Trastuzumab, powder for I.V. infusion, 150 mg, Herceptin®
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Public Summary Document
Product: Trastuzumab, powder for I.V. infusion, 150 mg, Herceptin®
Sponsor: Roche Products Pty Limited
Date of PBAC Consideration: July 2006
1. Purpose of Application
The submission sought an authority required PBS listing for the treatment of patients
with HER2 positive early breast cancer following surgery in association with chemotherapy.
2. Background
The PBAC had not previously considered a submission from the sponsor for listing the
product for early breast cancer.
3. Registration Status
Trastuzumab was registered on 4 September 2000 for the treatment of patients with metastatic breast cancer who have tumours that overexpress HER2:
- in combination with taxanes for the treatment of those patients who have not received chemotherapy for their metastatic disease; or
- as monotherapy for the treatment of those patients who have received one or more chemotherapy regimens for their metastatic disease.
Trastuzumab was registered on 21 April 2006 for the treatment of patients with HER2
positive localised breast cancer in association with chemotherapy.
Localised means node-positive disease, or node negative disease with a tumour diameter
greater than 20mm.
4. Listing requested and PBAC’s View
Authority required
Initial treatment for HER2 positive localised breast cancer, in patients with node
positive disease, or node negative disease with a primary tumour diameter greater
than 20mm, in association with chemotherapy. HER2 positivity requires demonstration
of 2+ or 3+ staining by immunohistochemistry (on a scale of 0, 1+, 2+, 3+) and subsequent
confirmation of HER2 positivity by in situ hybridisation (ISH).
Continuing treatment for HER2 positive localised breast cancer, where the patient
has previously been issued with an authority prescription for initial treatment with
this drug.
The treatment course is limited to 52 weeks.
The PBAC considered trastuzumab should be subsidised for up to 52 weeks of treatment
in HER2 positive early breast cancer patients with specified cardiac function.
The PBAC’s view was that women with HER2 positive disease who are receiving chemotherapy
when any listing takes effect, or who are already purchasing the drug privately, should
qualify for subsidy from the date of listing.
See also Recommendation and Reasons
5. Clinical place for the proposed therapy
Among females, breast cancer is the most frequently diagnosed cancer and it is the
most common cause of cancer-related death. Surgery is the main modality of local treatment
for breast cancer. Surgery and/or radiotherapy can control locoregional disease in
a large proportion of patients.
Adjuvant systemic therapy is defined as the administration of chemotherapy or hormonal
therapy after primary surgery for breast cancer in order to control clinically occult
micro-metastases. The aim of adjuvant chemotherapy is to treat undetectable cancer
cells, to reduce the risk of cancer recurrence, and thereby improve survival.
Because systemic adjuvant therapies have been proven effective, they should be considered
in the management of all women with high or moderate risk of recurrence after local
therapy for early breast cancer. The choice of treatment for early breast cancer depends
on a patients’ risk category and their responsiveness to endocrine therapies.
HER2 overexpression has been confirmed as an adverse prognostic factor and a predictive
factor for response to trastuzumab. Trastuzumab is a recombinant humanised monoclonal
antibody that specifically targets the epidermal growth factor receptor (HER2) protein.
6. Comparator
The submission appropriately nominated placebo as the comparator.
7. Clinical Trials
The PBAC considered the results from five randomised, controlled trials of trastuzumab
in early breast cancer. The trials published at the time of the submission were as
follows:
| Trial/First author | Protocol/Publication title | Publication citation |
|---|---|---|
| Piccart-Gebhart M (HERA trial) | Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. | New England Journal of Medicine 2005, 353: 1659-1672. |
| Romond E (US NCI trial B-31) |
Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. | New England Journal of Medicine 2005, 353: 1673-1684. |
| Romond E (US NCI trial N9831) * |
Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. | New England Journal of Medicine 2005, 353: 1673-1684. |
| Joensuu H (FinHer trial) |
Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. | New England Journal of Medicine 2006, 354: 809-820. |
| Slamon D (BCIRG 006) |
Phase III randomised trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. | San Antonio Breast Cancer Conference, December 2005. |
* The results from an exploratory interim analysis of the treatment arm of US NCI trial N9831, in which trastuzumab was administered sequentially to chemotherapy (ie, after paclitaxel), were located during the evaluation (Slide presentation by Edith Perez at May 2005 American Society of Clinical Oncology [ASCO] Annual Meeting. Abstract 556). These results have not been published in a peer-reviewed journal.
