda (6 cycles) 1,000 mg/m2 bidd1–14 q21d Standard anthracycline- and/or taxane-based chemotherapy (6 cycles) Operable, triple-negative, non-metastatic disease; node positive or tumour >2cm n=3,538 Observation Primary endpoint: 5-year disease-free survival (DFS)

  43. TACT2 UK adjuvant study: sequential Xelodamonotherapy RANDO MIS ATION Epirubicin (4 cycles) 100 mg/m2 d1 q21d CMF (4 cycles) C: 100 or 600 mg/m2 d1–14 M: 40 mg/m2 d1,8 F: 600 mg/m2 d1 q28d Completely resected or inoperable BC, no prior chemotherapy, hormonal therapy or radiotherapy n=4,400 Epirubicin (4 cycles) 100 mg/m2 d1 q21d Xeloda (4 cycles) 1,250 mg/m2 bidd1–14 q21d • Primary endpoint: 5-year DFS • 2 x 2 factorial design; accelerated epirubicin with G-CSF Hormonal therapy and/or Herceptin if appropriate

  44. new moves in breast cancer

  45. Staying at home for treatment andconvenient administration are the mostimportant factors influencing treatment choice Patients (%) 100 80 60 40 20 0 Górnas M et al ASCO 2007, poster 1111

  46. new moves in breast cancer

  47. MOSG: combination vs sequentialXeloda and taxane therapy XT XP R t X Soto C et al ASCO 2006, poster 570

  48. new moves in breast cancer

  49. Median overall survival: 26 months After a median follow-up of 29 months median TTF is 9 months (95% CI: 7−11) median OS is 26 months (95% CI: 22−30) Of the 90 patients analysed, 72% received second-line chemotherapy

  50. new moves in breast cancer