Gefitinib, tablet, 250 mg, Iressa®
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Product: Gefitinib, tablet, 250 mg,
Iressa®
Sponsor: AstraZeneca Pty Ltd
Date of PBAC Consideration: November 2010
1. Purpose of Application
The submission sought a first-line listing for gefitinib for the
treatment of patients with locally advanced or metastatic non-small
cell lung cancer (Stage IIb/IV NSCLC) who have an activating
mutation in the epidermal growth factor receptor gene (EGFR
M+).
2. Background
Gefitinib is currently PBS listed for the treatment, as
monotherapy, of locally advanced or metastatic non-small cell lung
cancer in patients with a WHO performance status of 2 or less,
where disease progression has occurred following treatment with at
least one chemotherapy agent and there is evidence that the patient
has an activating mutation(s) of the epidermal growth factor
receptor (EGFR) gene in tumour material.
Gefitinib was recommended for listing at the July 2004 meeting of
the PBAC on the basis of acceptable cost-effectiveness compared
with docetaxel and best supportive care for patients with an
activating mutation of the EGFR gene. Listing was effective from 1
December 2004.
At the March 2008 meeting, the PBAC considered a sponsor request to
amend the PBS restriction by removal of the requirement for the
activating EGFR mutation and alignment with the TGA indication at
that time, which specified two patient subgroups eligible for
gefitinib: those who have never smoked and those taking gefitinib
who have demonstrated some benefit. The PBAC considered that
inadequate evidence was provided to allow an assessment to be made
on the cost-effectiveness of gefitinib in the population that would
be covered under the requested listing and that more detailed
information from a recent clinical trial was required. PBAC
therefore recommended no changes be made to the PBS listing for
gefitinib pending a further submission from the sponsor.
At its November 2009 meeting, the PBAC recommended an amendment to
the current PBS restriction by removing the requirement that
analysis of the DNA sequence of the EGFR gene must be used to
detect a mutation in the EGFR gene. The PBAC noted that the
analysis by DNA sequencing methodology was not MBS reimbursed and
it was therefore considered reasonable to use other methodologies
to detect the specific activating mutations in the EGFR gene.
3. Registration Status
Gefitinib has been TGA registered since 28 April 2003. The TGA
registration for gefitinib was revised on 12 July 2010. It is
currently indicated for the treatment of patients with locally
advanced or metastatic non small cell lung cancer (NSCLC), whose
tumours express activating mutations of the EGFR tyrosine
kinase.
4. Listing Requested and PBAC’s View
Authority Required
Initial PBS-subsidised treatment, as monotherapy, of locally
advanced or metastatic non-small cell lung cancer in patients with
an activating mutation of the EGFR gene.
The authority application can be made over the telephone if a
pathology report shows the presence of activating mutation(s) of
the EGFR gene from an Approved Pathology Authority. A copy of this
report and the gefitinib (Iressa) PBS Authority application for use
in the treatment of NSCLC form must be sent to: Medicare Australia
Reply Paid 9826 GPO Box 9826 Hobart TASMANIA.
Authority required
Continuing PBS-subsidised treatment, as monotherapy, of a patient
who has previously been issued with an authority prescription for
gefitinib and who does not have progressive disease.
NOTE:
No applications for increased maximum quantities and/or repeats
will be authorised.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
The submission proposed that gefitinib is an alternative to
chemotherapy in the treatment of patients with EGFR mutation
positive non-small cell lung cancer.
6. Comparator
The comparator proposed by the submission was platinum based
chemotherapy. The submission stated that the combination of
carboplatin and gemcitabine was the most commonly used regimen in
Australia, but other platinum-based doublet chemotherapy regimens
were also used. The pivotal trial evidence (IPASS) compared
gefitinib with carboplatin and paclitaxel.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The key evidence presented in the submission was one of multiple pre-planned exploratory
sub-group analyses (of EGFR mutation positive (M+) patients) of the Iressa Pan Asia
Study (IPASS) randomised controlled trial, where gefitinib was compared to carboplatin
plus paclitaxel, as first-line treatments, in patients with locally advanced or metastatic
NSCLC, with adenocarcinoma (including bronchoalveolar carcinoma).
Three supportive first-line randomised trials (NEJ002, Study 0054 and WJTOG 3405)
were also presented in the submission although the trial results were not yet fully
available. NEJ002, Study 0054 and Study WJTOG 3405 respectively compared gefitinib
to carboplatin plus paclitaxel, cisplatin plus gemcitabine or cisplatin plus docetaxel.
