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Herceptin
Summarising the evidence
The facts not under debate
•
Herceptin (trastuzumab) indicated for metastatic HER2+ breast cancer and
now HER2+ early breast cancer
•
One of a new class of medicines, a monoclonal antibody
•
Given as an infusion –hospital setting
•
Funded for metastatic breast cancer by district health boards
•
Drug cost for 12 month sequential treatment approx $70,000 per person (or
approx $20-$25 million /yr, total DHB cancer spend approx $50million
currently)
•
Drug cost for 9 week concurrent treatment approx $15,000 per person (or
approx $5 million/yr)
12 months sequential treatment declined July
2006
•
Cost effectiveness
• Cost
• Clinical Benefit and Clinical Risks
• Cost Offsets (prevention of progression)
• 12 months sequential cost/QALY approx $70K (range $20K$140K)
• If data to be updated with 2 year HERA data cost
effectiveness would look worse
• If N9831 are B data were included cost effectiveness
would look worse
•
DHB resources
The Evidence
•
Herceptin is an add-on treatment, not stand alone so relationship
with the other cancer medicines in the overall treatment of the
patient is important.
•
Two variables:
•
•
•
Which order?: Sequential versus concurrent treatment; and
Which duration?: Long (12 months) versus short (9 weeks) treatment
Six trials: need to think about what they as a group are telling us,
not just one trial (HERA or FinHer) on its own.
About “12,000 patients taking Herceptin”
•
‘Data from >12,000 patients support 12 months treatment’
• NZ indication for ‘trastuzumab given following completion of
chemotherapy’ (sequential)
•
In fact 12 month sequential Herceptin data only available from 2,679
patients
• HERA = 1694 patients = Positive result
• N9831 Arm B = 985 patients = Negative result
13,609 patients
in all Clinical trials
Herceptin treated (8724)
Sequential treatment (post-chemotherapy)
Data from 2679 patients reported
Concurrent therapy (with chemotherapy)
Data from 4351 patients reported
HERA 1 year
treatment arm
HERA 2 year
treatment arm
N9831 arm B
N9831 arm C
B31
BCIRG 006
Finher
Sledge
1694 patients
(12 months
Post-chemo)
1694 patients
(not yet
reported)
985 patients
12 months
post-chemo
840 patients
52 weeks
1019 patients
52 weeks
2149 patients
52 weeks
116 patients
9 weeks
227 patients
52 weeks or
10 weeks
?
r
r
a
a
a
a
a
a
HERA – 2-year follow-up (Disease- Free Survival)
3 years
In other words for every 100 women treated…
6 benefited from Herceptin treatment (94 did not benefit)
4 suffered cardiac damage severe enough to require discontinuation of Herceptin
N9831 – sequential treatment worse than
concurrent
Sequential Herceptin no better than normal chemo
Sequential Herceptin worse than concurrent Herceptin
Romond ‘delayed administration of trastuzumab may be less effective than
concurrent administration’….’ further follow-up of groups B and C in trial N9831 is
necessary for an adequate evaluation of the efficacy of concurrent as compared with
sequential administration of trastuzumab’
Data for 12 months sequential worse than 12
months concurrent - meta-analysis across studies
Above the line = Herceptin no better than normal chemo
Below the line = Herceptin better than normal chemo
Trastuzumab treatment effects in early-stage breast cancer
1 - HERA 12-month followup - interim
2 - HERA 2-year followup - unquantified contamination
3 - N9831 arm B
5 - HERA 12-month f/u [interim] & N9831 arm B
6 - HERA 2-year f/u [contaminated] & N9831 arm B
8 - B31 & N9831 arm C
9 - BCIRG 006 arm AC-TH
11 - B31, N9831 arm C & BCIRG 006 arm AC-TH
13 - FinHer
1.2
hazard ratio (95% CI) for disease events
1.0
0.8
0.6
pooled N9831 B
& interim HERA
pooled N9831 B &
contaminated HERA
0.4
sequential post-anthracyclines
concurrent post-anthracyclines
(HERA, N9831 arm B)
(B31, N9831 arm C,
BCIRG 006 arm AC-TH)
0.2
concurrent preanthracyclines
(e.g. FinHer)
0.0
0
1
2
3
4
5
6
7
trial/combination
8
9
10
11
12
13
14
Sequential vs Concurrent summary
•
Roche’s indication is for 12 months sequential herceptin
•
sequential data available from 2,679 patients
• HERA 2 yr FU recurrence decreased by 6.4%
• Arm B of N9831 – no better than normal chemo
•
12 months concurrent appears to be better than 12 months
sequential
Data for concurrent - data for short and long
duration similar
Above the line = Herceptin no better than normal chemo
Below the line = Herceptin better than normal chemo
Trastuzumab treatment effects in early-stage breast cancer
1 - HERA 12-month followup - interim
2 - HERA 2-year followup - unquantified contamination
3 - N9831 arm B
5 - HERA 12-month f/u [interim] & N9831 arm B
6 - HERA 2-year f/u [contaminated] & N9831 arm B
8 - B31 & N9831 arm C
9 - BCIRG 006 arm AC-TH
11 - B31, N9831 arm C & BCIRG 006 arm AC-TH
13 - FinHer
1.2
hazard ratio (95% CI) for disease events
1.0
0.8
0.6
pooled N9831 B
& interim HERA
pooled N9831 B &
contaminated HERA
0.4
sequential post-anthracyclines
concurrent post-anthracyclines
(HERA, N9831 arm B)
(B31, N9831 arm C,
BCIRG 006 arm AC-TH)
0.2
concurrent preanthracyclines
(e.g. FinHer)
0.0
0
1
2
3
4
5
6
7
trial/combination
8
9
10
11
12
13
14
Short duration concurrent – ‘FinHer’
•
The 9-week regimen
• Good efficacy
•
•
•
patient friendly: chemo+Herceptin completed in 18 weeks (vs. 60
weeks)
More patients would get treated
•
•
•
•
comparable to studies that used 12-mo duration of administration (Joensuu
H et al. NEJM 2006:354:809-20)
no cardiotoxic anthracyclines given before Herceptin
Might be less cardiotoxic
Would spare hospital resources (6 visits vs. 20 visits + extra cardiac
monitoring + blood tests)
A more compact platform for further development of BC management
•
Cost effective (<$20K per QALY)
•
Affordable and managable for DHBs (cost/resources)
•
Supported by ’Sledge’ study (10 weeks concurrent)
Summary
•
There are doubts over 12 months sequential treatment
•
Concurrent treatment IS proven (and approved for use in USA,
Australia)
•
Exactly how long to use concurrent treatment has NOT been
established
• Efficacy seen with 12 months, 9 weeks and 10 weeks
• But 12 month concurrent (post anthracyclines) increases
cardiotoxicity
•
The international trial (SOLD) is planned to address the question –
does 12 months treatment add any benefit over concurrent 9 week
treatment?
Some Overseas commentary
•
Cancer Research UK’s director of clinical trials, during an appearance on
a BBC Radioshow January 2007:
• "Currently we give Herceptin for a year and there is no good evidence
why it should be given for a year. It is what the drug company decided
upfront. We are now doing trials in the UK that are following some
done in Finland that look as though nine to ten weeks would be
sufficient.“
•
The Belgian Health Care Knowledge Centre June 2006:
• “The KCE wonders why there is no comparative trial with a shorter
and possibly more safe treatment regimen.”
•
Daniel Hind, The Lancet January 2007 Editorial:
• “NICE might never have deemed the HERA schedule to be cost
effective if the FinHer study had been assessed as a comparator…”