Letrozole, tablet, 2.5 mg, Femara®, July 2006
Page last updated: 27 October 2006
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Public Summary Document
Product: Letrozole, tablet, 2.5 mg, Femara®
Sponsor: Novartis Pharmaceuticals Australia Pty Limited
Date of PBAC Consideration: July 2006
1. Purpose of Application
To extend the current restricted benefit listing for letrozole to include the treatment
of hormone-dependent early breast cancer in post-menopausal women, and for use in
the extended adjuvant setting.
2. Background
Letrozole was listed on 1 May 1998 on a cost-minimisation basis compared to anastrozole,
with 2.5 mg letrozole daily being considered to be equivalent to 1 mg anastrozole
daily for the treatment of advanced breast cancer in post-menopausal women with disease
progression following treatment with tamoxifen citrate.
At the March 2002 meeting, the PBAC considered a third submission to allow first-line
use in patients with advanced disease. The PBAC recommended the listing be amended
on the basis of acceptable cost-effectiveness in the context of a trend to improved
survival and an improved quality of life achieved with letrozole, compared with tamoxifen,
associated with clear evidence of a delay in the time to disease progression.
At the March 2005 meeting, the PBAC deferred a submission to extend the restricted
benefit listing of letrozole to include treatment of early-stage hormone-dependent
breast cancer in post-menopausal women who have completed standard adjuvant therapy
(known as the extended adjuvant setting). The PBAC sought clarification of the incremental
cost-effectiveness ratios based on distant recurrence alone, ie excluding local recurrence.
The November 2005 resubmission was rejected on the grounds the revised base case modelled
incremental discounted extra QALY gained of less than $60,000 for distant metastases
only was considered unacceptably high.
The July 2006 submission included updated cost-effectiveness ratios in the extended
adjuvant setting and presented new data in the early adjuvant setting.
3. Registration Status:
In April 2006 the TGA expanded the registration of letrozole to the treatment of post-menopausal
women with hormone receptor positive breast cancer.
4. Listing Requested and PBAC’s View
Restricted benefit
Treatment of hormone-dependent breast cancer in post-menopausal women.
NOTE:
This drug is not PBS-subsidised for primary prevention of breast cancer.
The PBAC considered the total duration of PBS-subsidised adjuvant hormonal treatment
(tamoxifen and aromatase inhibitors) should not exceed five years.
5. Clinical place for the proposed therapy
Letrozole will provide an alternative treatment to tamoxifen and anastrozole in the
treatment of early breast cancer in post-menopausal women.
6. Comparator
The submission appropriately nominated anastrozole as the comparator for adjuvant
treatment in the early breast cancer setting.
7. Clinical Trials
The submission presents an indirect comparison of two randomised trials in post-menopausal
women with early breast cancer comparing letrozole 2.5 mg/day with tamoxifen 20 mg/day
(BIG1-98) and anastrozole 1 mg/day with tamoxifen 20 mg/day (ATAC – first analysis
with a duration of 33.3 months).
The trials were published at the time of the submission as follows.
| Trial/First author | Publication title | Publication citation |
|---|---|---|
| BIG 1-98 Collaborative Group - Thuerlimann B, | A comparison of Letrozole and Tamoxifen in Postmenopausal Women with Early Breast Cancer | N Eng J Med 2005; 353 (26) 2747-57 |
| The ATAC Trialists’ Group – M Baum | Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial | The Lancet 2002; 359:2131-39 |
The clinical trial evidence for the extended adjuvant setting was not represented
in the submission before the PBAC in July 2006. These data can be found in the Public
Summary Documents following the November 2005 PBAC meeting.
8. Results of Trials
In the adjuvant treatment of early breast cancer, the event rates for tamoxifen were
similar across the letrozole versus tamoxifen and anastrozole versus tamoxifen trials.
Both letrozole and anastrozole resulted in a statistically significant increase in
disease free survival compared with tamoxifen. The hazard ratio was 0.81 (0.70, 0.93)
for letrozole vs tamoxifen and 0.83 (0.71, 0.96) for anastrozole vs tamoxifen. The
differences in the proportion of women who remained disease free at five years were
2.6% for letrozole and 2.8% for anastrozole versus tamoxifen. The submission did not
provide any Kaplan-Meier curves for the outcomes in each trial.
