Extending life for women with HER2-positive MBC Andreas Makris Mount Vernon Hospital Middlesex, UK

Herceptin + Xeloda (HX): highly active in a range of MBC settings RR, % Median PFS, months Median OS, months 1st line Yamamoto1 (subgroup) 20 65 9.2* 25.6 Xu2 43 63 NR 2nd line or later von Minckwitz GBG-263 78 48 8.2* 25.5 Schaller4 27 45 6.7 28.0 Bartsch5 40 8.0 24.0 36 42 4.3* 15.8 1Yamamoto D et al. Cancer Chemother Pharmacol 2008;61:509–14. 2Xu L et al. Breast Cancer Res Treat 2006;100(S1):S101 (Abst 2065). 3von Minckwitz G et al. J Clin Oncol 2008;26(15S):47S (Abst 1025) 4Schaller G et al. J Clin Oncol 2007;25:3246–50. 5Bartsch R et al. J Clin Oncol 2007;25:3853–8. 1Yamamoto et al 2008; 2Xu et al 2006; 3von Minckwitz et al 2008 4Schaller et al 2007; 5Bartsch et al 2007 *TTP 2

Can the efficacy of Herceptin-taxane regimens be further improved? Rationale for adding Xeloda to HT adding Xeloda to docetaxel improves efficacy in patients unselected for HER2 status1 Could the addition of Xeloda have the same effect in HER2-positive disease? 1O’Shaughnessy J, et al. J Clin Oncol 2002;20:2812-23. 1O’Shaughnessy et al 2002 3

CHAT trial: Herceptin plus docetaxel (HT) ± Xeloda HXT H: 8 mg/kg (loading dose), d1 followed by 6 mg/kg, d1, q3w T: 75 mg/m2, d1 X: 950 mg/m2 bid d1–14 No prior Herceptin, docetaxel or Xeloda HXT Stratification Prior paclitaxel Prior anthracycline Liver metastases KPS R HT H: 8 mg/kg (loading dose), d1 followed by 6 mg/kg, d1, q3w T: 100 mg/m2, d1 HT Wardley A, et al. Eur J Cancer Suppl 2008;6(7):109 (Abst 209). Primary endpoint: RR Secondary endpoints: duration of response, TTP, PFS, OS, safety Wardley et al 2008 4

Case history: May 2003 44-year-old premenopausal woman married with one child Cancer of the right breast invasive ductal carcinoma (IDC) grade II, 4 cm ER positive, PgR positive, HER2 positive (IHC 2+) staging CT scan and bone scan normal no comorbidities 5

Initial treatment Neoadjuvant FEC x 6 (600/60/600) clinical PR after 2nd cycle radiological PR after 6th cycle Wide local excision and axillary node dissection level II 22 mm, grade II, IDC, (4/9 nodes positive) Radiotherapy and tamoxifen 6

Clinical course September 2004: local relapse in breast, axillary nodes and multiple liver metastases CT scan: numerous large lesions within the right lobe of the liver consistent with metastases MRI scan: local breast relapse plus axillary relapse, multiple liver metastases LVEF 60% normal liver function tests 7

Right breast multifocal relapse Multiple liver metastases Relapse: September 2004 MRI scan Right breast multifocal relapse CT scan Multiple liver metastases MRI scan Right axillary relapse 8

Which regimen would you choose? Recap: positive HER2, ER, and PgR status; prior neoadjuvant FEC, radiotherapy, and adjuvant tamoxifen Herceptin + paclitaxel Herceptin + docetaxel Herceptin + docetaxel + Xeloda Herceptin + vinorelbine Herceptin + anastrozole Herceptin + Xeloda 9

Treatment choice Patient consented to CHAT trial Enrolled on 1 November 2004 Xeloda/docetaxel stopped after six cycles continued Herceptin Complete response in breast/axilla; PR in liver (CT scans) 10

Response in liver after enrolment in CHAT 6 months 20 months 11

CHAT: HXT significantly prolongs PFS versus HT Estimated probability HR 95% CI p value HXT 0.725 0.529, 0.99 0.0402 HT 1.0 0.8 0.6 0.4 0.2 Wardley A, et al. Eur J Cancer Suppl 2008;6(7):109 (Abst 209). 12.8 17.9 0 5 10 15 20 25 30 35 40 45 50 Months Wardley et al 2008 12

Summary of CHAT: consider first-line HXT HXT is an effective first-line regimen for HER2-positive MBC HXT significantly prolonged PFS versus HT median 5 months’ increase High RR and good tolerability Survival data immature 13

Right axilla relapse: 31 months after entry into CHAT Relapse in the right axilla Stable disease in the liver May 2007 14

Clinical course continued At relapse → Herceptin + pertuzumab trial Herceptin and pertuzumab: bind to different regions1 inhibit signalling through different mechanisms1 show preclinical synergy2 Pertuzumab 1Hubbard SR. Cancer Cell 2005;7:287–88. 2Scheuer W, et al. Poster presented at EORTC-NCI-AACR 2006 (Abstract 213). Herceptin 1Hubbard 2005 2Scheuer et al 2006 15

Clinical course continued Response to Herceptin + pertuzumab after 3 months: PR in axilla; SD in liver; 1 cm lesion at 6 months: axillary nodes normal size; liver lesion unchanged May 2008: clinically good response Total length of Herceptin therapy: 3 years, 6 months 16

Response in axillary nodes, stable disease in liver May 2007 July 2007 January 2008 17

Conclusions Xeloda + Herceptin is effective in HER2-positive disease after Herceptin and chemotherapy first line alone first line with docetaxel Herceptin + pertuzumab is an active therapy at disease progression 18