Cabazitaxel, injection set containing 1 single use vial concentrate for I.V. infusion, 60 mg (anhydrous) in 1.5 mL with 1 single use vial diluent 4.5 mL, Jevtana®
Page last updated: 21 December 2011
Public Summary Document
Product: Cabazitaxel, injection set containing 1
single use vial concentrate for I.V. infusion, 60 mg (anhydrous) in
1.5 mL with 1 single use vial diluent 4.5 mL,
Jevtana®
Sponsor: Sanofi-Aventis Pty Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission sought an Authority required listing for treatment
of hormone refractory metastatic carcinoma of the prostate (mHRPC),
in combination with prednisolone, in patients previously treated
with a docetaxel-containing regimen.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Cabazitaxel was TGA registered on 8 December 2011 for use in
combination with prednisone or prednisolone for the treatment of
patients with hormone refractory metastatic prostate cancer
previously treated with a docetaxel containing regimen.
4. Listing Requested and PBAC’s View
Authority Required
Treatment of hormone refractory metastatic carcinoma of the
prostate in a patient previously treated with a
docetaxel-containing regimen.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Prostate cancer is the most common cancer in Australian men and the
second leading cause of male deaths due to cancer. The initial
treatment choice is hormone therapy, however the disease often
develops into metastatic hormone-refractory prostate cancer (mHRPC)
as the tumour becomes androgen independent (hormone refractory).
Docetaxel is currently used first line in the treatment of patients
with mHRPC. Due to the nature of the disease, disease progression
after initial chemotherapy treatment occurs frequently. Treatment
options for mHRPC include secondary hormonal manipulations,
palliative radiotherapy, chemotherapy and best supportive care. The
submission states that mitozantrone is the most widely used drug in
the second line setting. The submission proposed that cabazitaxel
would provide an additional treatment option for second line
therapy for mHRPC.
6. Comparator
The submission nominated mitozantrone as the main comparator. The
PBAC agreed that this was appropriate.
7. Clinical Trials
The basis of the submission was one open-label randomised trial
(TROPIC) comparing cabazitaxel 25 mg/m2 once every three
weeks plus prednisolone 10 mg daily with mitozantrone 12
mg/m2 once every three weeks plus prednisolone 10 mg
daily in patients with mHRPC with disease progression post
docetaxel chemotherapy.
Publication details of the TROPIC trial and associated reports
presented in the submission are in the table below.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Direct randomised trials | ||
| TROPIC De Bono JS, et al Bouchet BP, et al | A randomised, Open Label Multicenter Study of XRP6258 at 25mg/m 2 in combination with prednisone every 3 weeks compared to mitoxantrone in combination with prednisone for the treatment of hormone refractory metastatic prostate cancer previously treated with a Taxotere ® -containing regimen. Prednisolone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Cabazitaxel, a new taxane with favourable properties. | Lancet 2010; 376: 1147-54. Drugs of Today 2010; 46(10): 735-742. |
8. Results of Trials
The table below summarises the primary outcome of the TROPIC trial,
overall survival.
Overall survival (ITT) in TROPIC
| Cabazitaxel/prednisolone (n=378) | Mitozantrone/prednisolone (n=377) | |
|---|---|---|
| Number of deaths (%) | 234 (61.9) | 279 (74.0) |
| Number of patients censored (%) | 144 (38.1) | 98 (26.0) |
| Median OS (months) [95% CI] | 15.1 (14.1–16.3) | 12.7 (11.6–13.7) |
| Kaplan-Meier estimates for OS 6 month estimate [95% CI] 12-month estimate [95% CI] 18-month estimate [95% CI] | 85.0% [81%, 89%] 64.0% [59%, 68%] 39.0% [33%, 44%] | 80.0% [76%, 84%] 53.0% [48%, 58%] 28.0% [23%, 33%] |
| Hazard Ratio: TPF/PF [95% CI] | 0.70 [0.59, 0.83] | |
| Log-rank p value | <0.0001 | |
Bolded typography indicates statistically significant differences
between treatment groups
Median overall survival was statistically significantly longer for
patients treated with cabazitaxel than for those treated with
mitozantrone (15.1 months versus 12.7 months; an incremental
overall survival of 2.4 months (p<0.0001)). The hazard ratio was
0.70 (95% CI: 0.59, 0.83) in favour of cabazitaxel, corresponding
to a 30% reduction in risk of death.