The analysis of DFS in which second primary malignancies are excluded is the same
definition of DFS used in the ATAC study. The hazard ratio of 0.79 (0.68, 0.92) for
letrozole vs tamoxifen is similar to the ATAC hazard ratio of 0.83 (0.71, 0.96) for
anastrozole vs tamoxifen.
In positive-hormone receptor patients, both letrozole and anastrozole resulted in
a statistically significant increase in disease free survival compared with tamoxifen.
Overall, the incidence of AEs in the two trials was similar. Treatment with either
letrozole or anastrozole resulted in a statistically significantly higher incidence
of fractures compared with tamoxifen. Letrozole resulted in significantly more arthralgia/arthritis
and osteoporosis, and anastrozole resulted in significantly more musculoskeletal disorders
than tamoxifen. In both trials, the use of tamoxifen was associated with a statistically
significantly higher incidence of hot flashes/flushes, vaginal bleeding and thromboembolic
events.
9. Clinical Claim
The submission claimed that letrozole was no worse than anastrozole in terms of effectiveness
and toxicity in the early breast-cancer setting. The PBAC accepted that, based on
the supporting data, this description was reasonable.
The equi-effective doses in the context of cost-minimisation were letrozole 2.5mg
and anastrozole 1mg. These are based on the doses used in the BIG and ATAC trials.
10. Economic Analysis
A preliminary economic evaluation in the adjuvant setting was not necessary as the
submission was based on cost-minimisation.
A modelled economic evaluation in the adjuvant setting was also not necessary.
The submission provided an updated cost-effectiveness analysis for the use of letrozole
in the extended adjuvant setting. The estimated cost-effectiveness ratios for letrozole
in the extended adjuvant setting were in the range of $15,000 - $45,000 per life year
gained and per QALY gained in the base case, and less than $55,000 per QALY in the
avoidance of distant recurrence. The submission asserted that letrozole is a cost-effective
intervention for the extended adjuvant treatment of women with early-stage breast
cancer.
11. Estimated PBS Usage and Financial Implications:
The submission estimated the likely number of packs dispensed per year to be less
than 120 000 in Year 4 for both the early breast cancer setting and the extended adjuvant
setting.
The submission estimates the financial cost per year to the PBS of < $10 million in
Year 4 (cost-offsets for drugs in the early setting only, not the extended setting).
The overall market was not expected to grow or to grow more rapidly as a result of
listing letrozole in the early breast cancer setting.
12. Recommendation and Reasons
The PBAC recommended listing on a cost-minimisation basis with anastrozole in the
early breast cancer setting. The equi-effective doses are letrozole 2.5 mg and anastrozole
1 mg. The total duration of PBS-subsidised adjuvant hormonal treatment (tamoxifen
+ aromatase inhibitors) should not exceed 5 years. The PBAC requested that the PBPA
negotiate a risk sharing agreement with the sponsor.
The PBAC did not agree that letrozole should be PBS-subsidised for use in the extended
adjuvant setting. The Committee considered that grounds upon which it had previously
rejected use in this setting remained largely unresolved and that the revised incremental
cost effectiveness ratio per quality adjusted life year (QALY) of less than $55,000,
remained unacceptable. This was only slightly decreased from that before the PBAC
in November 2005 because the price of letrozole had fallen to match that of anastrozole.
The PBAC recalled it had uncertainty about this estimate because no overall survival
gain was demonstrated in the MA17 trial; no adverse impact of letrozole on mortality
or health care resources was included in the economic model and that the clinical
course of people who relapse after prophylactic exposure to letrozole in the economic
model is no different to the natural history of those who had never received letrozole.
Recommendation
Amend the current listing to read:
Restriction: Restricted benefit
Treatment of hormone-dependent breast cancer in post-menopausal women.
NOTE:
This drug is not PBS-subsidised for primary prevention of breast cancer.
This drug is not PBS-subsidised for adjuvant hormonal treatment of early breast cancer
extended beyond 5 years.
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
Novartis is pleased that Femara (letrozole) will be PBS listed for adjuvant treatment
of early breast cancer and thanks the PBAC for this recommendation.
Novartis also provided evidence in the submission to support the cost-effectiveness
of letrozole in the extended adjuvant setting. Letrozole is the only endocrine therapy
shown to significantly reduce the risk of further disease recurrence in women who
have completed adjuvant tamoxifen therapy. Novartis is committed to helping women
with breast cancer gain access to treatment and will continue to pursue reimbursement
in the extended adjuvant setting.
