Vinflunine, solution concentration for I.V. infusion, 50 mg in 2 mL and 250 mg in 10 mL (as ditartrate), Javlor® - November 2011
Page last updated: 16 March 2012
Public Summary Document
Product: Vinflunine, solution concentration for
I.V. infusion, 50 mg in 2 mL and 250 mg in 10 mL (as ditartrate),
Javlor
Sponsor: Pierre Fabre Medicament Australia Pty
Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
The submission sought an Authority Required (STREAMLINED) listing
for the treatment of an adult patient with advanced or metastatic
transitional cell carcinoma of the urothelial tract (TCCU) after
failure of a prior platinum-containing regimen.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Vinflunine was registered by TGA on 11 February 2011 for the indication:
- Treatment of adult patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen.
4. Listing Requested and PBAC’s View
Authority Required (STREAMLINED)
Treatment of an adult patient with advanced or metastatic
transitional cell carcinoma of the urothelial tract after failure
of a prior platinum-containing regimen.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Cancer of the urothelium, known as transitional cell carcinoma of
the urothelial tract or TCCU, represents greater than 90% of
diagnosed bladder cancers. Urothelial tract tumours also include
tumours of the renal pelvis, ureters and urethra. In invasive or
metastatic TCCU, cancer that begins in the urothelial cells may
spread through the lining of the bladder and invade the muscle wall
of the bladder or spread to nearby organs such as the prostate,
uterus, vagina, pelvic or abdominal wall and lymph nodes.
Clinical management of advanced or metastatic TCCU typically
involves surgery, chemotherapy and radiotherapy. While bladder
cancers are sensitive to systemic chemotherapy such as
platinum-based treatment e.g. cisplatin in combination with
gemcitabine, patients with metastatic disease experiencing
recurrence or progression after an initial platinum-based treatment
regimen can have a poor response to subsequent therapies.
The submission proposed that the place in therapy of vinflunine is
as a further treatment option for patients with advanced or
metastatic TCCU who have failed treatment with chemotherapy
regimens containing a platinum compound.
6. Comparator
The submission nominated best supportive care (BSC) as the main
comparator, on the basis that there were no approved and/or
reimbursed medicines available currently on the PBS for these
patients.
The PBAC agreed that whilst best supportive care (BSC) is an
appropriate comparator in determining the efficacy of vinflunine,
it is not relevant in Australian clinical practice as vinflunine
will likely replace or defer other drugs.
7. Clinical Trials
The submission presented Study 302, a randomised unblinded trial
comparing BSC and vinflunine (280 mg/m2 or 320
mg/m2 every three weeks) depending on performance status
and prior pelvic irradiation or special haematological or
biochemical status with BSC alone in patients with advanced or
metastatic TCCU after failure of a prior platinum-containing
regimen. The PBAC considered that BSC, as it was defined in the
study, was not consistent with current practice in Australia.
The following trials had been published at the time of
submission:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Study 302 | ||
| Bellmunt, J.et al | Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. | Journal of Clinical Oncology (2009) 27(27): 4454-4461. |
| Bellmunt, J.et al | Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. | Journal of Clinical Oncology (2010) 28(11): 1850-1855. |
| Von Der Maase, H et al | Multicentre phase III trial comparing vinflunine (V) plus best supportive care (BSC) vs BSC alone as 2nd line therapy after a platinum-containing regimen, in advanced transitional cell carcinoma of the urothelium (TCCU). | Annals of Oncology (2008) 19(S8): viii202. |
| Culine, S et al | Updated survival results of the phase III trial comparing vinflunine (V) to Best Supportive Care (BSC) in advanced Transitional Cell Carcinoma of the Urothelium (TCCU) after failure of a prior platinum-containing regimen. Presentation at the 25th Annual EAU Congress. | Presentation at the 25th Annual EAU Congress. (2010) |
8. Results of Trials
The submission used the eligible intent-to-treat (ITT) result as
the base case, which is a sub-group of the ITT group, with 13
patients removed because it was identified post-randomisation that
they did not meet the inclusion criteria (9 in the BSC arm and 4 in
the vinflunine arm).
The PBAC noted that the exclusion of the 13 patients occurred
post-hoc, and given that these patients received treatment in a
clinical trial setting, it is likely that they would also receive
treatment in practice.
