Pemetrexed disodium, powder for IV infusion (base), 500 mg, Alimta® , November 2005
Public Summary Document for Pemetrexed disodium, powder for IV infusion (base), 500 mg, Alimta® , November 2005
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Public Summary Document
Product: Pemetrexed disodium, powder for IV infusion (base), 500 mg, Alimta®
Sponsor: Eli Lilly Australia Pty Ltd
Date of PBAC Consideration: November 2005
1. Purpose of Application
This submission sought a Section 85 Authority required listing for use ‘in combination
with cisplatin for the treatment of patients with malignant pleural mesothelioma (MPM)’
or, alternatively ‘patients with un-resectable locally advanced or metastatic pleural
mesothelioma’.
2. Background
At the November 2004 PBAC meeting the Committee considered two submissions from Eli
Lilly Australia for pemetrexed disodium. The application for the treatment of patients
with locally advanced or metastatic non-small cell lung cancer, after prior platinum
based chemotherapy was recommended for listing. However, the application for combination
with cisplatin in patients with malignant pleural mesothelioma was deferred to see
the effect of lowering the price on the incremental cost-effective ratio.
At the March 2005 meeting the PBAC rejected a submission on the basis of unacceptable
cost-effectiveness and uncertainty about the utility weight that would be associated
with the survival gain.
3. Registration Status
Pemetrexed in combination with cisplatin, is registered for the treatment of patients
with malignant pleural mesothelioma; and for the treatment of patients with locally
advanced or metastatic non-small-cell lung cancer, after prior platinum based chemotherapy.
4. Listing Requested and PBAC’s View
Authority required
Use in combination with cisplatin for the treatment of patients with malignant pleural
mesothelioma.
OR
Authority required
Use in combination with cisplatin for the treatment of patients with un-resectable
locally advanced or metastatic malignant pleural mesothelioma.
The PBAC noted that the first restriction mirrored that originally put forward in
November 2004, while the second highlighted the subgroup with advanced disease that
was the main focus of this submission.
For further comments, see the Recommendations and Reasons.
5. Clinical Place for the Proposed Therapy
Pemetrexed is an antifolate antineoplastic agent the submission which has been approved,
in Australia, for use in combination with cisplatin for the treatment of malignant
pleural mesothelioma.
6. Comparator
The submission nominates cisplatin as the main comparator, which the PBAC considered
appropriate.
7. Clinical Trials
The re-submission presented (a) updated survival data (i.e. an extra 3 months’ data)
for the ITT population from the key trial (H3E-MC-JMCH; Vogelzang, NJ et al, 2003)
presented in the original submission and (b) new data for fully supplemented patients
(low dose folic acid and vitamin B12) with advanced disease (a post hoc sub-group
analysis).
The re-submission reported the following:
· Clinical results and cost effectiveness analysis of the updated survival of ITT
population (Vogelzang et al; World Lung Cancer Conference July 3-7, 2005; Oral Presentation)
from the key trial.)
· Clinical results and cost effectiveness analysis for fully supplemented sub-group
from the key trial.
· Clinical results (i.e. overall survival, time to progressive disease and response
rates) and cost-effectiveness analysis for fully supplemented patients with locally
advanced and metastatic (stage III and IV) disease from the key trial.
8. Results of Trials
The results are summarised below:
Comparison of overall survival results by duration of follow-up and sub-group
| Trial population | PMT/cisplatin median survival (months) | Cisplatin median survival (months) | HR (95%CI) | p-value |
|---|---|---|---|---|
| ITT – 27 months (N=448) |
12.1 |
9.3 |
0.77 (0.61, 0.96) |
0.02 * |
| ITT – 30 months, adjusted (N=448) |
12.8 |
9.0 |
0.74 (0.60, 0.90) |
0.003 † |
| FS sub-group – 27 months (n=331) ‡ |
13.3 |
10.0 |
0.75 (0.57, 1.00) |
0.051 * |
| FS+AD sub-group – 27 months (n=247) |
13.2 |
8.4 |
0.63 (0.46, 0.86) |
0.0031 * |
* Log-rank test; † Chi-square test; ‡ no new data presented in re-submission; PMT
= pemetrexed disodium; ITT = intention-to-treat; FS = fully supplemented; AD = advanced
disease (Stage III/IV)
The results for overall survival in the ITT population (N=448) indicated a numerical
improvement in median survival at 30 months (PMT/cisplatin gain of 3.8 months over
cisplatin alone; log-rank p=0.003) compared to that observed at 27 months (gain of
2.8 months; log rank p=0.02). For the sub-group of fully supplemented patients with
advanced disease (Stage III/IV), the median overall survival was numerically better
in those patients treated with pemetrexed disodium combined with cisplatin (13.2 months)
than cisplatin alone (8.4 months; a gain of 4.8 months, log rank p=0.0031).
