EVEROLIMUS, tablets, 5 mg and 10 mg, Afinitor®
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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: July 2010
1. Purpose of Application
The submission sought an Authority Required listing for the 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
progressive disease on sunitinib or progressive disease following
cessation of treatment with sunitinib due to toxicity and meets
certain criteria.
2. Background
At the November 2009 meeting, the PBAC rejected the 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.
Full details in the November 2009 Public Summary
Document.
3. Registration Status
Everolimus was designated an orphan drug by the TGA on 17 July
2008.
Everolimus tablets 5 mg and 10 mg were TGA registered 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 with a WHO status of 2 or less who has:
(i) Progressive disease (as defined by the RECIST criteria) on sunitinib treatment;
or
(ii) Progressive disease (as defined by RECIST criteria) following permanent cessation
of sunitinib treatment due to toxicity that was sunitinib related.
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:
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) in a patient who was receiving treatment with everolimus
prior to (insert LISTING DATE) and who had:
(i) Progressive disease (as defined by the RECIST criteria) on sunitinib treatment;
or
(ii) Progressive disease (as defined by RECIST criteria) following permanent cessation
of sunitinib treatment due to toxicity that was sunitinib related.
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.
The PBAC did not comment on the requested restriction.
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.
Everolimus would be a new treatment option for patients with
advanced RCC who have failed sunitinib.
For PBAC’s view, see Recommendation and
Reasons.
6. Comparator
As previously, the re-submission appropriately nominated placebo
for best supportive care as the comparator.
7. Clinical Trials
The submission presented key clinical evidence from the RECORD-1 trial, a randomised
trial comparing everolimus, 10mg 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. The PBAC noted that
the resubmission provided updated overall survival evidence for RECORD-1.
Details of the published reports included in the submission are in the table below:
| Trial ID/First author | Protocol title/ Publication title | Publication citation |
|---|---|---|
| Direct randomised trial | ||
| Motzer R et al. 2008 | Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial | Lancet 2008; 372(9637):449-56 |
| Korhonen P et al. 2009 | Overall survival among metastatic renal cell carcinoma patients corrected for cross-over using a Rank Preserving Structural Failure Time (RPSFT) Model: analyses from the RECORD-1 Phase 3 trial. | Presented at the Joint 15th Congress of the European Society for Medical Oncology (ESMO), 20-24 September 2009, Berlin, Germany |
8. Results of Trials
The primary outcome for the study was progression free survival (PFS).
Everolimus showed a statistically significant improvement in progression free survival
(PFS) (HR: 0.33, 95% CI: 0.25, 0.43) but the extent of the benefit, three months,
was small.
The Kaplan Meier probability of progression free survival curve is shown below:
The updated overall survival (OS) data to November 2008 for the intention-to-treat
population showed no statistically significant difference for everolimus, with a hazard
ratio 0.87 (95% CI: 0.65-1.15).
Overall survival (OS) data to October 2007 presented in the previous submission also
showed no statistically significant difference between everolimus and placebo (HR
0.83, 95% CI: 0.50, 1.37).
The PBAC noted that the results indicate that over time the HR is getting closer to
the null (1.0).
The updated Kaplan Meier curve is shown below:
For PBAC’s view, see Recommendation and Reasons.
An exploratory post-hoc analysis of censored data, which excluded the patients who
crossed over to active treatment, was provided in the CHMP D120 report as an appendix
to the re-submission. The resultant HR for overall survival was insignificant at 0.67
(95% CI 0.39-1.14, p=0.069). This analysis would strongly favour everolimus, since
patients with progressed disease in the placebo arm who do not cross-over may have
more advanced disease and require palliative care rather than further active treatment.
A similar analysis with the sunitinib data showed strongly significant benefits of
treatment, with a doubling in median overall survival for sunitinib compared with
interferon treated patients (28 months v 14 months, respectively, HR 0.65 95% CI 0.48-0.87,
p=0.03) (Motzer et al., 2009).
The safety assessment of the RECORD-1 trial was not updated in this re-submission.
During the evaluation relative risks and risk differences were calculated for Grade
3/4 adverse events occurring in ?2% of either treatment group.
Everolimus patients were significantly more likely to experience hyperglycaemia, stomatitis,
anaemia, dyspnoea, vomiting, hypercholesterolemia, pneumonitis and lymphopenia, as
measured by the risk difference. In addition, discontinuation from treatment, primarily
due to adverse effects, was more common in everolimus patients (13.1%) than placebo
patients (1.5%).
9. Clinical Claim
The re-submission claimed everolimus has superior efficacy and
inferior safety in mRCC compared with placebo.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
An updated cost-utility analysis was presented.
The model took the form of a Markov process with three health
states-stable disease, progressive disease and death and had an
8-year horizon.
The costs were updated to include the costs of palliative care in
progressed disease.
The previous submission reported an incremental cost-effectiveness
ratio of between $45,000 and $75,000 for everolimus, calculated
using the inverse censoring probability weighted (IPCW) method.
This was compared with a lower ICER within the same range in the
current re-submission. The main reasons for the improved
cost-effectiveness of everolimus when modelled with the current
model include:
- modelling of overall survival used lower mortality risks beyond trial duration for both everolimus and placebo (5.4% and 10.7%, per monthly cycle, respectively), compared with the previous model (44% and 81%, per 2 month cycle, respectively); and
- the increased time horizon (increased from three years to eight years), which captures the higher overall survival, without appropriately modelling the associated increased costs from extended time in progressed disease
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated by the
re-submission to be less than 10,000 in Year 5, which was less than
the previous submission’s estimate, but within the same
range.
