Pemetrexed, powder for I.V. infusion, 100 mg and 500 mg (base), Alimta® , March 2009
Public summary document for Pemetrexed, powder for I.V. infusion, 100 mg and 500 mg (base), Alimta® , March 2009
Page last updated: 01 July 2009
Public Summary Document
Product: Pemetrexed, powder for I.V. infusion, 100
mg and 500 mg (base), Alimta®
Sponsor: Eli Lilly Australia Pty Ltd
Date of PBAC Consideration: March 2009
1. Purpose of Application
The submission sought an extension to the current Authority
Required listing to include first line treatment of non-small cell
lung cancer (NSCLC) with non-squamous cell histology in combination
with cisplatin.
2. Background
The PBAC has not previously considered pemetrexed for first-line
treatment of NSCLC.
At the November 2004 meeting, the PBAC recommended an Authority
Required listing for pemetrexed for locally advanced or metastatic
NSCLC, 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 listing for pemetrexed in line with changes to
the TGA approved indication for NSCLC pending full evaluation of
the submission received for the March 2009 PBAC meeting for
pemetrexed in first line use. The change to the Product Information
limited treatment to patients with advanced or metastatic NSCLC who
have histology other than predominantly squamous cell.
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
Initial treatment in combination with cisplatin for patients with
locally advanced or metastatic non-small cell lung cancer with
non-squamous cell histology (adenocarcinoma and/or large cell
carcinoma).
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.
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 comparator.
The PBAC agreed that this was the appropriate comparator.
7. Clinical Trials
The submission presented one multi-centre, Phase III, open-label,
randomised trial comparing pemetrexed disodium 500 mg/m2
IVI combined with cisplatin 75 mg/m2 IVI, with
gemcitabine 1,250 mg/m2 IVI combined with cisplatin 75
mg/m2 IVI in chemo-naive patients with Stage IIIB/IV
NSCLC. The basis of the submission was a pre-specified sub-group
analysis from this non-inferiority trial.
The study published at the time of the submission is as follows:
| Trial/First author | Protocol title | Publication citation |
| Direct randomised trial | ||
| Scagliotti et al. (2008) | Publication: Scagliotti GV, Parikh P, von Pawel J et al. 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. |
8. Results of Trials
The overall survival results for all randomised patients of the key
trial are summarised in the table below.
Summary of overall survival (months) – all randomised
patients
| All randomised patients (N=1725) | ||
| PEM/Cisplatin (n=862) | GEM/Cisplatin (n=863) | |
| Median (95% CI) overall survival (months) | 10.3 (9.8, 11.2) | 10.3 (9.6, 10.9) |
| Fixed Margin Method | ||
| Adjusted analysis - Hazard ratio (95%CI) | 0.94 (0.84, 1.05) | |
Abbreviations: CI = confidence interval; GEM = gemcitabine; HR =
hazard ratio; PEM = pemetrexed;
Both the adjusted (HR = 0.94; 95% CI: 0.84 to 1.05) and Cox
regressions for the ITT population support the conclusion of
noninferiority. The null hypothesis assumed that gemcitabine/
cisplatin would provide a ≥15% reduction in the risk of death
over pemetrexed/cisplatin, corresponding to a fixed margin of
1.176. The submission justified the 15% non-inferiority margin on
pragmatic reasons, as a non-inferiority margin of 10% would have
required an extra 2300 patients above the 1725 enrolled in the JMDB
trial. The non-inferiority margin was accepted by the PBAC.