A summary of the results for overall survival in the ITT and
eligible ITT populations are shown in the table below:
Summary of results on overall survival in ITT and eligible
ITT
| Median Overall survival (months) | HR (95% CI) p value | |||
|---|---|---|---|---|
| VFL+BSC | BSC | Stratified log-rank test | Extended multivariate analysis | |
| ITT | 6.9 | 4.6 | 0.88 (0.69,1.12) p = 0.2868 | 0.74 (0.57 , 0.96) p= 0.0221 |
| Eligible ITT | 6.9 | 4.3 | 0.78 (0.69, 0.99) p = 0.0403 | 0.68 (0.52, 0.88) p = 0.0035 |
The PBAC noted that the increment in overall survival (OS) is
uncertain and, at best, is between 2.3 (ITT) and 2.6 months
(eligible ITT). Therefore, the PBAC considered the choice of
population is important as the choice of analysis group determines
if the hazard ratio is statistically significantly different from
1. Therefore, the selection of the eligible ITT population was
considered highly uncertain.
The PBAC agreed that the ITT population should be used in
considering the effectiveness of vinflunine as the eligibility
criteria in the trial were tighter than the PBS restriction
criteria and the ITT population more closely approximates the
likely PBS population.
The results of overall survival analysis (OS) across the three
populations ITT, Per Protocol and Eligible ITT at three different
time cut-off points are shown below:
Main Results from Study 302
| ITT | Per Protocol | Eligible ITT | ||||
|---|---|---|---|---|---|---|
| VFL + BSC | BSC | VFL + BSC | BSC | VFL + BSC | BSC | |
| N=253 | N=117 | N=244 | N=107 | N=249 | N=108 | |
| OS analysis (Cut-off 30 Nov 2006) | ||||||
| HR (95% CI) | 0.88 (0.69, 1.12) | 0.75 (0.59, 0.96) | 0.78 (0.61, 0.99) | |||
| OS analysis (Cut-off 31 May 2007) | ||||||
| HR (95% CI) | 0.88 (0.69, 1.10) | 0.74 (0.59, 0.94) | 0.77 (0.61, 0.98) | |||
| OS analysis (Cut-off 30 Nov 2008) | ||||||
| HR (95% CI) | 0.88 (0.70, 1.10) | 0.78 (0.61, 0.96) | ||||
| No. of events | 204 | 103 | 198 | 98 | 202 | 98 |
| No. censored (%) | 49 (19.4) | 14 (12.0) | 46 (18.9) | 9 (8.4) | 47 (18.9) | 10 (9.3) |
| Median (95% CI) (month) | 6.9 (5.7, 8.0) | 4.6 (4.1, 7.0) | 6.9 (5.7, 8.0) | 4.3 (3.8, 5.4) | 6.9 (5.7, 8.0) | 4.3 (3.8, 5.4) |
| p value a | 0.2868 | 0.0197 | 0.0403 | |||
| No. of events | 223 | 108 | 216 | 102 | 220 | 102 |
| No. censored (%) | 30 (11.9) | 9 (7.7) | 28 (11.5) | 5 (4.7) | 29 (11.7) | 6 (5.6) |
| Median (95% CI) (month) | 6.9 (5.7, 8.0) | 4.6 (4.1, 6.6) | 6.9 (5.7, 8.0) | 4.3 (3.8, 5.4) | 6.9 (5.7, 8.0) | 4.3 (3.8, 5.4) |
| p value a | 0.2546 | 0.0130 | 0.0320 | |||
| No. of events | 237 | 115 | not performed | 234 | 108 | |
| No. censored (%) | 16 b (6.3) | 2 c (1.7) | 15 (6.0) | 0 | ||
| Median (95% CI) (month) | 6.9 (5.7, 8.0) | 4.6 (4.1, 6.6) | 6.9 (5.7, 8.0) | 4.3 (3.8, 5.4) | ||
| p value a | 0.2613 | 0.0227 | ||||
Abbreviations:VFL, vinflunine; BSC, best supportive care; HR,
hazard ratio; CI, confidence interval.
a: Stratified log-rank test;
b: Including 1 non eligible patient (#550543 lost to follow-up with
an OS=15.7 months);
c: Two non eligible patients alive at the cut-off (#600401 with an
OS=34.2 months & #110504 with an OS=45.4 months)
Statistically significant HR values noted in
bold.