Median time to progressive disease (TTPD) – FS+AD sub-group after 27 months’ follow-up
Pemetrexed disodium/cisplatin (n=125) |
Cisplatin (n=122) |
|
|---|---|---|
| Median (months) |
7.3 |
3.9 |
| 95% CI for median |
5.2-9.0 |
2.8-4.5 |
| p-value |
0.0001* |
* log-rank test; FS = fully supplemented; AD = advanced disease
In fully supplemented patients with advanced disease, the median time to progressive
disease (TTPD) was statistically significantly longer for patients treated with PMT/cisplatin
than for patients receiving cisplatin alone (7.3 months versus 3.9 months, respectively;
p=0.0001).
Best tumour response (independent reviewer-determined) – FS+AD sub-group
Pemetrexed disodium/cisplatin (n=125) |
Cisplatin (n=122) |
|
|---|---|---|
| Number of patients |
105 |
104 |
| Number of responders |
48 |
17 |
| Response rate |
45.7% |
16.3% |
| 95% CI for response rate |
36.0 – 55.7 |
9.8 – 24.9 |
| Fisher exact p-value |
<0.001 |
FS = fully supplemented; AD = advanced disease (Stage III/IV)
In fully supplemented patients with advanced disease, the tumour response rate was
statistically significantly greater for patients treated with PMT/cisplatin than for
patients receiving cisplatin alone (45.7% vs. 16.3%; p<0.001).
Although a number of secondary efficacy outcomes were presented in the original submission
(i.e. time to progressive disease (TTPD), duration of tumour response (TR), time to
treatment failure (TTTF), tumour response (TR), clinical benefit (CB) response rate,
quality of life measures, and pulmonary function tests), only TTPD and TR were reported
in the re-submission.
See Recommendations and Reasons for the PBAC’s view on the results of trials.
The re-submission presented toxicity data from the key trial for the fully supplemented
sub-group of patients with advanced disease (Stage III/IV). The results indicated
that fully supplemented patients with advanced disease (Stage III/IV) in the PMT/cisplatin
arm experienced more Serious Adverse Events (SAEs) and Treatment-Emergent Adverse
Events (TEAEs) than those patients treated with cisplatin alone.
9. Clinical Claim
In this re-submission the therapeutic relativity was not addressed, though in the
previous submission it was claimed that pemetrexed had significant clinical advantages
over cisplatin ie it was significantly more effective than cisplatin, but had more
toxicity.
The PBAC partially accepted this claim.
See Recommendations and Reasons for the PBAC’s views.
10. Economic Analysis
The re-submission presented a preliminary (trial-based) economic evaluation using
a cost-effectiveness approach. The preliminary economic evaluation in the re-submission
differed from that presented in the original submission due primarily to changes in
drug costs.
The trial-based incremental discounted cost/extra discounted life-year gained was
between $15,000 to $45,000 (for fully supplemented patients with advanced disease).
This estimate was based on an incremental median life-years gained/patient.
See Recommendations and Reasons for the PBAC’s views.
11. Estimated PBS Usage and Financial Implications
The submission estimated that the likely number of patients treated per year would
be < 2000 in Year 4 of listing with an estimated financial cost/year to the PBS of
< $10 million in Year 4 of listing.
12. Recommendation and Reasons
The PBAC noted that, as had been requested, the re-submission presented updated and
adjusted survival data (i.e. an extra 3 months’ data) for the ITT population from
the key trial (H3E-MC-JMCH) presented in the original submission. However, the re-submission
emphasised new data for fully supplemented patients with advanced disease (a sub-group
analysis derived from the previous 27-month follow-up dataset). The stated results
for overall survival in the ITT population (N=448) indicated a numerical improvement
in median survival at 30 months (PMT/cisplatin gain of 3.8 months over cisplatin alone;
log rank p=0.003) compared to the unadjusted median survival observed at 27 months
(gain of 2.8 months; log rank p=0.02). For the sub-group of fully supplemented patients
with advanced disease (Stage III/IV), the median overall survival was numerically
better in those patients treated with pemetrexed disodium combined with cisplatin
(13.2 months) than cisplatin alone (8.4 months; a gain of 4.8 months, log rank p=0.0031).
