Pemetrexed disodium, powder for I.V. infusion, 100 mg and 500 mg (base), Alimta®, November 2009
Public Summary Documents for Pemetrexed disodium, powder for I.V. infusion, 100 mg and 500 mg (base), Alimta®, November 2009
Page last updated: 05 March 2010
Public Summary Documents
Product: Pemetrexed disodium, powder for I.V.
infusion, 100 mg and 500 mg (base), Alimta®
Sponsor: Eli Lilly Australia Pty Ltd
Date of PBAC Consideration: November 2009
1. Purpose of Application
The re-submission sought an extension to the current Authority
Required PBS listing to include first line treatment of locally
advanced or metastatic non-small cell lung cancer (NSCLC) with
predominantly non-squamous cell histology in combination with
cisplatin.
2. Background
At the November 2004 meeting, the PBAC recommended an Authority
Required listing for pemetrexed for locally advanced or metastatic
non-small cell lung cancer, after prior platinum-based
chemotherapy, on a cost-minimisation basis compared with docetaxel.
Listing was effective from 1 April 2005.
At the November 2008 meeting, the PBAC deferred an application to
amend the current PBS listing for pemetrexed in line with changes
to the TGA approved indication for NSCLC pending full evaluation of
the submission for pemetrexed in first line use which the Committee
was advised had been received by the Department. The change to the
Product Information limits treatment to patients with advanced or
metastatic NSCLC who have histology other than predominantly
squamous cell.
At the March 2009 meeting, the PBAC recommended an extension to the
listing of pemetrexed on the PBS for the treatment of locally
advanced or metastatic non small cell lung cancer in combination
with cisplatin (first-line therapy) on a cost-minimisation basis
compared with gemcitabine based on the clinical data presented. The
equi-effective doses were considered to be pemetrexed 500
mg/m2 equivalent to gemcitabine 1250 mg/m2
each given on a 21 day cycle.
The PBAC did not recommend differentiating treatment based on
histology types as the evidence supporting this was insufficient.
There was also a great deal of uncertainty concerning the
specificity, sensitivity and accuracy of the histology testing and
as the economic model was based on diagnosis by histology types
there was also uncertainty regarding the economic model. Therefore,
a recommendation on the basis of cost-effectiveness for patients
with non-squamous cell histology could not be made.
3. Registration Status
On 22 September 2008, the approved indications were extended to include:
- In combination with cisplatin, for initial treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology.
The wording of the second-line indication was also changed as
follows:
- As monotherapy, for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology after prior platinum-based chemotherapy.
Pemetrexed is also registered for the following indication:
- In combination with cisplatin, for the treatment of patients with malignant pleural mesothelioma.
4. Listing Requested and PBAC’s View
Authority Required
Locally advanced or metastatic non-small cell lung cancer (Stage
IIIB and Stage IV) with predominantly non-squamous cell histology
in combination with cisplatin.
Doses greater than 500 mg per metre squared body surface area (BSA)
will not be approved for PBS subsidy. The patient’s BSA must
be provided at the time of the authority approval.
NOTE:
No application for increased maximum quantities for the 500 mg will
be authorised.
Definition of “Predominantly”: < 10% squamous
component (WHO Classification)
Definition of “non-squamous”: adenocarcinoma, large
cell carcinoma and other NSCLC histologies (that is disease that
does not clearly qualify as adenocarcinoma, large cell carcinoma or
squamous cell carcinoma).
For PBAC’s view see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Lung cancer is one of the most common malignancies worldwide with
an increasing incidence in Australia. It is the second leading
cause of cancer death in men and the third leading cause in women.
Almost 80% of lung cancers are classified as NSCLC, with 65% to 75%
of cases presenting as locally advanced or metastatic
disease.
There are three main histologic classifications of NSCLC, namely
squamous cell carcinomas, adenocarcinomas and large cell
carcinomas.
Pemetrexed offers an alternative first-line treatment for patients
with NSCLC.
