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Journal conference
Pertuzumab plus Trastuzumab plus
Docetaxel for Metastatic Breast
Cancer
José Baselga, M.D., Ph.D., Javier Cortés, M.D., Sung-Bae Kim, M.D., Seock-Ah Im,
M.D., Roberto Hegg, M.D.,Young-Hyuck Im, M.D., Laslo Roman, M.D., José Luiz
Pedrini, M.D., Tadeusz Pienkowski, M.D.,Adam Knott, Ph.D., Emma Clark, M.Sc.,
Mark C. Benyunes, M.D., Graham Ross, F.F.P.M., Sandra M. Swain, M.D., for the
CLEOPATRA Study Group
N Engl J Med 2012;366:109-19.
R2. Yujin Um / Prof. Sunkyung Beak
BACKGROUND
20% of all breast cancers
gene amplification,
Overexpression
Treatment with Trastuzumab
(anti-HER2 humanized
monoclonal antibody)
+ chemotherapy
of HER2
(human epidermal growth
factor receptor )
more aggressive phenotype
a poor prognosis
improves progression-free
and overall survival
among patients with HER2positive metastatic
breast cancer
N Engl J Med 2007;357:39-51.
Figure 1 . Signal Transduction by the HER Family and Potential Mechanisms of
Action of Trastuzumab
BACKGROUND
• Trastuzumab
- binds to subdomain IV of the HER2 extracellular domain
- antitumor effects
by blocking HER2 cleavage
stimulating antibody-dependent, cell-mediated cytotoxicity
inhibiting ligand-independent, HER2- mediated mitogenic
signaling.
BACKGROUND
HER2-positive metastatic breast cancer
disease progresses
=> the need for new targeted therapies for advanced disease.
BACKGROUND
• Pertuzumab
: Humanized monoclonal antibody
: binds HER2 at a different epitope
of the HER2 extracellular domain
(subdomain II)
: prevents HER2 from dimerizing
with other ligand-activated HER receptors, most notably HER3
: stimulates antibody-dependent, cell-mediated cytotoxicity
BACKGROUND
• pertuzumab and trastuzumab
: bind to different HER2 epitopes
: complementary mechanisms of action
: given together
=> more comprehensive blockade of HER2 signaling
=> result in greater antitumor activity than either agent alone
in HER2-positive tumor models
• pertuzumab–trastuzumab regimen
: shown activity
in patients with HER2-positive metastatic breast cancer
in patients with early breast cancer
BACKGROUND
Clinical Evaluation of Pertuzumab and Trastuzumab study
(CLEOPATRA)
: assessed the efficacy and safety
pertuzumab
+ trastuzumab
+ docetaxel
placebo
+ trastuzumab
+ docetaxel
: as first-line treatment
: for patients with HER2-positive metastatic breast cancer.
METHODS
Study Design
• randomized, double-blind, placebocontrolled, phase 3 trial
HER2-positive metastatic breast cancer
: not received chemotherapy or biologic therapy
for their metastatic disease.
• primary end point
- progression-free Survival
: on the basis of the assessment of tumors
at an independent review facility
• secondary end points
: overall survival, progression-free survival
METHODS
Patients
• Eligibility criteria
1) locally recurrent, unresectable, or metastatic
HER2-positive breast cancer.
HER2-positive status
immunohistochemistry
with 3+
fluorescence in situ
hybridization
with an amplification ratio
≥2.0
2) age of 18 years or older
3) left ventricular ejection fraction of 50% or more at Baseline
4) ECOG 0 or 1
METHODS
Patients
• Exclusion criteria
1) therapy for metastatic breast cancer
2) central nervous system metastases
3) prior exposure to a cumulative dose of doxorubicin
(> 360 mg per square meter of body-surface area )
4) previous decline in the left ventricular ejection fraction
to less than 50% during or after prior trastuzumab therapy
5) current uncontrolled medical conditions
- limit a patient’s ability to undertake study therapy.
METHODS
Procedures
Trastuzumab
loading dose
8 mg per kilogram of body weight
maintenance dose
6 mg per kilogram every
3 weeks until disease proression,
Docetaxel
starting dose
75 mg per square Meter Every 3 weeks
maintenance dose
increased to 100 mg per square meter
if the drug had toxic effects
reduce the dose by 25%,
Pertuzumab
fixed loading dose
840 mg
until disease progression
420 mg every 3 weeks
RESULTS
Study Population
Table 1. Baseline Characteristics of the Intention-to-Treat Population
control group
pertuzumab group
RESULTS
Study Population
Table 1. Baseline Characteristics of the Intention-to-Treat Population
RESULTS
Progression-free Survival
Figure 1 . Progression-free Survival, as Assessed at an Independent Review Facility.
RESULTS
Progression-free Survival
Figure 1 . Progression-free Survival, as Assessed at an Independent Review Facility.
RESULTS
Key Secondary Efficacy End Points
Figure 2. Overall Survival.
RESULTS
Key Secondary Efficacy End Points
Table 2. Overall Response, as Assessed at an Independent Review Facility
RESULTS
Side-Effect Profile and Cardiac Safety
Table 2. Overall Response, as Assessed at an Independent Review Facility
CONCLUSIONS
The combination of pertuzumab plus trastuzumab plus docetaxel,
as compared with placebo plus trastuzumab plus docetaxel,
when used as first-line treatment for HER2-positive metastatic
breast cancer, significantly prolonged progression-free survival,
with no increase in cardiac toxic effects.