8. Results of Trials
For the primary interim analysis of disease-free survival, a statistically significant
difference favouring trastuzumab administered sequential to chemotherapy for 1 year
compared to observation alone was observed in the HERA trial (hazard ratio [HR] at
2 years: 0.54; 95%CI 0.43, 0.67). However, no statistically significant difference
between trastuzumab administered sequentially to paclitaxel and paclitaxel alone was
observed in the US NCI trial N9831 (HR: 0.87; 95%CI: 0.67, 1.13). Statistically significant
reductions in the risk of a DFS event favouring trastuzumab were reported by the interim
analyses of other trials (HR for joint analysis of B-31 and N9831 = 0.48 [95%CI: 0.39,
0.59]; HR for FinHer trial = 0.42 [95%CI: 0.21, 0.83]; HR for BCIRG 006 =0.49 [95%CI:
0.37, 0.65]).
No statistically significant difference was detected in the hazard ratios for overall
survival in the 12-month analysis of HERA or the FinHer trial. The 23-month analysis
of HERA, provided prior to PBAC’s consideration, showed that overall survival with
sequential trastuzumab, compared with observation, was statistically significant (HR
0.66; 95% CI: 0.47, 0.91; p=0.0115). Although the hazard ratio for the joint analysis
of B-31 and N9831 was reported to be significant (0.67, p=0.0136), the p-value did
not cross the pre-specified formal boundary of p=0.0000015 required for statistical
significance.
Trastuzumab was generally associated with a higher incidence of toxicities compared
to no trastuzumab. The more commonly reported adverse events include infusion-related
toxicities (eg, headache and fatigue), musculoskeletal pain (eg, arthralgia), infections
(eg, nasopharyngitis and influenza), haematological abnormalities (eg, neutropenia),
pulmonary toxicities (eg, dyspnoea) and gastrointestinal disturbances (eg, diarrhoea).
For HERA, a statistically significantly greater risk of cardiac events was observed
in trastuzumab-treated patients compared with patients managed by observation (RR
= 10.2; 95% CI: 1.3 – 79.4). Similarly, a significantly higher risk of cardiac events
(ie, symptomatic CHF and cardiac death) was observed for trastuzumab-treated patients
compared with the control arm by the joint analysis of the US NCI trials (RR = 4.8,
95%CI: 2.5 – 9.2). Trastuzumab was associated with a statistically significantly greater
risk of LVEF decline when compared to patients not on trastuzumab in HERA and the
joint analysis of B-31 and N9832. Inconclusive results with respect to cardiac endpoints
were reported for the BCIRG trial – in the arm where trastuzumab was administered
with carboplatin, there was no statistically significant difference for trastuzumab
versus control patients. However, where trastuzumab was administered without carboplatin,
there was significantly more cardiac toxicity in the trastuzumab-treated group compared
with the control group. No statistically significant difference between the trastuzumab-treated
group and the control group in rate of cardiac events or in left ventricular function
was observed in the FinHer trial (which administered once-weekly trastuzumab for only
9 weeks).
9. Clinical Claim
The submission claimed that trastuzumab given either sequentially or concurrently
with adjuvant chemotherapy had significant advantages in effectiveness over adjuvant
chemotherapy alone but was associated with greater toxicity.
The PBAC concluded that based on the totality of evidence currently available, treatment
with trastuzumab should be restricted to commence concurrently with adjuvant chemotherapy.
The Committee also agreed that trastuzumab should not be used in patients with a left
ventricular ejection fraction (LVEF) < 45% and/or in those with symptomatic heart
failure.
See also Recommendation and Reasons
10. Economic Analysis
Two preliminary economic evaluations were presented. The choice of the cost-effectiveness
approach was valid. The resources included were drug costs, costs associated with
administration, and costs of monitoring patients. The trial-based incremental discounted
cost per extra disease-free year gained was > $200,000 over 3 years (based on the
HERA trial); and in the range $105,000 - $200,000 over 4.69 years (based on the US
NCI trials).