6. Comparator
The submission nominated gemcitabine in combination with cisplatin
as the main comparator. This was previously accepted by the
PBAC.
7. Clinical Trials
The re-submission presented the same key trial (JMDB) as in the
previous submission. Changes had been made to the subgroup analyses
presented in the previous submission. The previous submission
presented separate data for each of the histological subgroups
studied (ie. adenocarcinoma, large cell carcinoma, squamous cell
carcinoma, and ‘unknown or other’ histology NSCLC), but
the re-submission post-hoc combined the data of the
‘unknown or other’ histological subgroup with that of
the adenocarcinoma and large cell carcinoma subgroups to form one
subgroup (ie. non-squamous histology) and compared this result to
the non-squamous histology subgroup.
The published trial presented in the re-submission is reproduced
below:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Scagliotti et al. (2008) | Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced-stage non-small-cell lung cancer. | Journal of Clinical Oncology. Vol 26 (21) July 20, 2008. |
For PBAC’s view see Recommendation and
Reasons.
8. Results of Trials
The key results are summarised in the table below.
Overall survival in histological subgroups – all randomised patients
| Median (months) (95% CI) | Adjusted HR a (95% CI) | Non-inferiority p-value a | Superiority p-value a | |
| Non-squamous cell b (N=1252) | ||||
| PEM/C (n=618) | 11.0 (10.1, 12.5) | 0.84 (0.74, 0.96) | <0.001 | 0.011 |
| GEM/C (n=634) | 10.1 (9.3, 10.9) | |||
| Squamous cell (N=473) | ||||
| PEM/C (n=244) | 9.36 (8.4, 10.2) | 1.23 (1.00, 1.51) | 0.663 | 0.050 |
| GEM/C (n=229) | 10.84 (9.5, 12.1) | |||
Abbreviations: PEM/C = pemetrexed plus cisplatin; GEM/C = gemcitabine plus cisplatin;
HR = hazard ratio; mo = months;
a Adjusted HR and superiority and NI p-values from Cox model with treatment plus 4
cofactors: ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological).
b Non-squamous defined as adenocarcinoma, large cell and other.
The median overall survival time was greater with pemetrexed/cisplatin treatment (11.0
months) than with gemcitabine/cisplatin treatment (10.1 months) - a difference of
0.9 months (adjusted HR 0.84, 95% CI: 0.74 to 0.96) in the subgroup analysis of patients
with non-squamous cell histology (adenocarcinoma, large cell carcinoma, and ‘other’
histology).
Progression-free survival (PFS) by histological subgroup – all randomised patients
| Median PFS Months (95% CI) | Adjusted HR a (95% CI) | Non-inferiority p-value a | Superiority p-value a | |
| Non-squamous cell b (N=1252) | ||||
| PEM/C (n=618) | 5.26 (4.7, 5.5) | 0.95 (0.84, 1.06) | <0.001 | 0.349 |
| GEM/C (n=634) | 4.96 (4.6, 5.4) | |||
| Squamous cell (N=473) | ||||
| PEM/C (n=244) | 4.40 (4.1, 4.9) | 1.36 (1.12, 1.65) | 0.933 | 0.002 |
| GEM/C (n=229) | 5.52 (4.6, 5.9) |
Abbreviations: PEM/C = pemetrexed plus cisplatin; GEM/C = gemcitabine plus cisplatin;
HR = hazard ratio; PFS = progression-free survival.
a Adjusted HR and superiority and NI p-values from Cox model (as above)
b Non-squamous defined as adenocarcinoma, large cell and other NSCLC histologies.
Source:
The results for progression-free-survival (PFS) by histologic subgroup showed that
pemetrexed/cisplatin was non-inferior to gemcitabine/cisplatin in patients with non-squamous
histology (adjusted HR 0.95, 95% CI: 0.84 to 1.06).
