Sunitinib malate, capsules, 12.5 mg, 25 mg and 50 mg, Sutent®, March 2007
Public summary document for Sunitinib malate, capsules, 12.5 mg, 25 mg and 50 mg, Sutent®, March 2007
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Public Summary Document
Product: Sunitinib malate, capsules, 12.5 mg, 25
mg and 50 mg, Sutent®
Sponsor: Pfizer Australia Pty Ltd
Date of PBAC Consideration: March 2007
1. Purpose of Application
The submission sought a Section 85 Authority Required listing for
the treatment of advanced renal cell carcinoma (RCC).
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Sunitinib malate was registered by the TGA on 14 September 2006 for
the treatment of advanced renal cell carcinoma and gastrointestinal
stromal tumour (GIST) after failure of imatinib mesylate treatment
due to resistance or intolerance.
4. Listing Requested and PBAC’s View
Authority Required – Section 85
For the treatment of advanced renal cell carcinoma.
In addition, the submission presented analyses corresponding to
listings restricted by a PBS continuation rule requiring tumour
response at 12 weeks (after 2 cycles of treatment). The first
analysis requires patients be “stable or better” using
RECIST criteria, censoring patients who do not meet these
requirements. The second, “restricted listing #2
analysis,” censors patients if they do not show tumour
response (partial or complete) at 12 weeks (after 2 cycles).
See Recommendations and Reasons for PBAC’s
view.
5. Clinical Place for the Proposed Therapy
Renal cell carcinoma is a form of kidney cancer that arises from
the cells of the renal tubule. Currently, only interferon alfa is
registered in Australia for the management of metastatic RCC but is
not PBS listed for this indication. Sunitinib could be used as an
alternative treatment for patients with advanced RCC.
6. Comparator
The submission nominated best supportive care (BSC) +/- interferon
alfa-2a as the main comparator. The submission also nominated
sorafenib as a supplementary comparator.
The PBAC did not accept that best supportive care (BSC) +/-
interferon alfa is the appropriate comparator.
See Recommendations and Reasons for PBAC’s
views.
7. Clinical Trials
For the primary comparator (BSC + interferon-alfa), the submission
presented interim analysis of one Phase III open head-to-head trial
(Trial A618-1034) of sunitinib versus interferon-alfa as first line
therapy in advanced/metastatic RCC and three supportive single arm
studies (Study RTKC-0511-014, Study A618-1006, and Study A618-1039)
as second line therapy in cytokine-refractory RCC and one
supportive safety (QTc) study (Study A618-1005). For the
supplementary comparator, sorafenib, the submission presented two
trials (Ratain/2006, an open-label PHASE II study and TARGETS a
PHASE III secondline study vs placebo). The main evidence was
provided by Trial A618-1034. The three supportive studies for the
primary comparator were all small, single-arm studies in patients
having failed first line therapy. Because of limited data from the
sorafenib trials, the supplementary comparison was only
descriptive.
One of these studies had been published at the time of the
submission, as follows:
Trial/First author | Protocol title/Publication title | Publication citation |
Ratain | Phase II Placebo-Controlled Randomized Discontinuation Trial of Sorafenib in Patients With Metastatic Renal Cell Carcinoma | Journal of Clinical Oncology, Vol 24, No 16 (June 1), 2006: pp. 2505-2512 |
8. Results of Trials
The results of the time-to-first event analyses, Cox proportional
hazards models (CPH), and post hoc “restricted listing #2
analysis” of progression-free survival (PFS) and overall
survival (OS) from Trial A618-1034 were presented. There were no
data in the submission to determine if progression increased
symptoms, worsened quality-of-life, or shortened survival.
The PBAC agreed that this trial was well conducted with blinded
assessment of disease progression outcomes. The submission was
based on the second interim analysis of this trial, which
demonstrated that treatment with sunitinib was associated with a
significantly longer time to progression than treatment with
interferon alfa. It was noted that overall survival did not reach
the level of significance pre-specified in the trial for the
interim analysis. The PBAC acknowledged that because patients that
progressed were allowed to cross-over, interpretation of future
estimates of overall survival benefit would be difficult because of
an expected tendency to the null underestimating the likely true
difference between the therapies. The trial is on-going.
The PBAC noted sunitinib demonstrated more serious adverse events,
more treatment related serious adverse events, and more adverse
events with a frequency of 10% or more or a ratio of 2 or more
compared to interferon-alfa (see table below). The toxicity
differences with interferon-alfa were substantial. Of particular
concern were in the incidence of thrombocytopaenia and neutropaenia
in the sunitinib arm.
9. Clinical Claim
The clinical claim made in the submission is that sunitinib is
significantly more effective than the main comparator, interferon
alfa, but has more toxicity.
See Recommendations and Reasons for the PBAC’s
view.
10. Economic Analysis
A preliminary trial-based economic evaluation was presented. The
choice of the cost-effectiveness approach was considered valid. The
resources included were drug costs and adverse event management
costs. The overall comparative costs and outcomes for the base case
analysis and the restricted listing #2 analysis and the incremental
costs and outcomes are summarised in the following tables.
The trial-based (over interferon-alfa) incremental cost/extra
PFS-year gained was between $75,000 and $105,000. The trial-based
incremental cost/extra life-year gained was between $105,000 and
$200,000.
A modelled economic evaluation was not presented.
11. Estimated PBS Usage and Financial Implications
The cost to the PBS was estimated to be $10 to 30 million per year
in the first four years of listing.
