Exemestane, tablet, 25 mg, Aromasin®, July 2006
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Public Summary Document
Product: Exemestane, tablet, 25 mg, Aromasin®
Sponsor: Pfizer Australia Pty Ltd
Date of PBAC Consideration: July 2006
1. Purpose of Application
To extend the current restricted benefit PBS listing for exemestane to include the
treatment of early breast cancer following 2 years of tamoxifen therapy.
2. Background
At the December 2000 meeting, the PBAC recommended listing exemestane as a restricted
benefit for the treatment of oestrogen-receptor positive advanced breast cancer in
post-menopausal women with disease progression following treatment with tamoxifen
citrate on a cost-minimisation basis with 25 mg exemestane daily equivalent to 1 mg
anastrozole daily and 2.5 mg letrozole daily.
3. Registration Status
Exemestane was registered on 9 October 2000 for the treatment of advanced breast cancer
in women with natural or induced postmenopausal status whose disease has progressed
following anti-oestrogen therapy.
Exemestane was registered on 27 April 2006 for the sequential adjuvant treatment of
oestrogen receptor-positive early breast cancer in post-menopausal women who have
received prior adjuvant tamoxifen therapy.
4. Requested Listing and PBAC View
Restricted benefit
Treatment of hormone-dependent early breast cancer in post-menopausal women following
a minimum of 2 years treatment with tamoxifen citrate.
The PBAC recommended that the total duration of PBS-subsidised adjuvant hormonal treatment
(tamoxifen + aromatase inhibitors) should not exceed 5 years.
5. Clinical place for the proposed therapy
Exemestane may be used as an alternative to tamoxifen in the treatment of early breast
cancer in post-menopausal women after patients have been treated with tamoxifen for
2 years or more. Exemestane is also used in advanced breast cancer.
6. Comparator
The submission appropriately nominated tamoxifen as the main comparator, and anastrozole
as a secondary comparator.
7. Clinical Trials
The submission presented studies of treatments after at least 2 years of tamoxifen
treatment:
Exemestane vs tamoxifen: a single randomised trial (031) of post-menopausal women
who had received tamoxifen (20/30mg/day) for 2-3 yrs were then randomized to either
exemestane (25mg/day; N=2352) or continued tamoxifen (20/30mg/day, N=2372); follow-up
of 2-3 years (mean 27 months). The primary outcome was disease free survival (time
from randomisation to recurrence of breast cancer, diagnosis of 2o breast cancer or
death from any cause)
Exemestane vs anastrozole: indirect comparison of two ‘sets’ of trials comparing exemestane
(25mg/day) vs tamoxifen (20/30mg/day) and anastrozole (1mg/day) vs tamoxifen (20/30mg/day)
in early breast cancer
- exemestane vs tamoxifen: Study 031 (see above)
- anastrozole vs tamoxifen: two studies.
The trials published at the time of the submission were:
| Trial/First author | Publication title | Publication citation |
|---|---|---|
| Study 031/ Coombs, R et al | A randomised trial of exemestane after 2-3 years of tamoxifen therapy in postmenopausal women with primary breast cancer. | NEJM 2004;350 (11): 1081-92 |
| Jakesz, R et al | Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen:combined result of ABCSG trial 8 and ARNO 95 trial. | Lancet, 2005 (9484) 455-62. |
| Boccardo, F et al. | Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: preliminary result of the Italian Tamoxifen Anastrozole Trial. | J. of Clinical Oncology, 2005, 23 (22) 5138-47. |
8. Result of Trials
1. Exemestane vs tamoxifen
There was a statistically significant difference in disease free survival favouring
exemestane in the primary analysis, but there was no difference in overall survival.
Disease free survival (primary) and secondary outcomes
| Outcomes | Kaplan Meier probability at 3 years >randomisation | Hazard Ratio (95% CI) |
|
|---|---|---|---|
|
Exemestane |
Tamoxifen |
||
| Primary outcome Disease free survival a |
90% |
86% |
0.69 (0.58-0.82) a |
| Adjusted b |
0.66 (0.55, 0.79) |
||
| Secondary outcomes | |||
| Breast cancer free survival |
92% |
88% |
0.65 (0.54-0.79) |
| Contralateral breast cancer survival |
99% |
99% |
0.32 (0.15-0.72) |
| Distant recurrence free survival |
93% |
91% |
0.70 (0.56-0.86) |
| Overall survival |
95% |
94% |
NS |
a: number of patients at risk = 4724
b: adjusted for pre-specified prognostic factors: ER status, lymph node status, previous
chemo-therapy, previous HRT, and bisphosphonate therapy. There was no significant
difference in the proportion of women taking bisphosphonate: 1.8% in the exemestane
arm and 1.4% in the tamoxifen arm.
2. Exemestane vs anastrozoleThe event rates for tamoxifen were similar across the exemestane versus tamoxifen
and the anastrozole versus tamoxifen trials. Both exemestane and anastrozole resulted
in a statistically significant increase in disease free or event free survival compared
with tamoxifen. There was no statistically significant difference in overall survival
between treatments.
Distant recurrence free survival was significantly increased for exemestane (031)
and anastrozole vs tamoxifen (Jakesz). Contralateral breast cancer free survival was
significantly increased only for exemestane vs tamoxifen.
In the summary of the indirect comparison using meta-analysis, there were no statistically
significant differences between exemestane and anastrozole, using tamoxifen as the
common comparator, for any of the outcomes. Testing assumptions in sensitivity analyses
did not change the results.