The overall survival results for all randomised patients by
histological subgroups are summarised in the table below:
Overall survival in histological subgroups – all
randomised patients
| Median survival -months (95% CI) | Adjusted HR* (95% CI) | Superiority p-value* | |
| Adenocarcinoma & large cell ‡ (N=1000) | |||
| PEM/C (n=512) | 11.8 (10.4, 13.2) | 0.81 (0.70-0.94) | 0.005 |
| GEM/C (n=488) | 10.4 (9.6, 11.2) | ||
| Adenocarcinoma (N=847) | |||
| PEM/C (n=436) | 12.6 (10.7, 13.6) | 0.84 (0.71–0.99) | 0.033 |
| GEM/C (n=411) | 10.9 (10.2, 11.9) | ||
| Large cell (N=153) | |||
| PEM/C (n=76) | 10.4 (8.6, 14.1) | 0.67 (0.48–0.96) | 0.027 |
| GEM/C (n=77) | 6.7 (5.5, 9.0) | ||
| Squamous cell (N=473) | |||
| PEM/C (n=244) | 9.4 | 1.23 (1.00–1.51) | 0.050 |
| GEM/C (n=229) | 10.8 | ||
| Unknown or other histology (N=252) | |||
| PEM/C (n=106) | 8.6 | 1.08 (0.81–1.45) | 0.586 |
| GEM/C (n=146) | 9.2 |
Abbreviations: PEM/C = pemetrexed plus cisplatin; ECOG PS = Eastern
Cooperative Oncology Group performance status; GEM/C = gemcitabine
plus cisplatin
* Adjusted HR and superiority and non-inferiority (NI) p-values
from Cox model with treatment plus 4 cofactors: ECOG PS, gender,
disease stage, and basis for pathological diagnosis
(histopathological/ cytopathological).
The Cox adjusted analyses of overall survival by treatment arm for
the histology subgroups suggest that, in patients with
adenocarcinoma and large-cell carcinoma, pemetrexed/cisplatin
resulted in superior overall survival than gemcitabine/cisplatin
(HR 0.81; 95% CI: 0.70 to 0.94). In contrast, the analysis for
patients with squamous cell carcinoma suggests worse overall
survival (1.4 months) when treated with pemetrexed/cisplatin rather
than gemcitabine/cisplatin (HR 1.23; 95% CI: 1.00 to 1.51). The
treatment-by-histology interaction analysis (p=0.0011) also showed
that overall survival for patients with adenocarcinoma and large
cell histology was significantly improved on the
pemetrexed/cisplatin arm compared with the overall survival for all
other patients with adenocarcinoma and large cell or squamous
histology.
The results for progression -free survival (PFS) by histologic
group, a secondary efficacy outcome, are shown in the table below:
| Median PFS - months (95% CI) | Adjusted HR* (95% CI) | Superiority p-value* | |
| All randomised patients (N=1725) | |||
| PEM/C (n=862) | 4.8 (4.6, 5.3) | 1.04 (0.94-1.15) | |
| GEM/C (n=863) | 5.1 (4.6, 5.5) | ||
| Adenocarcinoma & large cell (N=1000) | |||
| PEM/C (n=512) | 5.3 (4.8, 5.7) | 0.90 (0.79-1.02) | |
| GEM/C (n=488) | 4.7 (4.4, 5.4) | ||
| Adenocarcinoma (N=847) | |||
| PEM/C (n=436) | 5.5 | 0.90 (0.78-1.03) | 0.125 |
| GEM/C (n=411) | 5.0 | ||
| Large cell (N=153) | |||
| PEM/C (n=76) | 4.5 | 0.89 (0.65-1.24) | 0.499 |
| GEM/C (n=77) | 4.2 | ||
| Squamous cell (N=473) | |||
| PEM/C (n=244) | 4.4 | 1.36 (1.12-1.65) | 0.002 |
| GEM/C (n=229) | 5.5 | ||
| Unknown or other histology (N=252)† | |||
| PEM/C (n=106) | 4.5 | 1.28 (0.99-1.67) | 0.064 |
| GEM/C (n=146) | 5.6 |
Abbreviations: PEM/C = pemetrexed plus cisplatin; ECOG PS = Eastern
Cooperative Oncology Group performance status; GEM/C = gemcitabine
plus cisplatin; HR = hazard ratio; N = number of patients per
histologic subgroup; n = number of patients per treatment arm; Sup
= superiority.
* 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).
† The subcategory of “other” represents patients
with a primary diagnosis of NSCLC whose disease did not clearly
qualify as adenocarcinoma, squamous cell carcinoma, or large cell
carcinoma.
Source: Table B.6.4, p57 of the submission
The results for PFS by histologic subgroup showed that
pemetrexed/cisplatin was non-inferior to gemcitabine/cisplatin in
patients with adenocarcinoma histology (adjusted HR 0.90, 95% CI:
0.78 to 1.03). However, pemetrexed/cisplatin failed the
non-inferiority test in patients with large cell carcinoma
(adjusted HR 0.89, 95% CI: 0.65 to 1.24), squamous cell carcinoma
(adjusted HR 1.36, 95% CI: 1.12 to 1.65), and unknown/other
histology (adjusted HR 1.28, 95% CI: 0.99 to 1.67). The wider
confidence intervals may reflect the smaller sample sizes in these
specific subgroups.