The NEJ002 study was only conducted in EGFR M+ patients, while an exploratory sub-group
analysis of EGFR M+ patients was conducted in Study 0054 to provide support for the
requested restriction. Study WJTOG 3405 was conducted in EGFR M+ patients, with inclusion
criteria specific for Exon 19 deletion and Exon 21 L858R activating mutations. All
studies presented in the submission were conducted in Asian populations. The studies
published at the time of the submission are as follows:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Key direct randomised trial | ||
| Iressa Pan Asia Study (IPASS) Mok TS, et al. | Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. | N Engl J Med 2009; 361(10): 947-57 |
| Supplementary randomised trials | ||
|
North East Japan 002 Study (NEJ002) Kobayashi K, et al Inoue A, et al |
First-line gefitinib versus first-line chemotherapy by carboplatin (CBDCA) plus paclitaxel (TXL) in non-small cell lung cancer (NSCLC) patients (PTS) with EGFR mutations: A phase III study (002) by North East Japan Gefitinib Study Group A randomized phase III study comparing gefitinib with carboplatin (CBCDA) plus paclitaxel (TXL) for the first-line treatment of non-small cell lung cancer (NSCLC) with sensitive EGFR mutations: NEJ002 study |
J Clin Oncol 2009 24[15s] Abstract available at www.ecco-org.eu/Conferences-and-Events/ECCO-15-ESMO-34/page.aspx/216 (accessed 4 January 2011) |
| Study 0054 (Korean) Lee JS, et al | A Randomized Phase III Study of Gefitinib (IRESSA) versus Standard Chemotherapy (Gemcitabine plus Cisplatin) as a First-line Treatment for Never-smokers with Advanced or Metastatic Adenocarcinoma of the Lung. | J Thor Oncol 2009 4[9], Supp 1. |
|
WJTPG3405 Mitsudomi T, et al Tsurutani J, et al |
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. A phase III, first-line trial of gefitinib versus cisplatin plus docetaxel for patients with advanced or recurrent non-small cell lung cancer (NSCLC) harbouring activating mutation of the epidermal growth factor receptor (EGFR) gene. |
Lancet Oncology 2010; 11(2): 121-8 Abstract available at www.ecco-org.eu/Conferences-and-Events/ECCO-15-ESMO-34/page.aspx/216 (accessed 4 January 2011) |
8. Results of Trials
The primary outcome of IPASS was progression-free survival in the
overall population. The outcome of interest in the submission was
the pre-specified exploratory analysis of progression-free survival
(PFS) in the EGFR M+ subgroup of patients. The key results are
summarised in the following table.
Results of progression-free survival (in months) across the direct randomised trials (Hazard ratios rounded to two decimal places)
| Trial ID | Gefitinib Median (95% CI) months | Carboplatin + paclitaxel Median (95% CI) months | Absolute difference (months) | Hazard ratio (between treatment comparison) (95% CI) |
| IPASS | ||||
| ITT (all patients randomised) | N = 609 5.7 | N = 608 5.8 | -0.1 | 0.74* §§ (0.65, 0.85) |
| EGFR M+ subgroup | N = 132 9.5 (8.0, 11.2) | N = 129 6.3 (5.6, 7.0) | 3.2 | 0.48* (0.36, 0.64) |
| EGFR M- subgroup | N = 91 1.5 (NR) | N = 85 5.8 (NR) | -4.3 | 2.85* (2.05, 3.96) |
| NEJ002 (all EGFR M+) | ||||
| Per protocol population | N = 114 10.8 (NR) | N = 110 5.4 (NR) | 5.4 | 0.30** (0.22, 0.41) |
| Study 0054 | ||||
| Gefitinib | Cisplatin + gemcitabine | |||
| EGFR M+ subgroup | N = 26 8.4 (NR) | N = 16 6.7 (NR) | 1.7 | 0.61^ (0.31, 1.22) |
| EGFR M- subgroup | N = 27 2.1 (NR) | N = 27 6.4 (NR) | -4.3 | 1.52^^ (0.88, 2.62) |
| WJTOG 3405 (all EGFR M+) | ||||
| Gefitinib | Cisplatin + docetaxel | |||
| Per protocol population | N = 86 9.2 (8.00, 13.90) | N = 86 6.3 (5.80, 7.80) | 2.9 | 0.49* (0.34, 0.71) |
Bolded: EGFR M+ population.