A modelled economic evaluation was presented. The choice of the cost-effectiveness
approach was valid. The resources included were drug costs, drug administration costs,
costs associated with monitoring of patients, costs for managing subsequent events
including recurrence (locoregional and distant) and CHF. The base case modelled incremental
discounted cost per extra QALY gained over 40 years was in the range of $15,000 -
$45,000.
Prior to the PBAC consideration, additional sensitivity analyses were conducted. The
analyses assumed the hazard ratio observed in the trial would apply for 5 years but
that beyond that time the curves for proportion of patients with progression of disease
will be parallel. The incremental discounted costs per extra QALY gained over 40 years
was in the range of $45,000 - $75,000.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was < 10,000, while the financial cost per
year to the PBS was > $100 million in Year 1 following listing.
12. Recommendation and Reasons
The PBAC recommended listing for the treatment for HER2 positive early breast cancer
commencing concurrently with adjuvant chemotherapy following surgery on a cost-effectiveness
basis over no treatment. The PBAC considered that, disease recurrence would be reduced
by around 30% in individuals with HER2 gene amplified early breast cancer. This conclusion
was based on the available evidence which included short-term follow up data combined
with a prediction of effects over the longer term (40 years). This estimate is based
upon the hazard ratio (HR=0.48 for concurrent therapy) observed in the clinical trials
being assumed in the model to persist for 5 years after initiation of therapy and
then to revert to 1, apportioned over a total period of 40 years. This assessment
may change as more evidence becomes available. The PBAC further recommended that women
with HER2 positive disease who are receiving chemotherapy when any listing takes effect,
or who are already purchasing the drug privately, should qualify for subsidy from
the date of listing.
The PBAC concluded that the optimal chemotherapy partner for trastuzumab is unknown,
and that based on the totality of evidence currently available, treatment with trastuzumab
should commence concurrently with adjuvant chemotherapy.
The PBAC noted that the trials presented in the submission used different adjuvant
chemotherapy regimens and in some trials (HERA, one arm of N9831) trastuzumab was
administered sequentially to chemotherapy, while in others (B-31, BCIRG006, one arm
of N9831) trastuzumab was commenced concurrently with chemotherapy. With the exception
of the sequential trastuzumab treatment arm of N9831, a statistically significantly
higher disease-free survival (DFS) was observed in all trials for trastuzumab-treated
patients compared with patients not receiving trastuzumab. No statistically significant
difference in DFS was observed in the sequential trastuzumab treatment arm of N9831
compared with the paclitaxel alone arm. In addition to not being statistically significant,
the magnitude of the treatment effect in DFS observed in the N9831 comparison is substantially
lower than that observed in the HERA trial (HR: 0.87 vs. 0.54 respectively). The PBAC
found it difficult to resolve the apparent inconsistency between the two sets of results.
The Committee further noted that there is some evidence to indicate that certain chemotherapy
is a treatment effect modifier of trastuzumab. This may occur indirectly with those
cytotoxic agents where HER2 gene amplification is a treatment effect modifier, such
as anthracyclines (NEJM; 2006; 354:2103-2111). Some chemotherapy agents interact directly
with trastuzumab both in vitro and in vivo (metastatic disease). This interaction
may be synergistic eg. vinorelbine, docetaxel, carboplatin, etoposide; additive eg.
paclitaxel, doxorubicin, vinblastine, methotrexate or antagonistic: eg 5 fluorouracil.
The HERA protocol allowed adjuvant chemotherapy at the investigators choice. This
was not taken into account in the subsequent randomization to treatment and may have
influenced subsequent responsiveness to trastuzumab.
The PBAC noted the ESC advice that the clinical trials available to date suggest that
there is no evidence of an efficacy advantage between trastuzumab administered for
one year as proposed by the submission compared with trastuzumab administered every
week for 9 weeks in the FinHer trial. However the Committee agreed that, although
this is a reasonable hypothesis, the FinHer data can be criticised on the grounds
that the difference in overall survival is not significant, the results are based
on a small pre-specified sub-study of 231 patients, the event numbers are small and
the upper age limit is lower than in other studies, the last two of which may also
have contributed to the reduced the rate of cardiac toxicity observed. Additionally,
the results of FinHer could not be independently validated as all other available
studies use prolonged treatment with trastuzumab.