The financial cost per year to the PBS was estimated by the
re-submission to be less than $10 million in Year 5, compared with
the previous submission’s estimate of between $10 million and
$30 million by Year 5.
12. Recommendation and Reasons
The PBAC acknowledged that there is a high clinical need for
treatment of patients who have progressed on sunitinib or those who
are ineligible or intolerant to sunitinib.
As previously, the PBAC agreed that the comparator of placebo for
best supportive care is appropriate.
The submission presented key clinical evidence from the RECORD-1
trial, a randomised trial comparing everolimus, 10mg 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. The PBAC noted
that the resubmission provided updated overall survival evidence
for RECORD-1.
The PBAC considered that RECORD-1 was a well conducted trial and
noted that everolimus showed a statistically significant
improvement in PFS (HR: 0.33, 95% CI: 0.25, 0.43) but also that the
extent of the benefit, three months, was small. The PBAC considered
that in the absence of direct trial-based evidence for either
prolonged survival or improved quality of life, the clinical
importance of a PFS benefit of 3 months was highly uncertain. The
PBAC noted that the advice from the oncologists included in the
Pre-Sub-Committee Response referred to other cancers where PFS has
been proven as a surrogate for overall survival, but that this
relationship has not been established for mRCC. In addition there
was no evidence provided that the radiological measure used to
determine progression was of direct patient relevance or could be
extrapolated into survival in this setting.
The updated overall survival (OS) data to November 2008 for the
intention-to-treat population showed no statistically significant
difference for everolimus, with a hazard ratio 0.87 (95% CI:
0.65-1.17). The PBAC considered that because of the high rate of
cross-over of patients to everolimus (77%) the trial provided no
information for life expectancy of patients treated with best
supportive care (BSC) only. The updated information also did not
demonstrate a statistically significant benefit of everolimus in
terms of other secondary outcomes, including quality of life.
However, these results are also confounded by the cross-over of
placebo patients to everolimus at radiological progression.
The PBAC considered that 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 agreed with the sponsor’s Pre-Sub-Committee Response
that it was appropriate to use data from the entire trial rather
than just the sunitinib-treated subgroup because there was a
constant hazard ratio across the patient populations and there was
a statistically significant advantage shown in each subgroup which
was maintained.
The PBAC noted that the monthly mortality risk (5.4%) for patients
in the everolimus group was calculated from the overall survival in
the RECORD-1 trial. This is considerably lower than the risk
modelled in the previous submission, which implied a 44.4% risk for
each two month cycle in the extrapolated period of the model. As a
result, patients are estimated to live longer in the updated model.
One percent of the everolimus-treated population is still alive at
the beginning of cycle 83 (6.9 years) and 0.38% at the beginning of
cycle 101 (8.3 years). The PBAC noted that this approach resulted
in some patients remaining alive after 8 years which seemed
improbable.
The PBAC considered that the modelled claim of a 4-7 month overall
survival advantage for everolimus was improbable, given that (i)
the extent of gain in overall survival beyond the effect on PFS (3
months in ITT and 2.1 months in sunitinib pretreated population) is
unlikely, (ii) the weighting given to the early (2 month) cross
over data, and (iii) the toxicity of everolimus. The modelled
estimates using IPCW and RPSFT models are also inherently
confounded by the design limitations of RECORD-1 which permitted an
early and extensive crossover of patients between the trial
arms.
The PBAC noted that the model was very sensitive to changes in the
assumed overall survival benefit of everolimus and the estimated
ICERs were therefore considered highly uncertain due to the impact
of the survival benefit on the ICERs. The most favourable ICER was
between $45,000 and $75,000 per extra QALY gained using the IPCW
method and between $75,000 and $105,000 per extra QALY gained when
calculated using the RPSFT method, but both were considered to be
highly uncertain and likely to favour everolimus.
The sponsor in its Pre-Sub-Committee Response considered that the
modelled OS gain using RPSFT of 5.6 months was reasonable because
the ratio of 1.6 of PFS advantage to OS advantage (i.e. 5.6 months
OS divided by 3.5 months PFS) is in agreement with the findings of
Delea et al. (2009). The sponsor further reiterated in its Pre-PBAC
response that the results of Delea et al. (2009) support the claim
that the advantage in OS is more than the advantage in PFS. The
PBAC was concerned that there may be differences in the way PFS is
measured across the studies used in Delea, especially between
earlier and later studies. Earlier studies generally had a stronger
relationship between PFS and OS, which may partly relate to less
crossover but may also relate to the measurement of progression in
the later studies at earlier stages and with fewer clinical
manifestations of progression. The PBAC noted that it was not clear
that the evidence from this set of studies translates to this
context where there is substantial cross over at 2 months following
the first radiological assessment. The PBAC further noted that the
linear regression analysis of PFS versus OS in Delea et al. (2009)
includes the confidence limits but not the prediction bands. The
prediction bands identify the minimum change in PFS required to
predict a significant change in survival and also the range of
benefit (rather than a point estimate). The possible range of
improvement in overall survival could then be determined. However,
the PBAC considered the key concern is that there are only limited
data available for the construction of the placebo arm using either
the IPCW or RPSFT methods due to the early and high cross over of
patients to everolimus.
The PBAC therefore rejected the submission on the basis of
uncertain clinical benefit and a high and uncertain
cost-effectiveness ratio.
The PBAC noted that the submission meets the criteria for an
independent review.
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 will continue to work with the PBAC to resolve the
issues identified in this re-submission.