* p<0.0001; ** p<0.001; ^ p = 0.084; ^^ p = 0.071.
§§ The HR was not constant over time,
with the probability of being progression free in favour of
carboplatin / paclitaxel doublet chemotherapy in the first 6
months, and in favour of gefitinib in the following 16 months. In
such a case, the use of HR is not valid. This was not the case for
EGFR M+ mutation status.
CI = Confidence interval; NR = Not reported; ITT = Intention to
treat; PP = per protocol; HR = hazard ratio.
The PBAC noted that an examination of the IPASS PFS data from EGFR
M+ and EGFR M- patients in the chemotherapy arm (there are limited
data to fully assess comparability of the EGFR groups) did not
indicate there was a prognostic effect, independent of treatment
effect, associated with EGFR mutational status (although it is
documented in the literature that some EGFR mutation types are
independent prognostic factors). The results for median PFS in the
carboplatin plus paclitaxel arm for EGFR M+ patients and EGFR M-
patients were similar (6.3 months and 5.8 months respectively). For
the doublet chemotherapy treatment arms, there was a higher
proportion of EGFR M- patients 1) with a WHO performance status of
2 or were in bed greater than or equal to 50% of the time (11% vs
5%), 2) who were ex-smokers (9% vs 5%) and 3) who had metastatic
disease (84% vs 78%) compared to EGFR M+ patients. These were
important prognostic factors for survival in NSCLC. However, tumour
burden and histology did not appear to differ substantially between
EGFR M+ and EGFR M- patients in the treatment arms. The extent of
any confounding on the relative PFS estimates observed in the EGFR
subsets allocated to chemotherapy, remained uncertain from the
available data.
Overall survival (OS) data were also reported in the submission,
although premature. From the updated OS data provided in the
Pre-Sub-Committee response, the possibility of an independent
prognostic effect of EGFR M+ unrelated to treatment could not be
ruled out (although such an effect was not observed with the PFS
data). It was possible that the observed differences in OS between
the EGFR M+ and EGFR M- groups were the result of EGFR M- patients
having fewer treatment options.
Gefitinib had a different toxicity profile to that of
platinum-based chemotherapy; overall, serious adverse events
appeared to be less common with gefitinib than with chemotherapy.
Adverse effects reported to occur with greater frequency with
gefitinib treatment included: eye disorders, hepatobiliary
disorders, infections, injury/poisoning events, abnormal findings
on laboratory investigations and renal/urinary disorders. An
increased risk of interstitial lung disease associated with
gefitinib which had been previously identified was also
described.
For PBAC’s view, see Recommendation and
Reasons
9. Clinical Claim
The submission described gefitinib as superior in terms of
comparative effectiveness and superior in terms of comparative
safety over platinum-based chemotherapy in EGFR M+ patients. The
superiority claim was based on PFS. The PBAC recalled that the
claim of any overall survival advantage was not supported by the
more mature data provided with the Pre-Sub-Committee
response.
10. Economic Analysis
A modelled economic evaluation of advanced/metastatic NSCLC was
presented.
Considering the updated data from IPASS showed no statistically
significant improvement in overall survival for first-line
gefitinib over first-line chemotherapy which allowed second-line
gefitinib, the model’s estimate of the incremental survival
benefit (0.152 life-years gained) did not reflect the updated data
from the most relevant available trial.
While the model appropriately incorporated costs and utility
decrements for adverse events associated with first-line treatment,
the submission neglected to include corresponding costs and utility
decrements for adverse events associated with second-line
treatment. These were likely to differ in the treatment arms, as
patients receiving gefitinib first-line were assumed to receive
chemotherapy after progression, while those initially receiving
chemotherapy were assumed to subsequently receive gefitinib
second-line. The Pre-Sub-Committee response reiterated that costs
of adverse events and quality of life decrements were not able to
be modeled in the second-line treatment position as there were no
data available to inform the model. The response concluded that the
use of gefitinib in the first-line treatment position was expected
to be cost-effective as the use of gefitinib followed by
chemotherapy was similar in treatment costs to chemotherapy
followed by gefitinib. Patients have a small quality of life gain
with the initial use of gefitinib compared to initial use of
chemotherapy, though recent data indicate that there was no
survival gain.