Overall the Committee considered that the optimal duration of therapy with trastuzumab
is unknown, but that the currently available evidence supports 52 weeks.
The PBAC considered it essential that all patients commencing therapy with trastuzumab
have demonstrated HER2 gene amplification as determined by a histopathologist using
an appropriately validated assay. This is due to the high incidence of false positive
and false negative results when HER2 status is determined by immunostaining, together
with safety concerns necessitating accurate targeting of the drug to the population
most likely to benefit. The PBAC recommended that Roche be requested to provide an
accessible gene amplification test to determine HER2 positivity free of charge, pending
consideration of Medicare funding by the Medical Services Advisory Committee.
The Committee agreed that trastuzumab should not be used in patients with a left ventricular
ejection fraction (LVEF) < 45% and/or in those with symptomatic heart failure. The
PBAC noted that patients with these conditions were excluded from the trials, that
use in these patient groups is contraindicated in the TGA Product Information and
that substantial safety concerns had been raised in relation to heart damage.
The major issue of concern to the PBAC with respect to the economic analyses presented
in the submission was the assumption that the hazard ratio (HR) observed at two/three
years remains the same for the 40-year duration of the model. The PBAC did not accept
this assumption, noting comments from the 2000 Early Breast Cancer Trialists’ Collaborative
Group (EBCTCG) overview that the main effect on recurrence for polychemotherapy is
seen in the first five years after which time (until 15 years at least) the curves
become parallel, and that the proportional reduction in recurrence will tend to be
systematically greater in the early results from new trials than when those same trials
mature. If the model for concurrent administration is rerun with the assumption that
the HR remains constant for 5 years and then reverts to one, the incremental cost
per extra quality adjusted life year is in the range of $45,000 - $75,000.
A final issue of concern to PBAC was the overall cost to Government of listing trastuzumab
on the PBS for HER2 positive early breast cancer. If it is assumed that around 25%
of all patients diagnosed with early breast cancer will test positive for HER2 gene
amplification using appropriate validated assays, and that 90% of these patients will
take up treatment, the cost to Government might be more than $100 million in Year
1 of listing. Epidemiological sources report that between 15% and 25% of early breast
cancer patients may test positive for HER2 gene amplification.
Recommendation
Section 100 Special Authority Program
TRASTUZUMAB
NOTE:
Any queries concerning the arrangements to prescribe trastuzumab may be directed to
Medicare Australia on 1800 700 270 (hours of operation 8 a.m. to 5 p.m. EST Monday
to Friday). Written applications for authority to prescribe trastuzumab should be
forwarded to: Medicare Australia Prior Written Approval of Specialised Drugs Reply
Paid 9826 GPO Box 9826 HOBART TAS 7001 Further prescribing information is on the Medicare
Australia website at www.medicareaustralia.gov.au.
Section 100 authority required
Initial treatment for HER2 positive early breast cancer commencing concurrently with
adjuvant chemotherapy following surgery. The total duration of PBS-subsidised treatment
(initial plus continuing) that will be authorised is 52 weeks. HER2 positivity must
be demonstrated by in situ hybridisation (ISH). Trastuzumab must not be used in patients
with a left ventricular ejection fraction (LVEF) of less than 45% and/or with symptomatic
heart failure. Cardiac function must be tested by a suitable method including, for
example, ECHO or MUGA, prior to seeking the initial authority approval and then at
3 monthly intervals during treatment. Authority applications for initial treatment
must be made in writing and must include: (a) a completed authority prescription form;
and (b) a completed Early Breast Cancer - PBS Supporting Information Form [may be
downloaded from the Medicare Australia website (www.medicareaustralia.gov.au)] which
includes: (i) a copy of the pathology report from an Approved Pathology Authority
confirming the presence of HER2 gene amplification by in situ hybridisation (ISH);
and (ii) a copy of the signed patient acknowledgement form [may be downloaded from
the Medicare Australia website (www.medicareaustralia.gov.au)]. The medical practitioner
should request sufficient quantity based on the weight of the patient to provide for
a maximum of 3 weeks' treatment (equivalent to the loading dose for the 3 weekly regimen,
and the loading dose and 2 weekly doses for the once weekly regimen).
