Temsirolimus, injection set containing 1 vial of powder for IV infusion 25 mg and 1 vial diluent, Torisel®, July 2008
Public summary document for Temsirolimus, injection set containing 1 vial of powder for IV infusion 25 mg and 1 vial diluent, Torisel®, July 2008
Page last updated: 14 November 2008
Public Summary Documents
Product:Temsirolimus, injection set containing 1
vial of powder for IV infusion 25 mg and 1 vial diluent,
Torisel®
Sponsor: Wyeth Australia Pty Ltd
Date of PBAC Consideration: July 2008
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drugs
Program) listing for the treatment of advanced renal cell carcinoma
(RCC) in patients with a poor prognosis who meet certain
criteria.
Highly Specialised Drugs are medications for the treatment of
chronic conditions, which, because of their clinical use or other
special features, are restricted to supply to public and private
hospitals having access to appropriate specialist facilities.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Temsirolimus was TGA registered on 4 June 2008 for the treatment of
advanced renal cell carcinoma.
4. Listing Requested and PBAC’s View
Section 100 (Highly Specialised Drugs Program) Private
hospital authority required
Initial treatment (up to 3 months) as the sole PBS-subsidised
therapy, except for the purposes of palliation, for adult patients
with histologically or cytologically confirmed advanced renal cell
carcinoma, who have at least three of the following six factors
predictive of poor prognosis:
- LDH more than 1.5 x upper limit of normal
- Haemoglobin less than the lower limit of normal
- Corrected calcium greater than 2.5 mmol/L
- No more than 1 year since diagnosis until initiation of treatment
- Karnofsky performance status (KPS) no greater than 70
- At least 2 sites of metastatic disease
Continuing treatment beyond 3 months, as the sole PBS-subsidised
therapy, except for the purposes of palliation, for patients who
have received PBS-subsidised initial treatment with temsirolimus
for advanced renal cell carcinoma and who have stable disease or
responding disease as defined by RECIST criteria.
For PBAC’s view of the requested listing, see
Recommendation and Reasons.
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. 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, three other agents including interferon alpha (IFN) are
registered in Australia for the management of advanced RCC but none
are PBS listed for this indication. Temsirolimus is an alternative
treatment for patients with advanced RCC. Patients with advanced
RCC receive best supportive care or are enrolled in special access
programs or clinical trials.
6. Comparator
The submission nominated medroxyprogesterone (MPA) as proxy for
placebo with best supportive care (BSC) as the main comparator, and
provided an indirect analysis of temsirolimus versus BSC with IFN
as the common comparator.
The PBAC considered that best supportive care was a valid
comparator.
For PBAC’s views, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented an indirect comparison of one randomised
trial, Trial TEM 304, comparing temsirolimus 25 mg IV per week with
IFN up to 18 mU three times per week subcutaneously in patients
with advanced RCC and one randomised trial, Trial MRC RCC 2000,
comparing IFN up to 10 mU three times per week subcutaneously with
MPA 300 mg per day in advanced RCC. The submission presented a
supplemental indirect comparison of Trial TEM 304 with a
meta-analysis (Coppin 2006) of four IFN randomised trials.
The randomised trial and associated reports published at the time
of submission, are as follows:
| Trial ID | Protocol title/ Publication title | Publication citation |
| Randomised trials used in Section B | ||
| Trial TEM 304 Hudes G et al. | Temsirolimus, interferon alpha, or both for advanced renal-cell carcinoma Clinical Study Report 3066K1-304-WW, 18 August 2006 | N Engl J Med 2007;356:2271-2281 |
| Trial MRC RCC | Interferon-alpha and survival in metastatic renal cell carcinoma: Early results of a randomized controlled trial | Medical Research Council Renal Cancer Collaborators Lancet 1999;353:14-17 |
| Meta-analysis of trials | ||
| Coppin 2006 (Cochrane) Coppin C, et al. | Immunotherapy for advanced renal cell cancer | Cochrane Database of Systematic Reviews 2004; Issue 3, updated 2006. |
8. Results of Trials
The efficacy results from trial TEM 304 showed that there was a
statistically significant difference in survival.