In the case of tumour response rates (the only other secondary
efficacy outcome reported for the histological subgroups), the
results of the histological subgroups suggest that, in patients
with adenocarcinoma, pemetrexed/cisplatin was superior to
gemcitabine/cisplatin. However, tumour response rates in patients
with large cell carcinoma histology were not different between
patients in the pemetrexed/cisplatin arm compared to patients in
the gemcitabine/cisplatin arm.
The proportion of patients with adenocarcinoma and large cell
carcinoma experiencing any possibly study-drug related treatment
emergent adverse events (TEAEs) was similar between treatment arms.
For both treatment arms, the most commonly reported possibly
study-drug related TEAEs were anaemia, neutropenia, nausea,
vomiting, anorexia, and fatigue. Patients treated with
gemcitabine/cisplatin experienced statistically significantly more
anaemia, thrombocytopenia, febrile neutropenia, alopecia, and
peripheral sensory neuropathy than patients receiving
pemetrexed/cisplatin treatment. Patients treated with
pemetrexed/cisplatin experienced statistically significantly more
conjunctivitis, increased lacrimation, and pigmentation disorder
than patients receiving gemcitabine/cisplatin treatment.
In patients with adenocarcinoma and large cell carcinoma histology
there were statistically significantly fewer transfusions (i.e. any
type of transfusion, red blood cell transfusions and platelets) in
patients randomised to pemetrexed/cisplatin treatment than those
patients treated with gemcitabine/cisplatin.
In patients with adenocarcinoma and large cell carcinoma histology
there were statistically significantly fewer anti-anaemia
medications (i.e. erythropoietin/darbepoetin and iron preparations)
and G-CSF/GM-CSF administered to patients in the
pemetrexed/cisplatin arm than patients randomised to
gemcitabine/cisplatin treatment.
For PBAC’s view, see Recommendation and
Reasons.
9. Clinical Claim
The submission claimed pemetrexed/cisplatin combination
chemotherapy is superior in terms of comparative effectiveness over
gemcitabine/cisplatin. The PBAC considered pemetrexed combined with
cisplatin was non-inferior to gemcitabine combined with cisplatin
in the treatment of locally advanced or metastatic NSCLC.
The submission also claimed that pemetrexed/cisplatin has better
tolerability, has reduced need for supportive treatment, and has a
more convenient administration than gemcitabine/cisplatin in the
treatment of patients with advanced metastatic NSCLC with
adenocarcinoma and large cell carcinoma. The PBAC agreed with this
claim, based on the results of Trial JMDB.
For PBAC’s views, see Recommendation and
Reasons.
10.Economic Analysis
A modelled economic evaluation was presented. The model calculated
mean survival for the two treatment arms, pemetrexed/cisplatin and
gemcitabine/cisplatin, based on the estimated Weibull survival
function, extrapolated for a total of 54 months. Survival, or life
years gained was the primary health outcome, however, utilities
were applied to the life years gained in sensitivity analyses.
Costs were calculated independently of health outcomes, based on
resource use during the (30 month) trial period, which are assumed
to occur within the first year. The costs included are those
associated with the primary chemotherapy agents, premedication,
post-discontinuation chemotherapy treatments, transfusion-related
costs and resource use associated with serious adverse events and
major toxicities.
The submission estimated the base case ICER per Life Year gained
(LYG) using the Weibull model to be in the range of $45,000 -
$75,000.
Similar results were obtained for the trial-based and calibration
model, both based on the 30-month duration of the trial.
Extrapolating two years beyond the trial period resulted in a more
favourable incremental cost per life year.
The results of the sensitivity analyses indicated that the model is
most sensitive to 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.
For PBAC’s views, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients/year to be
less than 10,000 patients in Year 5 at a financial cost per year to
the PBS of less than $10 million in Year 5 of listing. These
figures were considered to be understimates given that market share
for pemetrexed as first-line chemotherapy is likely to exceed that
predicted in the submission.