The incremental cost per extra quality adjusted life year (QALY)
gained in the submission was in the range of $15,000 - $45,000. If
61% of patients received second-line therapy the incremental cost
per extra QALY gained increased to be in the range of $75,000
– $105,000.
11. Estimated PBS Usage and Financial Implications
The financial cost per year to the PBS was estimated in the
submission to be less than $10 million per year in Year 5.
For PBAC’s view, see Recommendation and
Reasons
12. Recommendation and Reasons
The PBAC noted that the request for first-line listing would
increase the number of eligible patients beyond the current
listing. It agreed with the proposed use of gefitinib as being
monotherapy, and that the main comparator would be a platinum-based
doublet chemotherapy. Carboplatin and paclitaxel was accepted as a
representative doublet, including for carboplatin and gemcitabine,
the most widely used regimen in Australia.
The PBAC accepted that the most relevant direct randomised trial
was IPASS. The results of three other relevant direct randomised
trials (NEJ002, Study 0054 and WJTOG 3405) were not yet fully
available but broadly support the IPASS results. The trial design
allowed for switching such that patients randomised initially to
chemotherapy could later commence gefitinib and patients randomised
initially to gefitinib could later commence chemotherapy. The
former arm represented current clinical practice because gefitinib
was currently available second-line, and the latter arm represented
clinical practice with first-line gefitinib as requested, so an ITT
analysis including switching was a relevant comparison. In the
trial, about 50% of patients received an alternative treatment (49%
of patients randomised to gefitinib received subsequent carboplatin
and paclitaxel treatment and 52% of patients randomised to
carboplatin and paclitaxel received subsequent EGFR tyrosine kinase
inhibitor treatment including gefitinib). This was similar to the
submission’s estimates that 30% of current second-line
treatment was an EGFR tyrosine kinase inhibitor treatment and that
50% of patients would receive second-line treatment after
first-line gefitinib.
One source of concern in applying the trial results to the
Australian population was that, of 1217 randomised patients, only
437 (36%) provided tissue samples that were evaluable for mutation
testing. Of the remaining 64%, 179 (15%) did not provide consent
for biomarker analyses, 355 (29%) provided consent, but tissue
samples were not obtained, and 246 (20%) provided samples that did
not give an evaluable result. The proportion of Australian patients
that would provide evaluable tissue samples was not known.
Another source of concern was that the primary evidentiary basis
for the submission was one of multiple prespecified exploratory
subgroup analyses, focussing on EGFR mutation positive (M+)
patients of the IPASS trial. Further, in the subgroup of 437
patients with evaluable samples, 261 (60%) were M+, which is a much
higher proportion than in unselected Australian non-small cell lung
cancer (NSCLC) patients (9.5% estimated in the submission).
This concern was further complicated because IPASS (like the
supportive trials) was enriched so that, compared with an
unselected Australian population presenting with NSCLC, there were
higher proportions of Asians (97.7% vs. 8% of Asian descent in
Australia), females (81% vs. 41%), never smokers (93.9% vs. 15%
never smokers or passive smokers), younger (median age 57 years vs.
72 years) and non-squamous histology tumours (100% adenocarcinoma
or bronchioalveolar vs. approximately 45% adenocarcinoma or
unspecified). Although there was a higher proportion of EGFR
activating mutations in this enriched population, the evidence
available was not sufficient to determine whether these other
patient characteristics may also independently modify the
comparative treatment effect of first-line gefitinib beyond the
modification attributed to the status of the EGFR mutation. In
other words, there was little direct evidence for patients with
EGFR activating mutations who were non-Asians, males, smokers,
older and/or who had squamous or uncertain histology tumours.
In the subgroup of 437 IPASS patients providing evaluable EGFR
mutation results, gefitinib statistically significantly extended
progression-free survival (PFS) compared with carboplatin and
paclitaxel in EGFR M+ patients (HR 0.48, 95% CI: 0.36, 0.64; median
PFS 9.5 months compared with 6.3 months). By contrast, gefitinib
statistically significantly reduced progression-free survival
compared with carboplatin and paclitaxel in EGFR M- patients (HR
2.85, 95% CI: 2.05, 3.96; median PFS 1.5 months compared with 5.8
months). The PBAC accepted that these results supported the
conclusion of first-line gefitinib treatment effect modification by
EGFR mutation status for PFS.
