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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

Future development in breast cancer

Kathy Miller

Indiana University School of Medicine

USA

rational combinations with novel agents in mbc
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
antitumour activity of xeloda combined with avastin
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

xeloda avastin an active combination in heavily pretreated mbc
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

xeloda avastin minimal added toxicity in mbc
Xeloda/Avastin: minimal added toxicity in MBC

Miller K et al. J Clin Oncol 2005;23:792–9

xh shows at least additive activity against xenografts

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)

xeloda herceptin xh high first line activity in her2 positive mbc
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)

xeloda herceptin highly active in patients with pretreated her2 mbc
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)

acceptable incidence of neutropenia with htx

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)

ongoing trials evaluating xh in mbc
Ongoing trials evaluating XH in MBC

H = Herceptin; T = Taxotere; N = vinorelbine; X = Xeloda

rationale for combining avastin and herceptin
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

blockade of vegf and her2 significant effects on xenograft growth
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

phase i study shows avastin herceptin in her2 positive mbc is active
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

phase i study shows avastin herceptin in her2 positive mbc is well tolerated
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

ongoing phase ii avastin herceptin in her2 positive mbc study design
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