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

2. 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 Schaller et al 2007; 5Bartsch et al 2007
*TTP 2

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 J, et al. J Clin Oncol 2002;20:
1O’Shaughnessy et al 2002 3

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
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

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 5

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 6

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 7

8. 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

9. 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

10. 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

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

12. CHAT: HXT significantly prolongs PFS versus HT
Estimated probability
HR 95% CI p value
HXT , 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
Months
Wardley et al 2008 12

13. 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

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

15. 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

16. 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

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

18. 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