The summary of the results for the primary and secondary efficacy outcomes by sub-group,
presented in the previous submission is shown below.
| Outcome | Adjusted HR (95% CI) | Non-inferiority p-value | Superiority p-value |
| Overall survival | |||
| Adenocarcinoma & large cell carcinoma | 0.81 (0.70, 0.94) | <0.001 | 0.005 |
| Adenocarcinoma | 0.84 (0.71, 0.99) | <0.001 | 0.033 |
| Large cell carcinoma | 0.67 (0.48, 0.96) | <0.001 | 0.027 |
| Unknown or other histology | 1.08 (0.81, 1.45) | 0.291 | 0.586 |
| Non-squamous cell carcinoma | 0.84 (0.74, 0.96) | <0.001 | 0.011 |
| Squamous cell carcinoma | 1.23 (1.00, 1.51) | 0.663 | 0.05 |
| Progression-free survival | |||
| Adenocarcinoma & large cell carcinoma | 0.90 (0.79, 1.02) | <0.001 | 0.096 |
| Adenocarcinoma | 0.90 (0.78, 1.03) | <0.001 | 0.125 |
| Large cell carcinoma | 0.89 (0.65, 1.24) | 0.049 | 0.499 |
| Unknown or other histology | 1.28 (0.99, 1.67) | 0.74 | 0.064 |
| Non-squamous cell carcinoma | 0.95 (0.84, 1.06) | <0.001 | 0.349 |
| Squamous cell carcinoma | 1.36 (1.12, 1.65) | 0.933 | 0.002 |
Abbreviations: HR = hazard ratio; CI = confidence interval; NR = not reported in submission
or re-submission
There were no new toxicity data presented in the re-submission for all randomised
patients. The re-submission presented new subgroup analyses for treatment-emergent
adverse events (TEAEs) and laboratory toxicities. The proportion of patients with
non-squamous cell carcinoma (N=1213) experiencing at least one possibly study-drug
related TEAE was similar between treatment arms (89.7% in the pemetrexed/cisplatin
arm vs. 90.6% in the gemcitabine/cisplatin arm; p=0.63).
There were statistically significantly fewer transfusions (p<0.001), red blood cell
transfusions (p<0.001), and platelet transfusions (p=0.002) administered to non-squamous
cell carcinoma patients in the pemetrexed/cisplatin arm compared to the gemcitabine/cisplatin
arm.
For PBAC’s view see Recommendation and Reasons.
9. Clinical Claim
The re-submission claimed pemetrexed/cisplatin chemotherapy as
superior in terms of comparative effectiveness over
gemcitabine/cisplatin for first line treatment of non-squamous cell
advanced metastatic NSCLC, including the ‘Unknown or other
histology population’.
The re-submission claimed pemetrexed/cisplatin as having better
tolerability, reduced need for supportive treatment, and more
convenient administration than gemcitabine/cisplatin in the
treatment of patients with non-squamous cell advanced metastatic
NSCLC.
At the March 2009 PBAC meeting, the PBAC expressed concerns around
the accuracy of histological diagnosis in determining histological
sub-types of NSCLC. In order to support the argument that
non-squamous histology is distinguishable from squamous histology
in patients with NSCLC, the re-submission used five different
approaches. These approaches were:
1. Literature review of diagnostic performance of histology
sub-groups in NSCLC;
2. Meta-analysis of diagnostic performance of histology sub-groups
in NSCLC;
3. Identification of regulatory or reimbursement agencies that
accept NSCLC histology sub-groups;
4. Use of histology as the ‘gold standard’ test in
NSCLC;
5. Examination of PBS listings that include a ‘test’
for initiation of therapy.
To address PBAC’s concerns that the treatment of NSCLC
patients on the basis of their histological sub-type represented a
‘paradigm shift’ in the management of these patients,
the re-submission conducted a systematic review of prospective,
randomised controlled trials or meta-analyses that investigated
treatment effect modification by histology with respect to overall
survival, progression-free survival, or treatment response.