Efficacy results of Trial TEM 304 – temsirolimus and
interferon arms only
| Analysis | Result (95% CI) | |
| Survival | ||
| Comparison of time-to-first event curves | Median survival (months) | Temsirolimus = 10.9 (8.6, 12.7) Interferon = 7.3 (6.1, 8.8) |
| CPH | HR = 0.73 (0.58, 0.92) | |
| Progression-free survival by independent assessment | ||
| Comparison of time-to-first event curves | Median PFS (months) | Temsirolimus = 5.5 (3.9, 7.0) Interferon = 3.1 (2.2, 3.8) |
HR=hazard ratio, CPH=Cox proportional hazard model, PFS=Progression
free survival
Efficacy results of Trial MRC RCC 2000: BSC with MPA versus
interferon
| Analysis | Result (95% CI) | |
| Survival – 236 events: MPA-125 deaths, IFN-111 deaths | ||
| Comparison of time-to-first event curves | Median survival (months) | IFN = 8.5 BSC = 6.0 Difference = 2.5 (0.5, 5.0) |
| CPH | HR = 0.72 (0.55, 0.94) | |
| Progression-free survival – 264 events | ||
| Comparison of time-to-first event curves | Median PFS (months) | IFN = 4 BSC = 3 Difference = 1 (0.25, 2.5) |
| CPH | HR = 0.72 (0.56, 0.92) | |
HR=hazard ratio, CPH=Cox proportional hazard model, PFS=Progression
free survival
The results of the primary indirect comparison of Trial TEM 304 and
Trial MRC RCC 2000, and the secondary indirect comparison of Trial
TEM 304 and the Coppin (2006) meta-analysis are shown in the table
below.
Summary of the results used in the indirect
comparison
| Trial | TEM vs IFN HR (95% CI) | TEM | IFN | BSC | BSC vs IFN HR (95% CI) | Indirect analysis (TEMvsBSC) HR (95%CI) |
| Median survival (months) | ||||||
| TEM 304 | 0.73 (0.58, 0.92) | 10.9 (8.6, 12.7) | 7.3 (6.1, 8.8) | 0.53 (0.37,0.75) P=0.0004 | ||
| MRC RCC 2000 | 8.5 (NR) | 6.0 (NR) | 1.39 (1.81,1.06) | |||
| Coppin 2006 | 11.4 | 7.6 | 1.35 (1.59,1.14) | 0.54 (0.41,0.72) P<0.0001 | ||
In light of the difference in median survival of the two interferon
arms, 7.3 months in Trial TEM 304 and 8.5 months in Trial MRC RCC
2000, the submission “adjusted” for this difference by
using the Trial TEM 304 figure of 7.3 months also for the Trial MRC
RCC 2000 interferon arm and lowering the best supportive care arm
figure for Trial MRC RCC 2000 by the same proportion. Thus, the
value for Trial MRC RCC 2000 best supportive care arm is reduced
from 6.0 months to 5.15 months [= 6*(7.3/8.5)]. The adjustment was
made similarly for the supplemental indirect comparison with Coppin
(2006). The adjusted median differences in overall survival were
used in the trial-based economic evaluation. The results of these
“adjusted” indirect comparisons are shown in the table
below.
Results of the unadjusted and adjusted indirect comparisons
of survival in Trial TEM 304 versus and Trial MRC RCC 2000
(primary) and in Trial TEM 304 and the Coppin meta-analysis
(supplemental) using interferon as common comparator
| Trial Analysis | TEM vs. IFN | TEM | IFN | BSC | BSC vs. IFN | Indirect estimate (TEM vs BSC) |
| Median survival (months) | ||||||
| TEM 304 | 3.6 | 10.9 | 7.3 | |||
| MRC RCC 2000 unadjusted | 8.5 | 6.0 | 2.5 | 6.1 | ||
| MRC RCC 2000 adjusted | 7.3 | 5.15 | 2.15 | 5.75 | ||
| Coppin 2006 unadjusted | 11.4 | 7.6 | 3.8 | 7.4 | ||
| Coppin 2006 adjusted | 7.3 | 4.9 | 2.4 | 6.0 | ||
For trial TEM 304 the submission reported the Q-TWiST results . The
Q-TWiST is a measure of quality of life over the time interval of
the trial, similar to what is done over the time horizon of
economic models. The Q-TWiST results demonstrated a quality
adjusted life month gain of between 1 and 2 months, depending on
the analysis used.
Quality of life (QoL) in Trial MRC RCC 2000 was captured with the
Rotterdam Symptom checklist, a cancer quality-of-life instrument.
Compliance was equal in both arms at approximately 50%.
Statistically significant differences are reported at 4 weeks for 7
of 31 symptoms and at 12 weeks for 3 of 31 symptoms. At 6 months
there was no statistically significant difference in any of the 31
symptoms assessed.
A benefit in survival for temsirolimus compared to BSC was likely
although the magnitude of the benefit was difficult to determine.
The quality of life comparison was made more difficult by the use
of different assessment instruments in the two trials and
inadequate data were presented to support the non-inferiority of
temsirolimus compared with BSC in terms of quality of life.
