Everolimus, tablets, 5 mg and 10 mg, Afinitor® - November 2011
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Public Summary Document
Product: Everolimus, tablets, 5 mg and 10 mg,
Afinitor®
Sponsor: Novartis Pharmaceuticals Australia Pty
Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
To seek an Authority Required listing for initial and continuing
treatment of Stage IV clear cell variant renal cell carcinoma in a
patient with a WHO status of 2 or less, who has failed treatment
with sunitinib.
2. Background
This was the fourth submission for everolimus requesting listing
for clear cell renal carcinoma.
At the November 2009 meeting, the PBAC rejected a submission for
everolimus for treatment, as the sole PBS-subsidised therapy, of a
patient with Stage IV clear cell variant renal cell carcinoma after
failure of treatment with sorafenib or sunitinib on the basis of
uncertain clinical benefit and a high and uncertain
cost-effectiveness ratio.
For full details, see November 2009 Public Summary
Document.
At its July 2010 meeting, the PBAC rejected a re-submission on the
basis of uncertain clinical benefit and a high and uncertain
cost-effectiveness ratio.
For full details, see July 2010 Public Summary
Document.
At the November 2010 meeting, the PBAC rejected a minor
re-submission on the basis of a high and uncertain
cost-effectiveness ratio. The PBAC considered that despite the
clinical need and trial-based evidence of improved PFS, the
magnitude of the clinical benefit in relation to survival was
uncertain and that with plausible survival modelling, the ICER
remained unacceptably high.
3. Registration Status
Everolimus tablets 5 mg and 10 mg were registered by the TGA on 29
July 2009 for the treatment of patients with advanced renal cell
carcinoma after failure of treatment with sorafenib or
sunitinib.
4. Listing Requested and PBAC’s View
Authority Required
Initial treatment, as the sole PBS-subsidised therapy, of Stage IV
clear cell variant renal cell carcinoma (RCC) in a patient who has
failed treatment with sunitinib and has a WHO status of 2 or
less.
Failure of treatment with sunitinib is defined as:
(i) Progressive disease as defined by the RECIST criteria;
or
(ii) Toxicity that is sunitinib related and necessitates
permanent cessation of sunitinib.
NOTES:
Everolimus should not be used after disease progression on
temsirolimus.
RECIST criteria are defined as follows:
Complete response (CR) is disappearance of all target
lesions.
Partial response (PR) is a 30% decrease in the sum of the longest
diameter of target lesions.
Progressive disease (PD) is a 20% increase in the sum of the
longest diameter of target lesions.
Stable disease (SD) is small changes that do not meet above
criteria.
No applications for increased maximum quantities and/or repeats
will be authorised.
Authority Required
Continuing treatment beyond 3 months, as the sole PBS-subsidised
therapy, of Stage IV clear cell variant renal cell carcinoma (RCC)
in a patient who has previously been issued with an authority
prescription for everolimus and who has stable or responding
disease according to the RECIST criteria.
NOTES:
Everolimus should not be used after disease progression on
temsirolimus.
RECIST criteria are defined as follows:
Complete response (CR) is disappearance of all target
lesions.
Partial response (PR) is a 30% decrease in the sum of the longest
diameter of target lesions.
Progressive disease (PD) is a 20% increase in the sum of the
longest diameter of target lesions.
Stable disease (SD) is small changes that do not meet above
criteria.
No applications for increased maximum quantities and/or repeats
will be authorised.
Authority Required (grandfather)
Initial treatment, as the sole PBS-subsidised therapy, of Stage IV
clear cell variant renal cell carcinoma (RCC) after failure of
treatment with sunitinib in a patient who was receiving treatment
with everolimus prior to (insert LISTING DATE).
Failure of treatment with sunitinib is defined as:
(i) Progressive disease as defined by the RECIST criteria;
or
(ii) Toxicity that is sunitinib related and necessitates
permanent cessation of sunitinib.
NOTES:
Everolimus should not be used after disease progression on
temsirolimus.
RECIST criteria are defined as follows:
Complete response (CR) is disappearance of all target
lesions.
Partial response (PR) is a 30% decrease in the sum of the longest
diameter of target lesions.
Progressive disease (PD) is a 20% increase in the sum of the
longest diameter of target lesions.
Stable disease (SD) is small changes that do not meet above
criteria.
No applications for increased maximum quantities and/or repeats
will be authorised.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Renal cell carcinoma (RCC) is a form of kidney cancer that arises
from the cells of the renal tubule. The management and prognosis of
a patient with RCC is determined by the stage of the disease.
Surgery is the only curative treatment option for localised RCC
– radical nephrectomy is considered the gold-standard
treatment for all patients with localised tumours. In patients with
locally advanced or metastatic disease, nephrectomy may also be
considered. As RCC progresses, the tumour grows and enlarges, and
often spreads to adjacent organs. However, most patients are
diagnosed with advanced RCC which is often refractory to treatment
and associated with a poor prognosis.
Currently, only sunitinib is PBS listed for this indication. The
submission proposed that everolimus would be a new treatment option
for patients with advanced RCC who have failed sunitinib.
6. Comparator
Best supportive care (BSC) was nominated as the comparator. This
was previously considered appropriate by the PBAC.
7. Clinical Trials
No changes had been made to the trial data previously presented
from the RECORD-1 trial, a randomised trial comparing everolimus,
10 mg per day orally, with placebo in patients with metastatic
clear cell carcinoma (mRCC) with Karnofsky performance score of at
least 70 and previous progression on, or within six months of
treatment with, sunitinib and/or sorafenib. The primary clinical
outcome was progression-free survival (PFS), and patients in the
placebo arm could cross-over to everolimus after progression.
