Extending life for women with HER2-positive MBCAndreas MakrisMount Vernon HospitalMiddlesex, UK

1Yamamoto et al 2008; 2Xu et al 2006; 3von Minckwitz et al 2008 4Schaller et al 2007; 5Bartsch et al 2007

Herceptin + Xeloda (HX): highly active in a range of MBC settings

n RR, %Median PFS,

monthsMedian OS,

months

1st line

Yamamoto1 (subgroup) 20 65 9.2* 25.6

Xu2 43 63 NR NR

2nd line or later

von Minckwitz GBG-263 78 48 8.2* 25.5

Schaller4 27 45 6.7 28.0

Bartsch5 40 20 8.0 24.0

Yamamoto1 (subgroup) 36 42 4.3* 15.8

*TTP

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

HXT

H: 8 mg/kg (loading dose), d1 followed by 6 mg/kg, d1, q3wT: 75 mg/m2, d1 X: 950 mg/m2 bid d1–14

CHAT trial: Herceptin plus docetaxel (HT) ± Xeloda

No prior Herceptin, docetaxel or Xeloda

Primary endpoint: RRSecondary endpoints: duration of response, TTP, PFS,

OS, safety

Stratification

• Prior paclitaxel

• Prior anthracycline

• Liver metastases

• KPS

R

Wardley et al 2008

HXT

HT

HT

H: 8 mg/kg (loading dose), d1followed by 6 mg/kg, d1, q3w

T: 100 mg/m2, d1

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

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

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

Relapse: September 2004

CT scanMultiple liver metastases

MRI scanRight breast multifocal relapse

MRI scanRight axillary relapse

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)

Response in liver after enrolment in CHAT

6 months 20 months

CHAT: HXT significantly prolongs PFS versus HT

1.0

0.8

0.6

0.4

0.2

Estimated probability

0 5 10 15 20 25 30 35 40 45 50

Months

12.8 17.9

HR 95% CI p value

HXT 0.725 0.529, 0.99 0.0402HT

Wardley et al 2008

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

Right axilla relapse:31 months after entry into CHAT

May 2007

Relapse in the right axilla

Stable disease in the liver

Clinical course continuedAt relapse → Herceptin + pertuzumab trial Herceptin and pertuzumab:

– bind to different regions1

– inhibit signalling through different mechanisms1

– show preclinical synergy2

1Hubbard 20052Scheuer et al 2006

Herceptin

Pertuzumab

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

Response in axillary nodes, stable disease in liver

May 2007 July 2007 January 2008

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