12.Recommendation and Reasons
The PBAC recommended listing 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
(see below). 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.
The submission presented one key multi-centre, Phase III,
open-label, randomised trial (JMDB) comparing pemetrexed disodium
500mg/m2 IVI combined with cisplatin 75mg/m2
IVI, with gemcitabine 1,250mg/m2 IVI combined with
cisplatin 75mg/m2 IVI in chemo-naive patients with Stage
IIIB/IV NSCLC. This non-inferiority trial pre-specified a
non-inferior margin of 15%, which the PBAC accepted. Both the
adjusted (HR = 0.94; 95% CI: 0.84 to 1.05) and unadjusted (HR =
0.93 (0.83, 1.04) Cox regressions for the ITT population support
the conclusion of noninferiority.
The PBAC also agreed that, based on the results of JMDB,
pemetrexed/cisplatin treatment generally has a better safety and
toxicity profile than gemcitabine/cisplatin treatment, requires
fewer supportive therapies and is more conveniently
administered.
The basis of the submission was to differentiate eligible patients
according to histology. This arose from a number of pre-specified
sub-group analyses from JMDB, and which the PBAC did not
accept.
The PBAC noted that the Cox adjusted analyses of overall survival
by treatment arm for the histology subgroups suggest that, in
patients with adenocarcinoma and large-cell carcinoma,
pemetrexed/cisplatin resulted in superior overall survival than
gemcitabine/cisplatin (HR 0.81; 95% CI: 0.70 to 0.94). However, the
PBAC noted that the magnitude of the benefit seems numerically
greater for large-cell carcinoma than adenocarcinoma.
In contrast, the analysis for patients with squamous cell carcinoma
suggests worse overall survival (1.4 months) when treated with
pemetrexed/cisplatin rather than gemcitabine/cisplatin (HR 1.23;
95% CI: 1.00 to 1.51). The treatment-by-histology interaction
analysis for pemetrexed/cisplatin over gemcitabine/cisplatin in
overall survival was statistically significant (p=0.0011) for
patients with adenocarcinoma and large cell histology compared with
patients with squamous histology, which lent some support to the
submission’s claim. However, the PBAC noted that 15% (252) of
the patients had unknown or other histology. These patients of
unknown or other histology also had a numerically worse outcome on
pemetrexed/cisplatin.
Further, in the case of the secondary efficacy outcomes, the PBAC
noted that the results reported in the submission for the
histological subgroups were mixed. The PBAC noted that, for
progression-free survival (PFS) in patients with adenocarcinoma
histology, pemetrexed/cisplatin treatment appeared to be
noninferior but not superior to gemcitabine/cisplatin (adjusted HR
0.90; 95% CI: 0.78 to 1.03). In patients with large cell carcinoma
histology, pemetrexed/cisplatin failed to meet the defined
noninferiority criteria (i.e. HR<1.17647) with the upper limit
of the 95% confidence interval of the hazard ratio being greater
than 1.17647 (adjusted HR 0.89; 95% CI: 0.65 to 1.24).
In the case of tumour response rates (the only other secondary
efficacy outcome reported for the histological subgroups), the PBAC
noted that the results of the histological subgroups suggest that,
in patients with adenocarcinoma, pemetrexed/cisplatin was superior
to gemcitabine/cisplatin (superiority p-value: p=0.015). However,
tumour response rates in patients with large cell carcinoma
histology were not different between patients in the
pemetrexed/cisplatin arm compared to patients in the
gemcitabine/cisplatin arm (superiority p-value: p=0.960).
The PBAC observed that this lack of consistency of results for each
of the histology-defined subgroups across the three types of
outcomes analysed in JMDB weakens the claim of treatment effect
modification by histology for pemetrexed in this setting. The PBAC
noted the arguments in the Pre-Sub-Committee Response and Pre-PBAC
Responses that monotherapy randomised trials of pemetrexed in the
second-line (JMEI, post hoc subgroup analysis) and maintenance
(JMEN, prespecified subgroup analysis) settings of advanced
metastatic NCSLC provided subgroup results which were consistent
with the claim of treatment effect modification by histology. The
PBAC agreed that these data were supportive, including accepting
that the nature of the comparisons in these trials (ie pemetrexed
used as monotherapy and against other comparators including
placebo) helps isolate the claim with respect to pemetrexed, but
did not accept that these data were conclusive.