The PBAC noted that if the results for OS are evaluated from the
ITT population analysis, the hazard ratios at all three time
cut-off points were not statistically significantly different from
the null. Therefore, the evidence of a real increase in OS was
considered uncertain. The PBAC also noted that the results of a Cox
multivariate analysis presented in the sponsor’s
Pre-Sub-Committee Response demonstrated that potential differences
in the prognostic factors from excluding the 13 ineligible patients
did not alter overall survival in the eligible ITT.
The adverse events that were both common (reported by at least 10%
of the patient population of Study 302) and statistically
significantly more frequent in those receiving vinflunine were
abdominal pain, constipation, diarrhoea, nausea, stomatitis,
vomiting, fatigue, injection site reactions, weight decrease,
anorexia, myalgia, headaches, peripheral sensory neuropathy and
alopecia. The Grade III/IV adverse events experienced more
frequently in the vinflunine arm of Study 302 were abdominal pain,
constipation, nausea, vomiting, fatigue, infestations and
infections, anorexia, myalgia and headache.
One death due to pancytopenia was reported as directly related to
vinflunine, although sixteen patients (6%) in the vinflunine and
BSC group, and 1 patient (1%) in the BSC group died within 30 days
of either the final vinflunine dose (for the intervention arm) or
the final visit (for the BSC arm) for reasons other than
progressive disease.
The PBAC noted that the rates of adverse events (AE) were higher in
the vinflunine+BSC group than in the BSC group and that the pattern
of AE and serious adverse events (SAE) suggested very high levels
of toxicity that would need to be traded off for a relatively small
increase in overall survival.
The submission provided additional data on potential safety
concerns beyond those identified in the clinical trials. The PBAC
noted that neither of these identified different patterns of
adverse events from those noted in Study 302.
9. Clinical Claim
The submission described vinflunine as superior in terms of
comparative effectiveness and inferior in terms of comparative
safety over best supportive care.
The PBAC accepted that vinflunine may be superior in terms of
comparative efficacy over BSC although the magnitude of the overall
survival gain is uncertain (less than 3 months) and is at the
expense of significant toxicity. The PBAC agreed that vinflunine is
inferior in terms of comparative safety over best supportive
care.
10. Economic Analysis
The submission presented a cost-utility analysis (CUA) based on the
eligible ITT population in Study 302.
The economic model was a decision analysis comparing IV vinflunine
plus BSC with BSC alone for treatment of patients with advanced or
metastatic TCCU who have progressed after prior platinum-containing
treatment.
The model excluded costs of BSC that were not expected to differ
between treatment arms, and underestimated the cost of adverse
events (AEs) by assuming that all AEs were captured by the risk
difference for hospitalisations, based on the number of patients
hospitalised in each arm of Study 302.
The results of the stepped economic evaluation produced a base case
ICER between $45,000 and $75,000.
The results of the sensitivity analyses presented in the submission
indicated that the model was most sensitive to the number of
episodes of palliative radiotherapy (PRT).
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The net financial cost per year to the PBS was estimated by the
submission to be less than $10 M in Year 5, this was considered to
be very uncertain. The sources of uncertainty were the estimated
number of patients and number of treatment cycles per patient, the
number of palliative radiotherapy episodes and net costs of BSC and
AEs, which were considered to be underestimated.
12. Recommendation and Reasons
The submission presented one randomised, unblinded trial (Study
302) comparing vinflunine (280 mg/m2 or 320
mg/m2 every three weeks) and BSC with BSC alone in
patients with advanced or metastatic TCCU after failure of a prior
platinum-containing regimen as the key clinical trial. However, the
PBAC considered that BSC as it was defined in the study is not
consistent with current practice in Australia.
The PBAC agreed that whilst BSC is an appropriate comparator in
determining the efficacy of vinflunine, it is not relevant in
Australian clinical practice as vinflunine will likely replace or
defer other drugs. The PBAC considered that current standard of
care is preferable for the determination of relative effectiveness
and therefore the translatability of the trial data to the proposed
use in Australia is an area of significant uncertainty.