Grade 3 or 4 adverse events occurred in 67% of patients in the
temsirolimus group and 78% of patients in the IFN group. However,
treatment emergent adverse events occurred in all patients in the
trial. There was no formal comparison of safety between the Trial
TEM 304 and Trial MRC RCC 2000.
For PBAC’s comments on these results, see Recommendation
and Reasons.
9. Clinical Claim
The submission claimed that temsirolimus is superior in
effectiveness and superior in safety over interferon. The PBAC
noted that superiority in survival had been shown in Trial TEM 304,
but the data were insufficient to conclude superiority with respect
to safety.
The submission also claimed that temsirolimus is superior in
effectiveness to best supportive care and may be associated with
more toxicity than best supportive care but not at the expense of
quality of life.
For PBAC’s views, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a stepped economic evaluation. The model
estimated the cost-effectiveness of temsirolimus compared to best
supportive care in advanced renal cell carcinoma patients with poor
prognosis and also provided a comparison of temsirolimus and IFN in
a stepped economic evaluation. The model employed a Markov-like
structure with three primary health states – no progression,
progression, and death. The model horizon was three years and used
36 one-month cycles. Patients received temsirolimus until
progression. The model included only adverse events of grade 3 or 4
severity.
The submission estimated the base case incremental
cost-effectiveness ratio to be >$100,000 per quality of life
year gained.
11.Estimated PBS Usage and Financial Implications
The financial cost/year to the PBS was estimated to be less than
$10M in Year 5.
12.Recommendation and Reasons
The PBAC agreed that BSC was a valid comparator despite the fact
that the direct comparison of temsirolimus against IFN provides a
higher standard of evidence than the indirect comparison with BSC
using interferon as a common comparator. However, it was noted that
IFN is not on the PBS as it was not considered effective or
cost-effective for RCC.
The PBAC noted that temsirolimus was more effective when used as a
single agent than when used in combination with IFN and that, in
the event listing is recommended, the restriction should indicate
that temsirolimus must be used as sole PBS-subsidised
therapy.
The PBAC agreed that there was uncertainty about the magnitude of
the treatment effect of temsirolimus compared with BSC because of
the indirect comparison and the lack of exchangeability across the
trials use to estimate the hazard ratios. The submission claims
that temsirolimus is better than IFN which is, in turn better than
BSC, but the indirect comparison which normalised IFN survival
across the studies to estimate the magnitude of survival makes the
analysis very uncertain. It was noted that in some studies survival
in the IFN arm is 11.4 months, the current study 7.3 months, and in
others 8.5 months. Therefore, the survival in the IFN arm depends
on the inclusion criteria for the study. Even though, the sponsor
acknowledged this in its pre sub-committee response by stating that
the difference is due to the inclusion of different Memorial Sloan
Kettering Cancer Centre (MSKCC) patient risk groups and also
adjusted the survival data to allow for the indirect analysis, the
PBAC considered that the residual uncertainty in the extent of
clinical benefit was too large.
The PBAC noted that adverse events occurred at a statistically
significant greater frequency in temsirolimus treated patients
compared to IFN patients in Trial TEM 304 and concluded that the
profile of side effects for temsirolimus was different to IFN,
rather than that temsirolimus was better tolerated than IFN.
However, the PBAC considered that the submission did not consider
the relative harms in comparison with BSC, including their impact
on incremental QALYs and cost-effectiveness. The PBAC also
considered that there was uncertainty regarding the effect of
temsirolimus on QoL, as the two trials in the submission used
different QoL instruments.
It was also noted that the dose intensity of the drug is quickly
lost if adverse events lead to delayed treatment which may impact
on outcome and QoL.
The PBAC agreed, that the main areas of uncertainty in the economic
analysis are the:
- Lack of exchangeability across trials in indirect comparison to
estimate hazard ratios – particularly differences in IFN
(common arm) dosing and extended period of time (10 years) between
when trials were undertaken.
- Not reporting major sources of uncertainty within the trial
period or their impact on cost effectiveness – e.g. not
reporting a confidence interval for the temsirolimus-placebo
treatment effect or absolute LY difference. The Pre-Sub-Committee
Response states that it was not possible to determine confidence
intervals for the temsirolimus-placebo effect in terms of overall
survival as the confidence intervals associated with treatment
effect of interferon over BSC were not reported.
- Challenges in estimating mean survival benefit.
The resulting base case incremental cost effectiveness ratio for
temsirolimus over best supportive care > $100,000 per QALY, was
considered by the Committee to be both unacceptably high and
unacceptably uncertain.
Therefore, the PBAC rejected the application on the basis of
uncertain evidence of clinical effectiveness and an unacceptably
high and uncertain incremental cost-effectiveness ratio.
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 be considering the PBAC’s advice.