The table below summarises the adverse events reported in the
TROPIC trial.
Summary of adverse events in the TROPIC trial
| TROPIC Trial | CP N=371 n (%) | MP N=371 n (%) | RR (95% CI) |
|---|---|---|---|
| Patients with any TEAE | 355 (95.7%) | 328 (88.4%) | 1.08 (1.04,1.13) |
| Patients with grade ≥3 TEAE | 213 (57.4%) | 146 (39.4%) | 1.46 (1.25, 1.70) |
| Patients with any serious TEAE | 145 (39.1%) | 77 (20.8%) | 1.88 (1.49, 2.38) |
| Patients discontinuation due to TEAE | 68 (18.3%) | 31 (8.4%) | 2.19 (1.47, 3.27) |
| Patients with any TEAE leading to death AE other than disease progression Disease progression reported as AE Disease progression, hepatic failure | 19 (5.1%) 18 (4.9%) 1 (0.3%) 0 (0.0%) | 17 (4.6%) 7 (1.9%)* 9 (2.4%) 1 (0.3%) | 1.12 (0.59, 2.12) 2.57 (1.09, 6.08) 0.11 (0.01, 0.87) 0.33 (0.01, 8.16) |
| Patients with AE of grade ≥1 | 355 (95.7%) | 328 (88.4%) | 1.08 (1.04,1.13) |
| Patients with AE of grade ≥2 | 316 (85.2%) | 258 (69.5%) | 1.22 (1.13, 1.33) |
| Patients with AE of grade ≥3 | 213 (57.4% | 146 (39.4%) | 1.46 (1.25, 1.70) |
| Patients with AE of grade ≥4 | 99 (26.7%) | 47 (12.7%) | 2.11 (1.54, 2.89) |
| Patients with AE of grade ≥5** | 19 (5.1%) | 17 (4.6%) | 1.12 (0.59, 2.12) |
TEAE = Treatment Emergent Adverse Event; CP = Cabazitaxel +
Prednisone/Prednisolone;
MP = Mitozantrone + Prednisone/Prednisolone
* Five patients died due to disease progression coded as adverse
events and one patient died because of a motor vehicle accident. **
TEAE including Disease Progression reported as an AE
A statistically significantly greater number of patients treated
with cabazitaxel reported treatment emergent adverse reactions
(TEAEs), TEAEs grade ≥3, serious TEAEs and TEAEs leading to
discontinuation. A significantly higher incidence of neutropenia
(RR=3.04; 95% CI: 2.00, 4.62), febrile neutropenia (RR=5.60; 95%
CI: 2.19, 14.34) and diarrhoea (RR=23.00; 95%CI: 3.12, 169.43) was
reported in patients treated with cabazitaxel.
For PBAC’s comments on these results, see Recommendation
and Reasons.
9. Clinical Claim
The PBAC considered that the submission’s claim that
cabazitaxel is superior in terms of comparative effectiveness and
inferior in terms of comparative safety over mitozantrone was
reasonable.
10. Economic Analysis
The submission presented a stepped economic evaluation, based on
the TROPIC trial. The type of economic evaluation presented was a
cost-utility analysis.
The submission presented a 5-state Q-TWiST analysis of patient
level data to determine the time spent in each of the five health
states during the clinical trial period:
- Time with treatment response and toxicity;
- Time with treatment response without toxicity;
- Time without response or progression but with toxicity;
- Time without response or progression or toxicity; and
- Disease progression.
Treatment response in the Q-TWiST was defined as PSA (Prostate
Specific Antigen) response and disease progression was defined as
the earliest occurrence of pain, PSA increase or tumour progression
from the trial data.
Overall survival was extrapolated by fitting Weibull distributions
to patient level data in each arm of the TROPIC trial.