The Boccardo study, which assessed anastrozole and tamoxifen, was not included in
the main analysis as the patient population was deemed to be different in terms of
disease severity. In order to assess the robustness of the results from the main analysis,
the analyses were re-run including Boccardo data in the anastrozole comparison. Including
Boccardo did not alter the conclusions from the main analyses.
There were significantly more adverse events in exemestane-treated patients than in
tamoxifen-treated patients. The most common all causality treatment-emergent illnesses
or events occurring with an incidence of ?5% in patients in either treatment group
or achieving statistical significance at 1% level included arthralgia, insomnia, cardiovascular
disorder, osteoarthritis and osteoporosis. Adverse events more common with tamoxifen
treatment included thromboembolism, endometrial hyperplasia and uterine polyp.
In the Jakesz study there were significantly more fractures and fewer thromboses in
patients treated with anastrozole compared with tamoxifen. In contrast, there were
no statistically significant differences between exemestane and tamoxifen in terms
of fractures, but the exemestane trial, via an amendment to the original trial protocol,
allowed the prophylactic use of bisphosphonates with exemestane.
9. Clinical Claim
The submission claimed:
- exemestane has significant advantages in effectiveness over tamoxifen and having similar or less toxicity; and
- exemestane was no worse than anastrozole in terms of effectiveness and toxicity.
The PBAC accepted that exemestane has advantages in the adjuvant treatment setting
for those already taking tamoxifen. The Committee however noted that the follow-up
in the trial 031 is short, and that a consequence of this was that the reported hazard
ratio for overall survival of 0.69 (95% CI 0.58 – 0.82) was probably an overestimate.
The Committee further noted that exemestane has a different toxicity profile to tamoxifen.
The equi-effective dose in the context of cost minimisation was exemestane 25 mg /day
equivalent to anastrozole 1 mg/day.
10. Economic Analysis
In the comparison of exemestane vs tamoxifen, a preliminary economic evaluation is
presented. The choice of the cost-effectiveness approach was valid.
The trial-based incremental cost per extra disease free year was estimated to be <
$15,000. The trial-based incremental cost per contralateral breast cancer prevented
was estimated to be > $200,000.
A modelled economic evaluation was presented. The choice of the cost-utility approach
was valid. The type of model used was a Markov model, constructed using Excel software.
The model has two treatment arms: exemestane and tamoxifen. The model has a 38-year
duration (starting age of 63), with a 6 monthly cycle length. The model discounts
both costs and health benefits at 5% per annum. Half cycle corrections are incorporated
into the model. The utilities were from the Harvard List of Preference scores and
did not include any decreased utility component for adverse events. The resources
included were drug costs, and health care costs (breast cancer recurrence, palliative
care and adverse events).
The base case modelled incremental discounted cost per extra discounted QALY is estimated
to be in the range of $15,000 - $45,000. The base case modelled incremental discounted
cost per extra discounted life year is estimated to be in the range of $15,000 - $45,000.
The base case modelled incremental discounted cost per extra discounted disease free
year is estimated to be in the range of $15,000 - $45,000.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients per year to be up to < 10,000
in Year 4 of listing.
The financial cost/year to the PBS was estimated to be < $10 million in Year 4. The
overall market was not expected to grow or to grow more rapidly as a result of listing
exemestane.
12. Recommendation and Reasons
The PBAC recommended listing on a cost-effectiveness basis against tamoxifen for the
adjuvant hormonal treatment of early breast cancer. The total duration of PBS-subsidised
adjuvant hormonal treatment (tamoxifen + aromatase inhibitors) should not exceed 5
years.
The PBAC accepted that exemestane has advantages in the adjuvant treatment setting
for those already taking tamoxifen. The Committee however noted that the follow-up
in the trial is short, and that a consequence of this was that the reported hazard
ratio for overall survival of 0.69 (95%CI 0.58 – 0.82) was probably an overestimate.
The Committee further noted that exemestane has a different toxicity profile to tamoxifen.
The modelled cost-effectiveness ratios presented in the submission were considered
acceptable by the Committee. The Committee considered that a question which was not
addressed by the submission was whether adjuvant hormonal treatment with tamoxifen
for 2 years followed by exemestane for 3 years is equivalent to 5 years of adjuvant
treatment with an aromatase inhibitor. If this is the case, then 5 years of aromatase
inhibitor treatment should be cost-minimised against this. The Committee noted that
the BIG study will answer this question, and requested that the sponsor provide the
results from this study as soon as they become available.
The PBAC requested that the PBPA negotiate a risk sharing agreement with the sponsor
to take into account the potential for usage in adjuvant hormonal treatment of early
breast cancer extending beyond 3 years for exemestane (or 5 years in total), for which
there is no evidence. The PBAC also advised the PBPA that the aromatase inhibitors
should remain listed on a cost-minimisation basis overall.
Recommendation
Add to the existing listing:
Restriction: Restricted benefit
Treatment of hormone-dependent early breast cancer in post-menopausal women following
a minimum of 2 years treatment with tamoxifen citrate.
NOTE:
This drug is not PBS-subsidised for adjuvant hormonal treatment of early breast cancer
extended beyond 5 years, i.e. a patient who has received 2 years of tamoxifen therapy
may only receive 3 years of PBS subsidised treatment with exemestane.
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
The Sponsor has entered into a risk sharing arrangement with the Commonwealth.