12. Recommendation and Reasons
Although sympathetic of the clinical need for additional treatments
for this condition and encouraged by the benefits shown in the
submitted clinical trials, the PBAC deferred consideration of this
item pending the provision of further economic analyses to
demonstrate whether the treatment is acceptably cost
effective.
The PBAC had a number of concerns with the requested restriction
wording. Treatment should be limited to clear cell disease as this
reflects the trial population and biological rationale for
treatment. “Advanced” is an ambiguous descriptor of
disease status and should be replaced by Stage IV disease, which,
although it would encompass a slightly wider population with
metastatic disease than included in the key trial, would be more
acceptable. WHO performance status should be less than 2 at
initiation. A continuation rule based on restricting treatment to
only those who are responders (using RECIST criteria) would not be
appropriate because it is neither clinically sustainable nor
consistent with the logic of the submission’s argument where
clinical benefit equals no progression. For this reason, the PBAC
did not consider those aspects of the submission which reported
clinical and economic results based on sub-group analyses
corresponding to continuation rule of responders only
(“Restricted listings #2”).
The PBAC did not accept that best supportive care (BSC) +/-
interferon alfa is the appropriate comparator. The Committee
considered that although the survey presented in the submission
suggests that some oncologists use interferon alfa in a proportion
of patients, this is not the norm and furthermore, interferon alfa
is not PBS subsidised and has not been assessed as being
cost-effective for use in RCC. Thus, although a comparison with
interferon alfa may be reasonable on the grounds that it would be
substituted to some extent, such a comparison alone would not
assist the PBAC in assessing the cost effectiveness of sunitinib,
i.e. the cost-effectiveness of interferon alfa would also need to
be established as a pre-requisite to enabling a PBAC judgement
about the cost-effectiveness of sunitinib in relation to interferon
alfa. The PBAC considered that BSC alone is the more informative
comparator and accepted that, as in the Pre-PBAC Response, this
would involve an indirect comparison of randomised trials with
interferon alfa as the common reference.
The PBAC agreed that the primary efficacy data in support of
listing sunitinib were derived from a randomised, head-to-head
Phase III trial (Trial A618-1034) of sunitinib versus interferon
alfa as first-line therapy in advanced/metastatic RCC. This trial
was well conducted with blinded assessment of disease progression
outcomes. The submission was based on the second interim analysis
of this trial, which demonstrated that treatment with sunitinib is
associated with a significantly longer time to progression than
treatment with interferon alfa (median progression-free survival
sunitinib 47.3 weeks, interferon alfa 22.0 weeks, multivariate
hazard ratio: 0.37, 95% CI 0.28 – 0.48). It was noted that
overall survival did not reach the level of significance
pre-specified in the trial for the interim analysis. The PBAC
acknowledged that because patients that progressed were allowed to
cross-over, interpretation of future estimates of overall survival
benefit would be difficult because of an expected tendency to the
null underestimating the likely true difference between the
therapies.
The submission reasonably argued there is an association between
progression-free survival and overall survival on the basis that,
although only 7% of progressions are deaths, it can be shown that
death was more likely in patients with tumour progression than
those without tumour progression. However, the PBAC considered that
the demonstration of this association alone does not provide
sufficient evidence to enable a confident prediction of the extent
of survival gain based on the estimated difference in time to
progression and that survival data is and should be used in the
economic analyses directly.
The PBAC agreed with the ESC that sunitinib is associated with more
toxicity than interferon alfa in some patients. Of particular
concern were the incidence of thrombocytopenia and neutropenia in
the sunitinib arm of the key study.
The PBAC had concerns about the additional cost of therapy and
consequently worse cost-effectiveness, if patients are treated with
sunitinib on a continuous daily basis at a dose of 37.5 mg and a
continuous daily basis at a dose of 50 mg, rather than the
intermittent dosing schedule in the submission. This was thought to
be a possibility because clinicians would be concerned that
patients may relapse when therapy is suspended for the 2 weeks
break in treatment. The PBAC also considered it unlikely that, in
clinical practice, patients would discontinue treatment upon
progression.
The Committee considered the estimated incremental cost per life
year gained over BSC provided in the preliminary economic
evaluation in the Pre-PBAC Response was unacceptably high at
between $75,000 and $105,000 and also uncertain. The PBAC
considered that that the “Responder analysis #1”, for a
restriction allowing continuation of sunitinib in patients with
stable disease or better, was less informative because applying
such a continuation rule was not clinically sustainable and this
analysis relied on inadequately supported post-trial sub-group
analyses. The PBAC noted that a modelled economic analysis had not
been presented and deferred the submission to allow such an
analysis to be provided by the appropriate submission deadline to
allow full evaluation by the PES and consideration by the ESC
before it is reconsidered by the PBAC. The longer-term survival
with BSC can be sourced from epidemiological studies stratified by
relevant prognostic criteria. Quality-adjustment of the modelled
survival gains would be appropriate. The PBAC also requested that
appropriate sensitivity analyses be conducted to investigate the
impact on the cost-effectiveness of treatment of varying the
sunitinib dose regimen, in particular replacing the intermittent
dose schedule proposed in the submission with a continuous dosing
schedule, and of treating to death rather than to a defined
“stopping” point.
Any submission should also discuss the basis upon which the PBAC
should assess the plausibility of any particular estimate in the
range of variations examined in these analyses.
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 is working with the PBAC to achieve PBS listing for
sunitinib in RCC.