Quality-adjusted time spent in each health state was derived by
applying utilities relevant to each health state to the time spent
in that state
The costs included in the modelled economic evaluation
included:
second-line drug and administration costs;
second-line adverse event costs - only costs associated with
hospitalisation of adverse events of grade 3 or greater;
second-line non-drug costs (excluding from adverse events);
third-line chemotherapy costs.
The results of the base case modelled economic evaluation showed
that cabazitaxel was associated with an incremental cost per extra
quality adjusted life year (QALY) gained of between $75,000 and
$105,000.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The financial cost per year to the PBS was estimated in the
submission to be in the range of $10–30 million in Year
5.
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendation and Reasons
The PBAC acknowledged that there was a clinical need for
cabazitaxel for the second line treatment of hormone refractory
metastatic prostate cancer in patients who have failed docetaxel
and agreed that mitozantrone was the appropriate comparator.
The PBAC considered that the requested restriction should stipulate
use of cabazitaxel in combination with prednisone/prednisolone,
progression or intolerance to docetaxel rather than “patients
previously treated with a docetaxel containing regimen”, WHO
status of 2 or less, no use of cabazitaxel beyond progression and
no return to docetaxel after progression on cabazitaxel.
The key clinical trial in the submission was TROPIC, an open-label
randomised trial comparing cabazitaxel 25 mg/m2 once
every three weeks plus prednisolone 10mg daily with mitozantrone 12
mg/m2 once every three weeks plus prednisolone 10mg
daily in patients with mHRPC with disease progression post
docetaxel chemotherapy. The PBAC noted that the median survival was
significantly longer for patients treated with cabazitaxel (15.1
months) than for those treated with mitozantrone (12.7 months),
with an incremental overall survival of 2.4 months (p<0.0001).
The hazard ratio was 0.70 (95% CI: 0.59, 0.83) in favour of
cabazitaxel, corresponding to a 30% reduction in risk of
death.
A statistically significantly greater number of patients treated
with cabazitaxel reported treatment emergent adverse reactions
(TEAEs), TEAEs grade ≥3, serious TEAEs and TEAEs leading to
discontinuation. A significantly higher incidence of neutropenia
(RR=3.04; 95% CI: 2.00, 4.62), febrile neutropenia (RR=5.60; 95%
CI: 2.19, 14.34) and diarrhoea (RR=23.00; 95%CI: 3.12, 169.43) was
reported in patients treated with cabazitaxel. The PBAC noted that
the submission did not include the costs of other PBS therapies
likely to be co-administered and/or prescribed for the treatment of
adverse events with cabazitaxel and that the cost of cabazitaxel is
therefore likely underestimated in the submission.
Cabazitaxel is associated with higher rates of neutropenia and
patients on cabazitaxel are much more likely to require G-CSF.
Without G-CSF, the treatment outcomes are also likely to be less
favourable. Inclusion of G-CSF costs is likely to increase the
ICER. Further there were differences across trial sites in the
deaths due to neutropenic complications, with these being less in
settings where neutropenia was managed with G-CSF. The cost of
treating neutropenic complications was not factored into the model
and this would also potentially increase the ICER
There was an early inflexion in the Kaplan Meier curve of
cabazitaxel as a result of several early deaths due to neutropenic
complications. More cycles of cabazitaxel were given compared with
mitozantrone (5.96 versus 4.6) and greater toxicity is seen with
cabazitaxel. The PBAC noted that the trial protocol allowed only
one dose reduction but that this did not reflect current clinical
practice where further dose reductions are likely to occur or
treatment may be delayed. The PBAC noted that this is not captured
in the sensitivity analysis, and that this increased uncertainty in
relation to the estimated survival advantage. the PBAC noted that
the number of cycles is likely to be higher in the Australian
setting and as the economic model is sensitive to the number of
treatment cycles, the PBAC considered that the ICER is likely to be
higher than estimated in the submission.
The PBAC agreed that the clinical claim that cabazitaxel is
superior in terms of comparative effectiveness and inferior in
terms of comparative safety over mitozantrone is reasonable.