Overall survival data from a recently published phase III,
multicentre, open-label, randomised trial (Gronberg et al. 2009) of
pemetrexed/carboplatin versus gemcitabine/carboplatin were pooled
with data from the key pivotal trial (JMDB) to obtain a pooled
estimate of effect. The re-submission claimed that the results of
the meta-analysis clearly indicated that pemetrexed provided
improved survival for patients with non-squamous histology when
compared to gemcitabine (HR 0.86, 95% CI 0.76 to 0.97,
p=0.02).
For PBAC’s view see Recommendation and
Reasons.
10. Economic Analysis
The re-submission presented an updated modelled economic
evaluation.
The re-submission’s economic analysis calculated an
incremental cost per QALY gained between $45,000 - $75,000, similar
results for the trial-based and calibration model (Steps 1 and 2),
both based on the 30 month trial duration. Extrapolating two years
beyond the trial period results in a more favourable incremental
cost per life year gained of between $15,000 - $45,000. The PBAC
considered that although the re-submission’s results are
numerically different from the previous submission the overall
findings are generally consistent with the results of previous
submission.
The re-submission also presented a number of sensitivity analyses
varying utility weights, costs, and outcomes.
The results of the re-submission’s other sensitivity analyses
(by varying selected model inputs by ±10%) indicated that
the model is most sensitive to changes in the price of pemetrexed
(by changing the price directly or by changing the assumed body
surface area of the cohort) and the incremental survival between
treatment arms. This was consistent with the previous
submission.
For PBAC’s view see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated to be less
than 10,000 in Year 5 (First-line + second-line pemetrexed).
The financial cost per year to the PBS was estimated to be less
than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC noted that the key differences from the March 2009
submission were a price decrease for pemetrexed in the first-line
setting, 12.5% price decrease for gemcitabine (generic
introduction), the requested listing for predominantly non-squamous
cell histology rather than adenocarcinoma and large cell only, two
base case analyses, an additional sensitivity analysis that uses a
pooled overall survival estimate from the pivotal JMDB trial and
the recently published randomised trial by Gronberg et al. (2009),
and exclusion of the cost of erythropoiesis stimulating agents from
transfusion costs.
The PBAC noted that the key trial (JMDB) remained the same, but
changes had been made to the subgroup analyses presented in the
previous submission. The previous submission presented separate
data for each of the histological subgroups studied (ie.
adenocarcinoma, large cell carcinoma, squamous cell carcinoma, and
‘unknown or other’ histology NSCLC), but the current
re-submission post-hoc combines the data of the
‘unknown or other’ histological subgroup with that of
the adenocarcinoma and large cell carcinoma subgroups to form one
subgroup (ie. non-squamous histology) and compares this result to
the non-squamous histology subgroup.
The PBAC noted that in the subgroup analysis of patients with
non-squamous cell histology (adenocarcinoma, large cell carcinoma,
and ‘other’ histology), the median overall survival
time was greater with pemetrexed/cisplatin treatment (11.0 months)
than with gemcitabine/cisplatin treatment (10.1 months) - a
difference of 0.9 months (adjusted HR 0.84, 95% CI: 0.74 to 0.96).
However, the results presented in the previous submission showed
that pemetrexed/cisplatin was neither non-inferior (p=0.291) or
superior (p=0.586) to gemcitabine/cisplatin in patients with
‘Unknown or other’ histology (HR 1.08, 95% CI: 0.81 to
1.45).
Therefore, the PBAC considered that the clinical claim that
pemetrexed/cisplatin chemotherapy is superior in terms of
comparative effectiveness over gemcitabine/cisplatin for first line
treatment of non-squamous cell advanced metastatic NSCLC was
supported by data from JMDB trial, based on the primary efficacy
outcome (i.e. overall survival).
However, the claim that pemetrexed/cisplatin is more effective than
gemcitabine/cisplatin in treating the subgroup of NSCLC patients
with ‘unknown or other’ histology was not reasonable as
there appears to be no evidence of a beneficial effect of
pemetrexed/cisplatin treatment over gemcitabine/cisplatin in this
subgroup of patients. The PBAC considered that the claim that
pemetrexed/cisplatin is better tolerated than gemcitabine/cisplatin
was reasonable based on the supporting safety data in the
re-submission.