The PBAC was concerned about the reliability of the results of the sub-group analysis
in patients with advanced disease, given that they appear to be one of the multiple
analyses presented in the trial report. The PBAC noted that this indicated that there
were multiple post hoc decisions taken about which “potential prognostic factors”
should be further analysed and which of these should be compared across the treatment
groups of the trial. Thus interpretation of the reported “statistically significant”
test for interaction for the advanced disease sub-group was hindered by the multiplicity
of exploratory analyses from which this reported test is presented.
On examining the sub-groups that would be excluded from treatment by the requested
restriction because they are at Stage I or II of the disease, the PBAC would have
to accept that these patients would have a worse overall survival on pemetrexed plus
cisplatin than on cisplatin alone. The PBAC considered this was implausible. In addition,
this reversal of treatment effect was not supported by the corresponding analysis
across the same sub-groups but assessing the outcome of time to disease progression,
which although likely to be a more direct reflection of treatment effect, suggested
that although achieving a numerically smaller hazard ratio pemetrexed plus cisplatin
was more effective than cisplatin alone in patients at Stage I or II of the disease.
Thus, in the absence of a convincing basis to conclude that the treatment effect on
survival for PMT plus cisplatin over cisplatin alone was enhanced in patients with
advanced disease, the PBAC considered the trial’s ITT results represented the most
scientifically rigorous basis for estimating the magnitude of the treatment effect
in this requested sub-group. The issue of restriction of use to advanced disease would
require accurate staging of mesothelioma, which is difficult, and involves an element
of clinical judgement. This suggested the likelihood of misclassification and disagreement
across experts, which was likely to be exacerbated when the result of the assessment
determined the patient’s eligibility for subsidy to a therapy which was likely to
be accepted as therapeutically superior to the current option of cisplatin for the
excluded patients. Misclassifications represent a loss of sensitivity and specificity,
both of which contribute to reducing any claimed improvement in incremental cost-effectiveness
claimed for the targeted sub-group. Thus, the PBAC did not support the proposed targeting
of the drug to patients with advanced disease.
A further concern to the Committee was the use of the median survival in the economic
evaluation, which favours pemetrexed, as opposed to the mean survival. The PBAC noted
that, in principle, the mean is to be preferred for the purposes of an economic evaluation
because it describes the overall impact on a per patient basis by calculating the
average. The PBAC also noted that most deaths have been captured given the follow-up
in this particular dataset and integrating the area between the full Kaplan Meier
curves for the two arms of the trial intrinsically relies upon a richer dataset than
calculating the difference in medians, which relies on two single point estimates
of time estimated from where the respective Kaplan Meier curve crosses the line representing
50% of patients alive. Thus, the PBAC indicated its preference for relying on differences
in mean survival rather than differences in median survival, for the purposes of generating
the incremental cost-effectiveness ratios.
The PBAC noted that the presented incremental cost per extra life-year gained increased
from the base-case of between $15,000 to $75,000 (for fully-supplemented patients
with advanced disease, using median survival) to between $45,000 to $75,000 (for fully-supplemented
patients, ITT population, using mean survival). The PBAC considered the latter ratio
to be the more plausible, given the concerns indicated above about the sub-group analysis
and the use of median survival as opposed to mean survival. The PBAC considered that
there was no demonstration of an improvement in quality of life. It was also recalled
from its previous consideration in November 2004 that, on average, patients would
spend an extra month of the survival period without disease progression or toxicity
from the drug. Thus, if this ratio is quality adjusted, assuming a nominal utility
of 0.7, as in November 2004, it increases to between $75,000 to $105,000.
The PBAC acknowledged the severity of the condition and the lack of an effective treatment
for patients with mesothelioma. However, even these important factors were insufficient
to reverse the PBAC’s decision not to recommend the listing of pemetrexed for this
patient group. The PBAC therefore rejected the submission because of unacceptable
cost-effectiveness.
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 questions the approach taken by PBAC to derive QALY. There has been no
formal utility study available for PBAC to assume a utility of 0.7. Thus, the cost
per quality adjusted life years derived by PBAC is speculative and not accurate.
The sponsor believes that the application submitted to PBAC provided an updated survival
data and also a sub-group analysis which clearly demonstrated the survival advantage
with pemetrexed.
Eli Lilly Australia is committed to finding a means to provide equitable access to
pemetrexed for malignant pleural mesothelioma patients.