The PBAC noted that the economic evaluation presented a Q-TWiST
analysis of patient level data to determine the time spent in each
of the five health states during the clinical trial period. Overall
survival was extrapolated by fitting Weibull distributions to
patient level data in each arm of the TROPIC trial. The PBAC
considered that the incremental median survival of 2.4 months
captured the early toxicity and death. However, the PBAC considered
that the cabazitaxel Weibull function appeared to overestimate the
extrapolated incremental mean overall survival (4.26 months) which
was attributed to difference in progression-free survival. At the
30 month time point all patients had progressed at the end of the
trial and few patients were alive (16.9% of cabazitaxel and 8.9%
mitozantrone). The average survival gain per patient over 30 months
was 3.18 months. The PBAC noted that the mean within-trial survival
for cabazitaxel (3.2 months) presented in the sponsor’s
Pre-PBAC Response is quite different from the median (2.4 months),
unlike the mean and median within-trial survival for docetaxel in
the first-line mHRPC setting, which is very similar (2.3 months
versus 2.4 months respectively). The PBAC concluded that the
Weibull function appears to underestimate survival in some parts of
the curve and over-estimate in other parts, and therefore is
relatively uncertain. The PBAC noted that the extrapolation of the
model from 30 months to lifetime has a huge impact on the
ICER.
The extrapolated incremental mean overall survival gain of
second-line mHRPC cabazitaxel versus mitozantrone (4.26 months) is
also compared with that of first-line mHRPC docetaxel versus
mitozantrone (3.73 months) in the sponsor’s Pre-PBAC
Response. However, most of the 4.26 months for patients receiving
cabazitaxel is spent in the progressive disease state (3.14 months)
which was not the case for patients treated with docetaxel, where
the greatest proportion of the 3.73 months gain in extrapolated
mean overall survival was spent in the TWIST state (no toxicity and
no progression). Therefore, the PBAC considered that most of the
gain with cabazitaxel is beyond the trial period and is based on
time spent in the terminal or end of life phase of the
disease.
In the TROPIC trial no G-CSF was given in the first cycle of
treatment and was administered at the discretion of the treating
clinician for subsequent cycles. Neutropenic complications were
lower in centres that used G-CSF. The PBAC considered that without
G-CSF supportive therapy, efficacy may be reduced due to lower
starting and subsequent doses of cabazitaxel being administered to
reduce the likelihood of toxicity. Alternatively, a larger number
of patients receiving cabazitaxel in the Australian setting would
be co-prescribed G-CSF. However, as G-CSF is currently not PBS
subsidised for patients receiving chemotherapy for prostate cancer
the PBAC noted that there may be issues with equity of
access.
The sponsor’s Pre-PBAC response addressed the issue regarding
the inclusion of G-CSF in the modelled economic evaluation which
increased the ICER by about 1%. However, as the early adverse
events due to neutropenic complications, and neutropenia adverse
events and complications were less common when G-CSF was used, the
PBAC considered that the addition of this trial based cost may
understate the impact on the ICER, as G-CSF use was reported in
TROPIC to be in 10.9% of cycles and use is likely to be
considerably higher in clinical practice in Australia.
The PBAC considered that the utility states may also be
overestimated as the utility values are derived from vignettes
designed for first-line mHRPC patients and there may be key quality
of life differences between first- and second-line therapy that
will not be captured in these vignettes (the study was conducted in
a general population sample). The PBAC noted that the ICER is very
sensitive to the QALY weights as evidenced by the large difference
in the incremental cost per life year gained ($45,000 - $75,000)
and incremental cost per quality-adjusted life year gained ($75,000
- $105,000). In view of the issues raised above, the PBAC
considered these ICERs to be uncertain.
The PBAC considered that it was highly likely that lower doses
would be required in clinical practice due to toxicity and
therefore considerable wastage would result from only a 60mg vial
being available.
The PBAC considered that the 43% uptake rate of cabazitaxel is an
overestimation and that the increase in significant adverse events
for many patients will limit the suitability of this
treatment.
The PBAC therefore rejected the submission on the basis of a high
and uncertain cost-effectiveness ratio.
The PBAC also acknowledged and noted the consumer comments received
in its consideration of cabazitaxel.
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.
14. Sponsor’s Comment
Sanofi is disappointed by this decision but is committed to continuing to work with the PBAC to ensure that Jevtana is made available on the PBS for Australian men who have prostate cancer.