Regarding the classification by histology, the PBAC considered that
the results of the literature review of individual studies suggest
a degree of diagnostic agreement for some histological subtypes but
not for others. The results tend to suggest greater diagnostic
agreement amongst study pathologists for adenocarcinoma but less
diagnostic agreement in the case of large cell carcinoma. The PBAC
considered that since the current requested listing for pemetrexed
includes use in patients with adenocarcinoma, large cell carcinoma,
and ‘other’ NSCLC histologies (predominantly
non-squamous cell histology) the impact of misclassifying patients
may be significant. The PBAC also considered that if the
‘unknown or other’ histology are included in the
requested restriction, the Government would be paying a higher cost
for these patients who do no better on pemetrexed than gemcitabine.
Therefore, a further price decrease may be needed to offset the
lack of response for this patient group.
The PBAC noted that a recently published trial of Gronberg et al.
(2009) found that there was no difference in median overall
survival in patients with non-sqaumous histology (adenocarcinoma
and large cell carcinoma) treated with pemetrexed/carboplatin = 7.8
months compared with gemcitabine/carboplatin = 7.5 months; P =
0.77. This study also reported that multivariate and interaction
tests did not reveal any significant associations between histology
and survival. The PBAC considered that the results of the
systematic review of studies that examined treatment effect
modification by histology amongst other NSCLC therapies (a total of
21 systematic reviews and 163 potentially relevant primary studies)
did not show any convincing evidence that there was a treatment
effect by histology for drugs other than pemetrexed. In the case of
pemetrexed, this effect was demonstrable in certain circumstances
eg monotherapy, use with cisplatin but not carboplatin.. However,
if listing were to be recommended on the basis of predominantly non
squamous cell histology, there should be a NOTE specifying use in
patients with less than 10% squamous component so that use in mixed
tumours is excluded, as these patients did not benefit or did worse
on pemetrexed. In addition the inclusion of histology in the
first-line listing should flow on to the second-line listing for
pemetrexed for NSCLC.
The PBAC noted that the Gronberg et al (2009) trial was excluded
from the submission as pemetrexed plus carboplatin is not a TGA
approved NSCLC couplet and fewer treatment cycles were permitted in
the trial by Gronberg et al (2009) than the key pivotal trial (4
vs. 6 cycles, respectively). However, the PBAC considered that
carboplatin would be used in clinical practice but that the costs
and clinical implications of switching to carboplatin for
first-line use with pemetrexed were not captured in the model. The
March 2009 submission previously noted that platinum based
therapies are generally considered interchangeable and the decision
relating to use of one over the other will be a clinical
decision.
The PBAC considered that the ICER between $15,000 - $45,000 /QALY
in the model is acceptable, however, is high given the magnitude of
the clinical benefit (0.9 months median overall survival
time).
The PBAC agreed that the choice of QALY weights were disease
specific not treatment specific and were not appropriate. Earlier
stage disease was given a lower utility than later stage disease,
which lacked face validity and the arbitrary reduction in utility
of the gemcitabine treatment had also not been justified. Also, the
application of QALY weights in the model as a single value
inappropriately assumed that all quality of life is equal,
regardless of duration of disease. Further, the model had included
cost offsets of G-CSF use with gemcitabine, when such use is not
subsidised by the PBS, making it likely that the true ICER per QALY
is higher than calculated.
The PBAC considered that the cost-effectiveness was high and
uncertain and that further negotiation regarding the price was
necessary as the requested listing included patients with
‘unknown or other histology’ who did not benefit from
pemetrexed/cisplatin combination. In addition there was uncertainty
regarding the use of carboplatin with pemetrexed which needed to be
accounted for in the model.
Therefore the PBAC deferred the submission to allow further
dialogue with the sponsor on the issues identified above.
Recommendation:
Defer
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 to address issues raised by the PBAC to enable subsidised access to pemetrexed as a first line agent for patients with NSCLC.
