Bevacizumab, solution for I.V. infusion, 100 mg in 4 mL, 400 mg in 16 mL, Avastin, March 2008
Public summary document for Bevacizumab, solution for I.V. infusion, 100 mg in 4 mL, 400 mg in 16 mL, Avastin, March 2008
Page last updated: 18 July 2008
Public Summary Documents
Product: Bevacizumab, solution for I.V. infusion, 100 mg in 4 mL, 400 mg in
16 mL, Avastin
Sponsor: Roche Products Pty Ltd
Date of PBAC consideration: March 2008
1. Purpose of Application
To seek a Section 100 (Special Authority Program) listing for bevacizumab for the treatment of metastatic colorectal cancer.
2. Background
This drug has not previously been considered by the PBAC.
3. Registration status
The TGA has registered bevacizumab for use in combination with fluorouracil, folinic acid and irinotecan or fluorouracil and folinic acid, for the treatment of patients with metastatic colorectal cancer.
4. Listing Requested and PBAC’s views
Section 100 Special Authority Program
Authority required
Treatment of metastatic colorectal cancer in previously untreated patients with a
WHO performance status of 0 or 1 in combination with:
(1) 5-fluorouracil and folinic acid; or
(2) irinotecan, 5-fluorouracil and folinic acid
Treatment of metastatic colorectal cancer in patients with a WHO performance status
of 0 or 1 in combination with chemotherapy where disease progression has occurred
following first-line treatment which includes bevacizumab.
For PBAC's comments on the requested restriction see Recommendations and Reasons.
5. Clinical place for the proposed therapy:
Bevacizumab is a recombinant humanised monoclonal antibody that selectively binds to and neutralises the biologic activity of human vascular endothelial growth factor (VEGF). Neutralising the biologic activity of VEGF reduces the vascularisation of tumours, thereby inhibiting tumour growth. Bevacizumab would provide an additional treatment for patients being treated with chemotherapy for colorectal cancer.
6. Comparator:
7. Clinical trials
The submission presented three randomised trials comparing bevacizumab 5mg/kg with
placebo in the treatment of previously untreated metastatic colorectal cancer in combination
with either 5-fluorouracil (FU)/leucovorin (LV) or irinotecan plus 5-FU/LV (IFL).
The submission also presented a supporting observational study comparing bevacizumab
5mg/kg plus chemotherapy to chemotherapy alone in the second-line treatment of metastatic
colorectal cancer following first-line treatment involving the use of bevacizumab.
The trials and study as published at the time of submission are listed below.
|
Trial/Author |
Publication title |
Publication citation |
|---|---|---|
|
AVF2107g |
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal
cancer. |
New England Journal of Medicine 2004; 350(23):2335-42 |
|
AVF0780g |
Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. |
Journal of Clinical Oncology 2003; 21(1):60-5 |
|
AVF2192g |
Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. |
Journal of Clinical Oncology 2005; 23(16):3697-3705 |
|
BRiTE |
Association between exposure to bevacizumab (BV) beyond first progression (BBP) and
overall survival (OS) in patients (pts) with metastatic colorectal cancer (MCRC):
Results from a large observational study (BRiTE). |
ASCO 2007, Poster 4036 |
8.Results of trials
The key results showed that the addition of bevacizumab to first-line chemotherapy
was associated with a significant increase in progression free survival in all three
of the randomised trials. The addition of bevacizumab to first-line chemotherapy also
led to an increase in overall survival, although the differences were not statistically
significant in two of the three randomised trials.
The results from the observational study (BRiTE) used to support second-line treatment
with bevacizumab reported significant benefits associated with second-line treatment
with bevacizumab (in terms of overall survival and survival beyond disease progression).
However, the PBAC was advised the interpretation of results was problematic given
the potential for serious confounding and bias in the study.
Based on the data submitted, relative to placebo, bevacizumab was associated with
additional toxicities.
In Study AVF2107g, hypertension and diarrhoea were the only Grade 3/4 adverse events
that occurred with significant increased incidence among patients receiving bevacizumab
in combination with IFL chemotherapy (Arm 2), compared with patients receiving placebo
in combination with IFL (Arm 1). Arterial thromboembolic events occurred with significant
increased incidence in Arm 2, compared with Arm 1.
In Study AVF0780g, asthenia was the only Grade 3/4 adverse event that occurred with
significant increased incidence among patients treated with bevacizumab in combination
with 5-FU/LV (Arm 2), compared with patients with 5-FU/LV alone (Arm 1). Diarrhoea
was the only treatment-related adverse event that occurred with significant increased
incidence in Arm 2, compared with Arm 1.
In Study AVF2192g, hypertension was the only Grade 3/4 adverse event that occurred
with significant increased incidence among patients treated with bevacizumab in combination
with 5-FU/LV (Arm 2), compared with patients treated with placebo in combination with
5-FU/LV (Arm 1).
Overall, the risk of several adverse events, particularly hypertension, proteinuria
and arterial thromboembolic events, was found to be elevated following the addition
of bevacizumab to chemotherapy.
9. Clinical claim
The submission described bevacizumab as superior in terms of comparative effectiveness
and inferior in terms of comparative safety over placebo in the treatment of previously
untreated metastatic colorectal cancer in combination with 5-FU/LV or irinotecan plus
5-FU/LV.
The submission described bevacizumab as superior in terms of comparative effectiveness
over placebo in the treatment of metastatic colorectal cancer in combination with
chemotherapy where disease progression has occurred following first-line treatment
involving the use of bevacizumab.
For PBAC's views see Recommendations and Reasons.
10. Economic analysis
A cost-effectiveness approach was presented.
