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Future development in breast cancer

Future development in breast cancer. Kathy Miller Indiana University School of Medicine USA. Rational combinations with novel agents in MBC. Proven activity Avastin, Herceptin, Xeloda monotherapy Avastin plus chemotherapy (paclitaxel) Herceptin plus chemotherapy (taxanes)

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Future development in breast cancer

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  1. Future development in breast cancer Kathy Miller Indiana University School of Medicine USA

  2. Rational combinations with novel agents in MBC • Proven activity • Avastin, Herceptin, Xeloda monotherapy • Avastin plus chemotherapy (paclitaxel) • Herceptin plus chemotherapy (taxanes) • Xeloda plus Taxotere • Preliminary activity/ongoing trials • Avastin plus Xeloda (± taxanes) • Herceptin plus Xeloda (± taxanes) • Avastin plus Herceptin

  3. Antitumour activity of Xelodacombined with Avastin Mean tumour volume (mm3) 1000 800 600 400 200 0 KPL4 ER– xenograft Control X ½ MTD X MTD A A + X ½ MTD A + X MTD 14 16 18 20 22 24 26 28 30 32 Days post-tumor cell implant

  4. Xeloda/Avastin: an activecombination in heavily pretreated MBC • 3-weekly regimen • Xeloda 1250mg/m2 twice daily, days 1–14 • Avastin 15mg/kg, day 1 Miller K et al. J Clin Oncol 2005;23:792–9

  5. Xeloda/Avastin: minimal added toxicity in MBC Miller K et al. J Clin Oncol 2005;23:792–9

  6. Large ongoing trial program investigating Xeloda/Avastin

  7. Control X HT XT XHT H XH XH shows at least additive activity against xenografts Tumour volume (mm3) • 1000 • 800 • 600 • 400 • 200 • 100 1000 100 10 BT474 xenograft KPL-4 xenograft 20 30 40 50 60 20 30 40 50 60 Days after inoculation Fujimoto-Ouchi K et al. Cancer Chemother Pharmacol 2002;49:211–16Adapted from Sawada N et al. Proc Am Assoc Cancer Res 2002;43:1088 (Abst 5388)

  8. Xeloda + Herceptin (XH): high first-line activity in HER2-positive MBC • Favourable safety (n=43) • only grade 3 adverse events HFS 9%, leucopenia 2%; no grade 4 Xu L et al. Eur J Cancer Suppl 2005;3:125 (Abst 446)

  9. Xeloda/Herceptin: highly active in patients with pretreated HER2+ MBC • No significant additional toxicity with addition of Herceptin to Xeloda monotherapy *Dose intensity 25% less than standard 1Yamamoto D et al. J Clin Oncol 2005;23:78s (Abst 802) 2Schaller G et al. J Clin Oncol 2005;23:57s (Abst 717)

  10. HTX HT Acceptable incidence of neutropenia with HTX • Herceptin (8mg/kg loading dose, 6mg/kg q3w), Taxotere (75 or 100mg/m2, q3w), Xeloda (950mg/m2 b.i.d., d1–14, q3w) Patients (%) 80 60 40 20 0 Grade 3/4 neutropenia Complicated neutropenia Congestive heart failure Wardley A et al. SABCS 2005 (Abst 6094)

  11. Ongoing trials evaluating XH in MBC H = Herceptin; T = Taxotere; N = vinorelbine; X = Xeloda

  12. Rationale for combiningAvastin and Herceptin • Avastin and Herceptin target different factors involved in tumour growth and progression • combining the two agents may enhance antitumour activity • Activation or overexpression of HER2 is associated with upregulation of VEGF in human breast cancer cells • both are predictive factors for the clinical outcome of primary breast cancer • HER2-positive tumours have significantly increased levels of angiogenesis Konecny G et al. Clin Cancer Res 2004;10:1706–16

  13. Blockade of VEGF and HER2: significant effects on xenograft growth Xenograft volume (mm3) 800 700 600 500 400 300 200 100 0 Vehicle control Herceptin Avastin Avastin + Herceptin * 0 7 14 22 29 35 Treatment day *p<0.05 compared with vehicle control and Herceptin-treated groups Provided by Dr Mark Pegram, UCLA

  14. Phase I study shows Avastin/Herceptin in HER2-positive MBC is active • One partial response following progression on Herceptin • Five patients continue on study, three patients for >1 year • Recommended doses: Avastin 10mg/kg every 2 weeks; Herceptin 2mg/kg weekly (after a 4mg/kg loading dose) Pegram M et al. Breast Cancer Res Treat 2004;88:Abstract 3039

  15. Phase I study shows Avastin/Herceptin in HER2-positive MBC is well tolerated Pegram M et al. Breast Cancer Res Treat 2004;88:Abstract 3039

  16. Ongoing phase II Avastin/Herceptin in HER2-positive MBC: study design • Endpoints: efficacy and safety • Study started: August 2003 • Expected enrolment: 50 • Non-randomised, open-label, uncontrolled study HER2-positive recurrent or MBC (n=50) Avastin 10mg/kg every 2 weeks + Herceptin PD

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