Karianne Johansen, PhD, Senior Advisor,
Torbjørn Wisløff , Researcher
Inger Natvig Norderhaug , Research Director
Norwegian Health Service Research
Centre
HTA OF TRASTUZUMAB IN
ADJUVANT TREATMENT
Expert Group
Professor dr.med.
Per Eystein Lønning
, University of Bergen,
Haukeland University hospital, Bergen
Professor dr.med.
Ivar Sønbø Kristiansen
, HERO, University of
Oslo
Overlege dr.med.
Bjørn Naume,
The National hospital, Oslo
Professor dr. med.
Jan Norum,
Cancer Unit, University hospital
Northen Norway, Tromsø
Professor dr.philos.
Jan Abel Olsen,
HERO, Universitetet i Tromsø
Professor dr. med.
Erik Wist,
Cancer department, Ullevaal
University Hospital, Oslo
Background and Issues
Promising interim data from large trials of Herceptin in treatment of HER2 positive adjuvant breast cancer published Q4 2005 /Q1 2006
Manufacturing authorization expected in Norway soon
HER2 amplification recognized in 20-30% of breast cancers
Associated with an aggressive form of the disease and shortened disease-free survival and overall survival
Pressure was put on an HTA of the new treatment prior to regulatory approval
Part 1. A systematic review of the existing data to evaluate the effect and safety was performed
Search for literature
All relevant databases were searched according to a predefined protocol
(Medline, Embase,the Cochrane Database of Systematic Reviews (CDSR), the
Cochrane Controlled Trials Register (CCTR), the Science Citation index og the NHS Centre for Reviews and Dissemination databases (DARE, NHS EED, HTA)and OHE HEED)
Web sites for conferences and international clinical trial databases
Manufacturer's were asked to submit relevant documentation according to
the protocol
Results from the systematic review
Search result
5 trials included - rated to medium quality
Event driven interim analysis focusing on disease-free survival (DFS)
Direction of effect
Disease Free Survival A highly significant effect compared with the control group were found in all trials
A meta-analysis of the hazard ratio for a risk of an event in the trastuzumab group compared with the control group were 0.5 (95% CI, 0.4 to 0.6)
The absolute differences
– 7.5 % to 8.4 % at 2 years
– 11.0 % to 19.0 % at 4 years
Overall Survival
All reported results were in favor of trastuzumab
Only one analysis (JOINT) of two trials showed statistical significant effect
We concluded
There is not enough data available to draw certain conclusions regarding overall survival due to short follow-up
Results from the systematic review
Direction of adverse events
Trastuzumab was associated with increased risk of cardio toxicity, despite very strict cardiovascular exclusion criteria in the protocols
NYHA Class III or IV congestive heart failure or death from cardiac causes
– Trastuzumab group: 0.5 % to 4.1 % – Control group: 0.0 % to 1.0 % Decrease in LVEF – Trastuzumab group: 7.1 % to 17.3 % – Control group: 2.2 % to 9.0 % Discontinuations of trastuzumab : 8.5 % - 31.4 %. We concluded
Further need for evaluation – Issues ?
A Hazard Ratio of 0.5 for a risk of a disease-free event in the trastuzumab
group compared with the control group is a relative number
How effective is today's adjuvant treatment of breast cancer in Norway?
What is the incremental risk of death for HER2 positive patients?
Treatment with trastuzumab is costly with potentially serious adverse
event – whom are eligible for treatment?
Is the incremental effect of trastuzumab reasonable relative to the
incremental cost?
Patients eligible for treatment
Not women who have an LVEF of 55% or less, or any of the following:
• a history of documented congestive heart failure • high-risk uncontrolled arrhythmias
• angina pectoris requiring medication • clinically significant valvular disease
• evidence of transmural infarction on electrocardiograph (ECG) • poorly controlled hypertension.
Age
Incidence of Breast Cancer
Eligible for
adjuvant chemotherapy
HER2 positive and eligible for trastuzumab 20 - 54 845 676 203 55 - 69 1078 344 103 70 + 771 0 0 Total 2694 1021 306
*Age 55-70 years, eligibility for adjuvant chemotherapy depend on hormone receptor status
Health Economic evaluation
Standard treatment: FEC100 + observationNew treatment: FEC100 + 1 year trastuzumab every 3 weeks
A markow model, one year cycles was constructed
Inputs were based on
The results from the clinical trials (Event rates and Hazard ratios)
Data from the Norwegian Cancer Registry used for breast cancer survival
Different assumptions were made together with the expert group to show different variations on extending the effect beyond the clinical trials
Both cost and LYG were discounted at 3 %
In the base case costs are presented from a health care perspective
Average age in the model, 50 years, time horizon - life time perspective
*
FEC100 = 5-flurouracil, epirubicin-og cyklofosfamidModel Structure
1. Disease free
2. Local recurrence
3. Distant recurrence
4. Death*
*Dead from metastatic breast cancer or from non-cancer causes while in any of the first 3 disease states.
Base case Scenarios A and B
Scenario A
Stadium I and II from the Cancer Registry as a total sum of survival
Events
– Years 0 - 4: Results from clinical trials
– Years 5 – 10: Results gradually decline
– Years 11 + : = 0
Probability of death from breast cancer
Comparator arm
– Years 0 – 10: Survival taken from the Norwegian Cancer Registry
– HER2 additional risk factor of 1.3 was applied for the first 10 years Trastuzumab
– Years 0 to 4: HR from the JOINT analysis used (0.67)
– Years 5 – 10 : The cancer registry with equal risk
– Years 11 + : Patients alive follow normal survival in the population
Probability of death from other causes than breast cancer
– Survival rates from Norwegian Statistics
Scenario B
Stadium IV from the Cancer Registry used for risk of death from metastatic phase