The PBAC noted that the biological plausibility argument was that,
although a multi-targeted anti-folate, pemetrexed largely acts by
inhibiting thymidylate synthase (TS) and so is likely to be less
effective in tumours which tend to overexpress TS (ie. squamous
cell carcinomas rather than adenocarcinomas or large cell
carcinomas). However, the PBAC noted that pemetrexed shares its
pharmacological action on TS with other long-established
chemotherapy agents such as 5-fluorouracil and this claimed
differentiation of treatment effect by histology has not been
previously observed. In addition, the PBAC considered that the
argument that TS overexpression is associated with histology type
was weak and largely retro-fitted to “suit” the trial
data. The proposal to examine the histology subgroups in JMDB was
based on a study published in 2006 involving 56 surgically resected
samples (ie in less than Stage IIIA NSCLC) which examined TS levels
(TS mRNA in formalin fixed tissue) in adenocarcinomas (30),
squamous cell carcinomas (21) and other types (5) of NSCLC. Large
cell cancers were not measured and this small study contradicts
previous studies which found no association between TS
overexpression and histology.
The PBAC particularly noted a concern with the accuracy of the
determination of histology type. Two studies (Stang et al., Lung
Cancer 2006 and Field et al., JNCI 2004) which looked at the
histology of lung cancers at initial diagnosis and a central review
diagnosis. The overall agreement between the initial diagnosis and
the central review diagnosis was 65% and 71.5 % respectively and,
in the Stang et al study, 40% of squamous and adenocarcinoma cases
were reclassified. These studies highlighted the difficulties with
histological classification. This difficulty of ascertaining and
classifying the histology has important implications for the
interpretation of the results of the subgroup analyses and also for
the implementation of a PBS restriction based on histology. If the
treatment effect modification is true, and the accuracy of
histology diagnosis is poorer in Australian practice than in the
trial, then the effect of misclassification is to reduce the
effectiveness of pemetrexed and make its cost-effectiveness less
favourable. The existence of unknown and mixed histology types of
NSCLC will have the same effects, noting that the proportions of
types in the trial broadly reflects Australian epidemiology.
The PBAC was also aware that the impact of accepting the
submission’s claim of differential pemetrexed effectiveness
by histology type would have consequences for other PBS-listed
therapies in locally advanced or metastatic NSCLC, including
second-line pemetrexed.
The PBAC considered that a systematic review demonstrating
treatment effect on the basis of histology for pemetrexed and other
drugs could be conducted and that there should be a way of
accurately classifying lung cancers before changing treatment
algorithms based on a histological classification system. The true
factor mediating any treatment effect modification also needs to be
identified.
The PBAC considered that the base case of the modelled economic
evaluation should not include transfusion-related costs associated
with the use of erythropoietin/darbepoetin because the role of
these drugs in oncology has not been accepted by the PBAC and is
subject to debate in relation to their overall safety
profile.
The PBAC noted comments from consumers and a letter from a doctor
in support of the listing which noted that, if pemetrexed was
listed for this new indication, there would be a change in the
overall treatment paradigm for non small cell lung cancer.
Recommendation
PEMETREXED DISODIUM, powder for I.V. infusion, 100 mg and 500 mg
(base)
Extend the listing as follows to include:
Restriction:
Authority Required
Locally advanced or metastatic non-small cell lung cancer (Stage
IIIB and Stage IV) 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 applications for increased maximum quantities for the 500
mg vial will be authorised.
Max. Qty: 1
Repeats: 3
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 disagrees with the PBACs recommendation to list
pemetrexed/cisplatin on a cost minimisation basis to
gemcitabine/cisplatin for NSCLC as this listing proposed by PBAC
falls outside of the current TGA approved indication for
pemetrexed. Furthermore, this recommendation is not reflective of
the prospective clinical trial data which demonstrated superior
overall survival and an improved tolerability profile for the
predominantly nonsquamous population compared to gemcitabine, the
accepted standard of care. The sponsor is committed to working with
the PBAC to enable pemetrexed access as a first line agent for
NSCLC patients with predominantly nonsquamous histology.