One additional publication (Motzer et al 2010) arising from the
RECORD-1 trial was identified in an updated literature search, see
below:
| Trial ID/ First author | Protocol title/ Publication title | Publication citation |
|---|---|---|
| Direct randomised trial(s) | ||
| RECORD-1 | ||
| Motzer R et al. | Phase 3 trial of everolimus for metastatic renal cell carcinoma. Final results and analysis of prognostic factors. | Cancer 2010; 116 (18):4256-4265. |
8. Results of Trials
The PBAC recalled that everolimus demonstrated a statistically
significant improvement in progression-free survival (PFS) (HR:
0.33, 95% CI: 0.25, 0.43) compared with placebo but the extent of
the benefit, three months, was small. The overall survival (OS)
data for the intention-to-treat population demonstrated no
statistically significant difference for everolimus compared with
placebo, with a hazard ratio 0.87 (95% CI: 0.65-1.17). As
previously noted, this result was biased towards no treatment
effect because the RCT was designed to allow for switching to
everolimus on progression. That is, the result for OS is confounded
by the extensive (77%) cross-over of placebo patients to everolimus
at progression.
The PBAC also noted that the RECORD-1 trial did not demonstrate a
statistically significant benefit for everolimus compared with
placebo in terms of other secondary outcomes, including quality of
life. However, these results are also confounded by the extensive
(77%) cross-over of placebo patients to everolimus at
progression.
No new toxicity data were presented in the re-submission and the
safety assessment of the RECORD-1 trial had not been updated.
9. Clinical Claim
The re-submission claimed everolimus has superior efficacy and
inferior safety in mRCC compared with placebo.
The PBAC considered that the main uncertainty was whether there is
a survival gain associated with treatment with everolimus and if
so, the magnitude of the gain. The PBAC noted that the clinical
importance of the PFS gain had not been demonstrated in terms of
improvements in the symptoms of RCC.
The PBAC had previously considered that the re-submission’s
claim of inferior safety of everolimus compared with placebo was
reasonable.
10. Economic Analysis
An updated modelled economic evaluation was presented.
The submission presented additional UK historical control survival
data and a revised extrapolation method to derive overall survival
curves for the placebo arm to be used in the modelled economic
evaluation.
The base case ICER (time horizon 5 years) using the Rank Preserving
Structural Failure Time method (RPSFT) was calculated to be between
$45,000 - $75,000 per QALY.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients treated was estimated by the
submission to be less than 10,000 over the first 5 years. The
estimation was considered uncertain due to uncertainty in the
projected sunitinib patient numbers and uncertainty in the
proportion of sunitinib patients eligible for everolimus.
The net financial cost to the PBS was estimated by the submission
to be less than $10 million in Year 5. The estimation was
considered uncertain.
12. Recommendation and Reasons
The PBAC noted it had previously accepted that BSC was the
appropriate comparator. The PBAC recalled that in July 2010 there
was uncertainty about a conclusion of superior efficacy in mRCC
with everolimus compared with placebo based on the benefit in terms
of PFS, when no benefit in terms of OS or quality of life was
observed in RECORD-1. Based on the supporting data the claim for
inferior safety was considered reasonable.
The PBAC noted there were no new trial data provided in the
re-submission. However, the submission presented additional UK
historical control survival data and a revised extrapolation method
to derive overall survival curves for the placebo arm to be used in
the modelled economic evaluation. The results of this survival
analysis were compared with community-based survival data sourced
from Medicare on sunitinib patients, to further validate the UK
data’s applicability to the Australian population. There was
also an update (in the manuscript form) of the systemic review by
Delea et al to estimate the ratio of incremental OS benefit to
incremental PFS.
The PBAC noted that the sunitinib data show survival appears worse
in the community than in the trial (Motzer et al 2010),
highlighting that trial results may overestimate the benefit of
therapy. The PBAC considered that these additional data had
increased rather than decreased the uncertainty regarding survival
by indicating that the time horizon of 5 years may be too
optimistic.
The PBAC also noted that the study population for everolimus is a
combination of failed TKIs (sunitinib) and patients who have never
been exposed to an effective TKI (sorafenib). The PBAC has
previously noted that sorafenib has failed to show any benefit as a
first line agent in RCC, and hence this may have influenced the
benefit observed for everolimus.
The base case ICER (time horizon 5 years) using the RPSFT was
calculated to be between $45,000 - $75,000 per QALY in the current
re-submission.
The PBAC noted the results of the sensitivity analyses indicate
that the model is most sensitive to the model duration due to the
relatively large proportion of the QALY gain extrapolated to occur
beyond the duration of the trial. The PBAC noted that in
calculating the ICERs there is an assumption that treatment would
be ceased on progression, which may not happen in clinical practice
as everolimus is administered orally. Also, clinicians may not
routinely monitor patients with scans to detect progression at this
stage of the disease. Therefore, the PBAC considered that the ICERs
could potentially be higher.
The PBAC accepted that there is a high clinical need for
alternative therapies for renal cancer. However, the main
uncertainty for the PBAC is whether there is a survival gain
associated with this drug and if so, the magnitude of the gain. The
PBAC noted that the clinical importance of the PFS gain has not
been demonstrated in terms of improvements in the symptoms of
RCC.
Therefore, the PBAC rejected the submission on the basis of a high
and uncertain cost-effectiveness ratio.
The PBAC acknowledged and noted the consumer comments on this
item.
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
The sponsor has no comment.