The PBAC noted that both the proposed clinical management algorithm
and the requested restriction allow use in patients who are
intolerant to first-line therapy with a platinum compound. However,
the trial data did not provide information on this group of
patients. The PBAC also noted that patients who had received
neoadjuvant or adjuvant treatment were excluded from the trial, but
would meet the requested restriction if they failed adjuvant
treatment with a platinum compound (second-line therapy). The
sponsor acknowledged the patient’s exclusion in its
Pre-Sub-Committee Response.
The PBAC noted that the submission used the eligible ITT result as
the base case, which is a sub-group of the ITT group, with 13
patients removed because it was identified post-randomisation that
they did not meet the inclusion criteria (9 in the BSC arm and 4 in
the vinflunine arm). The PBAC noted that the exclusion of the 13
patients occurred post-hoc, and given that these patients received
treatment in a clinical trial setting, it is likely that they would
also receive treatment in practice. The PBAC agreed that whilst the
eligible ITT population may be reasonable to assess the efficacy of
vinflunine, the ITT population should be used in considering the
effectiveness of vinflunine as the eligibility criteria in the
trial are tighter than the PBS restriction criteria and the ITT
population more closely approximates the likely PBS
population.
The PBAC accepted that vinflunine is superior in terms of
comparative efficacy over BSC but noted that the increment in
overall survival is uncertain and, at best, is between 2.3 (ITT)
and 2.6 months (eligible ITT) and was at a cost of significant
treatment-related toxicity. The PBAC agreed that vinflunine is
inferior in terms of comparative safety over best supportive care.
The PBAC considered that realising the possible beneficial effects
of vinflunine in clinical practice may be challenging because of a
patient’s age (likely to be older in clinical practice), the
effect of previous radiotherapy and performance status on dose and
hence the ability to adhere to the dose escalation protocols. In
this regard, vinflunine also appears to have a narrow therapeutic
window. The PBAC acknowledged that although vinflunine may have
efficacy in some patients with high clinical need, the magnitude of
survival gain is uncertain (less than 3 months) and this benefit is
at the expense of significant toxicity. Therefore, the PBAC
considered that there is uncertainty regarding the clinical place
of vinflunine.
The PBAC agreed that the selection of pre-modelling issues in the
submission is appropriate. However, the degree to which Study 302
represents the Australian setting was uncertain for three reasons:
(1) treatment for those with a poorer performance status is not
excluded under the proposed listing and is not considered in Study
302; (2) BSC does not adequately represent the set of replaced
interventions in an Australian setting where other therapies are
often used in the second-line; (3) the age of the patient
population in Study 302 is likely to be lower than the age of
patients in an Australian population.
The economic evaluation was a cost-utility analysis (CUA) based on
the eligible ITT population in Study 302. The PBAC noted that the
results from this analysis are uncertain as they are based on the
eligible ITT population rather than the ITT population. The overall
survival gain in the ITT population was less than observed in the
eligible ITT and was not statistically significant. The PBAC
considered that the results are highly uncertain as they are based
on the eligible ITT population rather than the ITT population. The
PBAC agreed that the results of the CUA, which compare vinflunine
to BSC, do not reflect the cost effectiveness of vinflunine
relative to the range of second line treatments currently used in
50-60% of patients. Therefore, it is likely that the ICER of
between $45,000 and $75,000 per QALYG is an underestimate in the
submission.
The PBAC considered that an Authority Required (STREAMLINED)
listing is appropriate.
The PBAC rejected the submission on the basis of uncertainty about
the clinical benefit and a high and highly uncertain incremental
cost-effectiveness ratio.
The PBAC noted that the submission meets the criteria for an
independent review.
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
Pierre Fabre Medicament wishes to emphasise that vinflunine is the
only registered drug in Australia for the treatment of advanced or
metastatic transitional cell carcinoma of the urothelial tract
after failure of a prior platinum containing regimen. All other
drugs which are currently used to treat second line metastatic
bladder cancers in Australia are used “off
label”.
Pierre Fabre Medicament Australia is disappointed with the
recommendation and is committed to working with the PBAC to provide
an approved treatment for patients with metastatic TCCU after
failure of a prior-platinum containing regimen.