The preliminary trial based economic evaluation results showed an incremental cost
per extra life-year gained when bevacizumab was compared to placebo (bolus irinotecan/5-fluorouracil/leucovorin
(IFL)) of between $105,000 to $200,000.
The results of the stepped modelled economic evaluation gave an incremental cost per
extra QALY gained in first-line use of between $105,000 to $200,000 when bevacizumab
was compared to placebo (various chemotherapy regimens).
In first- and second-line use, the base case discounted incremental cost per extra
QALY gained was less than in first line use alone, but still more than $105,000.
The sensitivity analyses performed indicated the model was somewhat sensitive to the
time horizon, treatment effects and uptake rates, but not in the extreme.
11. Estimated PBS Usage and Financial Implications
12. Recommendation and Reasons
The PBAC considered that the requested listing was highly ambiguous and expressed
concern about leakage of bevacizumab to patients with poor performance status (i.e.
WHO 2 and not just 0 and 1), into second line therapy when bevacizumab has not been
used first line, and as single agent bevacizumab. The Committee considered these issues
could be best addressed through a cap on expenditure and through including a NOTE
stating “not for use as monotherapy” in the restriction.
The PBAC also considered it would be poor clinical practice to endorse a restriction
which might encourage use of the irinotecan/Saltz regimen (IFL - Trial AVF2107) given
the toxicity and efficacy profile of this protocol, which was no longer accepted as
best practice in Australia or the USA.
The PBAC noted that placebo (standard medical management) was nominated as the comparator.
However, if the treatment algorithm as proposed in the restriction is accepted, then
FOLFIRI (folinic acid/fluorouracil/irinotecan)/bevacizumab would replace FOLFOX (folinic
acid/fluorouracil/oxaliplatin) as the current most widely used oxaliplatin-based regimen
and therefore the appropriate main comparator would be FOLFOX. The committee noted
that, according to the sponsor’s survey, the most commonly prescribed first line regimen
in Australia contained oxaliplatin (85% of treatments).
The PBAC noted that in the first-line setting, the addition of bevacizumab to first-line
chemotherapy (5FU/LV) was associated with a significant increase in progression free
survival in all three of the randomised trials presented. The addition of bevacizumab
to first-line chemotherapy also led to an increase in overall survival, although the
differences were not statistically significant in two of the three randomised trials.
The Committee agreed that overall, the observed survival gain of 3 – 4 months was
clinically meaningful. It did note however that in Australian practice the commonly
used chemotherapy regimens are infusional rather than bolus, and that there is a possibility
that this could alter the incremental effectiveness of bevacizumab in clinical practice.
The PBAC agreed that there is uncertainty concerning the magnitude of the clinical
benefit of bevacizumab in the second line setting following progression after use
of bevacizumab in the first-line setting. The data on the use of bevacizumab in this
setting come from an observational study (BRiTE) and although the study reported significant
benefits associated with first-line followed by second-line treatment with bevacizumab
(in terms of overall survival and survival beyond disease progression), the interpretation
of these results was problematic given the potential for serious confounding and bias
in the study.
The Committee considered that the toxicity of bevacizumab in day to day practice is
generally not an issue, but that occasional patients experience life-threatening adverse
events, including arterial thromboemboli, bleeds from metastases, poor wound healing
and gastrointestinal perforations.
The PBAC did not agree that a longer time horizon was appropriate for the economic
model but confirmed the submission’s choice of a 5 year time horizon. In this context,
the Committee noted that the registry data overestimated survival in the patient group
likely to be treated under a PBS listing, as it included patients whose metastatic
disease is fully resected and who therefore survive for a longer period.
The PBAC also could not see any reason not to quality adjust the survival gains included
in the incremental cost-effectiveness ratios for bevacizumab.
The PBAC noted that the submission provided a stepped economic evaluation. Step 7
in the model related to first-line followed by second-line therapy use. Step 7, as
it initially appeared in the submission, included the costs of second-line chemotherapy
regimens as well as the costs and outcomes of continuing bevacizumab use as part of
second-line therapy, using the results from the BRiTE study to estimate the outcomes
of second line therapy (bevacizumab assumed to be continued in 50% of patients in
the second-line setting following first-line use).
The Pre-Sub-Committee response provided a more complete analysis of Step 7, in that
even when the bevacizumab is not continued as part of second line therapy (0% bevacizumab
use beyond progression), it remains relevant to include the costs associated with
second-line chemotherapy therapy in the model. The base case was also recalculated.
This resulted in reduced incremental cost-effectiveness ratios, though still more
than of $75,000 per extra LYG and per extra QALY gained for the scenario which assumed
no usage of bevacizumab in second line therapy. However, the PBAC did not accept these
calculations because it considered that the original submission’s time horizon of
5 years was more appropriate.
Overall, the Committee considered that even the most favourable incremental cost effectiveness
ratios per extra QALY gained in both the first line setting and in the combined first
and second line setting were too high to be acceptable. In addition, the ICER allowing
for post-progression (second-line) use of bevacizumab remained subject to considerable
uncertainty arising from the uncertainty in the magnitude of clinical benefit in second-line
use.
The PBAC also considered that there was uncertainty surrounding the uptake of the
drug and hence total expenditure due to potential for use outside the restriction.
Finally, the PBAC noted advice from the Highly Specialised Drugs Working Party which
did not support the inclusion of bevacizumab under the HSD program.
Thus the PBAC rejected the submission on the grounds of an unacceptably high cost
effectiveness ratio in the first line setting only and an unacceptably high and uncertain
cost-effectiveness ratio in combined first- and second-line use, and noting the high
overall cost to Government should listing proceed.
Recommendation
Reject
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.
