Extending life for women with HER2-positive MBC

1. Extending life for women with HER2-positive MBC Andreas Makris Mount Vernon HospitalMiddlesex, UK

2. Herceptin + Xeloda (HX): highly active in a range of MBC settings 1Yamamoto et al 2008; 2Xu et al 2006; 3von Minckwitz et al 2008 4Schaller et al 2007; 5Bartsch et al 2007 *TTP

3. 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 et al 2002

4. 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 • Primary endpoint: RR • Secondary endpoints: duration of response, TTP, PFS, OS, safety Wardley et al 2008

5. 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

6. 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

7. 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

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

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 20 months 6 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 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 continuedAt relapse → Herceptin + pertuzumab trial Herceptin and pertuzumab: bind to different regions1 inhibit signalling through different mechanisms1 show preclinical synergy2 Pertuzumab 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 January 2008 July 2007 May 2007

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