Section 100 authority required
Initial treatment for HER2 positive early breast cancer in patients receiving treatment
with adjuvant chemotherapy following surgery at 1 October 2006. The total duration
of PBS-subsidised treatment (initial plus continuing) that will be authorised is 52
weeks. HER2 positivity must be demonstrated by in situ hybridisation (ISH). Trastuzumab
must not be used in patients with a left ventricular ejection fraction (LVEF) of less
than 45% and/or with symptomatic heart failure. Cardiac function must be tested by
a suitable method including, for example, ECHO or MUGA, prior to seeking the initial
authority approval and then at 3 monthly intervals during treatment. Authority applications
for initial treatment must be made in writing and must include: (a) a completed authority
prescription form; and (b) a completed Early Breast Cancer - PBS Supporting Information
Form [may be downloaded from the Medicare Australia website (www.medicareaustralia.gov.au)]
which includes:
- a copy of the pathology report from an Approved Pathology Authority confirming the presence of HER2 gene amplification by in situ hybridisation (ISH); and
- a copy of the signed patient acknowledgement form [may be downloaded from the Medicare Australia website (www.medicareaustralia.gov.au)]. The medical practitioner should request sufficient quantity based on the weight of the patient to provide for a maximum of 3 weeks' treatment (equivalent to the loading dose for the 3 weekly regimen, and the loading dose and 2 weekly doses for the once weekly regimen).
Section 100 authority required
Initial PBS-subsidised treatment for HER2 positive early breast cancer where the patient
was receiving treatment with trastuzumab at 1 October 2006. The patient is eligible
to receive sufficient trastuzumab to complete 52 weeks of combined PBS-subsidised
and non-PBS-subsidised therapy. Trastuzumab must not be used in patients with a left
ventricular ejection fraction (LVEF) of less than 45% and/or with symptomatic heart
failure. Cardiac function must be tested by a suitable method including, for example,
ECHO or MUGA, at 3 monthly intervals during treatment. Authority applications for
initial PBS-subsidised treatment must be made in writing and must include: (a) a completed
authority prescription form; and (b) a completed Early Breast Cancer - PBS Supporting
Information Form [may be downloaded from the Medicare Australia website (www.medicareaustralia.gov.au)]
which includes: (i) the date upon which the patient commenced non-PBS-subsidised treatment
with trastuzumab and the number of weeks of treatment received; and (ii) a copy of
the signed patient acknowledgement form [may be downloaded from the Medicare Australia
website (www.medicareaustralia.gov.au)]. The medical practitioner should request sufficient
quantity based on the weight of the patient for 3 weeks' supply (equivalent to 1 dose
for the 3 weekly regimen, or 3 doses for the once weekly regimen). Up to a maximum
of 3 repeats may be authorised.
Section 100 authority required
Continuing treatment for HER2 positive early breast cancer where the patient has previously
received treatment with PBS-subsidised trastuzumab. The patient is eligible to receive
sufficient trastuzumab to complete 52 weeks of combined PBS-subsidised and non-PBS-subsidised
therapy. Trastuzumab must not be used in patients with a left ventricular ejection
fraction (LVEF) of less than 45% and/or with symptomatic heart failure. Cardiac function
must be tested by a suitable method including, for example, ECHO or MUGA, at 3 monthly
intervals during treatment. Authority applications for continuing treatment may be
made by telephone on 1800 700 270 (hours of operation 8 a.m. to 5 p.m. EST Monday
to Friday). The medical practitioner should request sufficient quantity based on the
weight of the patient for 3 weeks' supply (equivalent to 1 dose for the 3 weekly dosing
regimen, or 3 doses for the once weekly dosing regimen). Up to a maximum of 3 repeats
may be authorised.
Maximum quantity: 1
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia.
It considers submissions in this context. A PBAC decision not to recommend listing
or not to recommend changing a listing does not represent a final PBAC view about
the merits of the medicine. A company can resubmit to the PBAC or seek independent
review of the PBAC decision.
14. Sponsor’s Comment
No comment.