In the subgroup of EGFR M+ patients, updated overall survival (OS)
data (78% maturity) showed no difference between those initially
randomised to gefitinib and those initially randomised to
carboplatin and paclitaxel (HR 1.0, 95% CI: 0.76, 1.33; median OS
21.6 months compared with 21.9 months). As already noted, these ITT
analyses were relevant to the requested listing and did not support
the claim of an overall survival advantage for gefitinib generated
by the submission’s model (0.09 years for the deterministic
model or 0.152 years for the probabilistic model). The PBAC
therefore concluded that the submission’s estimate of
first-line gefitinib’s overall effectiveness was an
overestimate and its estimate of first-line gefitinib’s
cost-effectiveness was therefore also more favourable than was
supported by the evidence provided.
In the absence of an improvement in overall survival with
first-line gefitinib, the therapeutic advantages for first-line
gefitinib related to quality of life improvements, due to
difference in adverse event profiles, oral therapy rather than
intravenous therapy and possibly due to prolonged progression free
survival. The net impact of such quality of life improvements on
improving quality-adjusted survival cannot be estimated from the
model in isolation from the model’s projected advantages in
overall survival.
In relation to testing, the PBAC affirmed that the mutation testing
in any PBS restriction should be limited to tumour material because
this was supported by the trial evidence available, and should not
be extended to possible alternative sample options such as sputum
or pleural fluid. In addition, the PBAC advised that mutation
testing should be restricted to detecting exon 19 deletions and
exon 21 L858R point mutations because (a) these account for 247/261
(95%) of patients with the mutations detected and (b) some
resistance mutations such as exon 20 T790M have already been
documented.
Although the test used in determining EGFR mutation status was a
commercially available dideoxy sequencing test, the PBAC advised
that it would not be necessary to specify this particular test in
any PBS or MBS restriction. Rather a minimal performance of
eligible tests should be specified in terms of analytical validity,
in order to minimise both false positives and false negatives. The
sensitivity and specificity of the EGFR tests affects the
cost-effectiveness and these aspects are the subject of an ongoing
assessment by the Medical Services Advisory Committee (MSAC).
An additional effect was that a lower prevalence of EGFR M+ made
the cost-effectiveness less favourable by increasing the number of
tests required to detect one patient who is EGFR M+ and so eligible
for first-line gefitinib as requested. Although this latter effect
of reduced prevalence was included in estimating the costs of
testing the extent that prevalence was still overestimated
influenced the extent to which submission’s estimates still
favoured first-line gefitinib.
A further concern in relation to testing was that, of 683 patients
providing samples, 246 (36%) did not provide an evaluable result.
This compared to estimates of approximately 5% in the Peter
MacCallum Cancer Centre and 11% in the United Kingdom. The PBAC
noted that the reasons for this were unclear, but were likely to be
related to the amount of tumour cells in the biopsy sample. A
greater percentage of cells was required for the dideoxy sequencing
test compared to other tests, so retesting may be required at
greater cost. If the initial sample was inadequate, a new sample
may be required at both greater cost and risk of harm to the
patient. Additional samples may also be required if new EGFR
mutations were encountered in the tumour, or resistance had
developed due to prior radiation exposure. The PBAC considered that
these concerns further suggested that the submission’s
cost-effectiveness estimates favoured first-line gefitinib.
A final concern in relation to testing was the estimated unit cost.
The submission estimated a cost based on a range provided by two
sources, which differed from that estimated by the Medicare
Financing and Analysis Branch of the Department of Health and
Ageing.
The submission presented a modelled economic evaluation of
advanced/metastatic NSCLC. The 5-year Markov model was based on
Weibull regressions for progression and early survival results
derived from the EGFR M+ subgroup of the IPASS trial, and results
were presented using both deterministic and probabilistic
approaches. Given the nature of the disease, this time horizon
captured the remaining lifetime of most patients. The model
compared first-line therapies (gefitinib or platinum doublet
chemotherapy) followed by second-line treatment, assuming that,
post-progression, patients initially treated with gefitinib receive
platinum-based chemotherapy, and patients initially treated with
chemotherapy received gefitinib.
The PBAC recalled that the claim of any overall survival advantage
was not supported by the more mature data provided with the
pre-subcommittee response. Other assumptions favouring first-line
gefitinib were (a) the duration of second-line gefitinib as a cost
offset (713 days in the base case based on IPASS compared with 405
days based on utilisation data from Medicare Australia), (b) the
assumption that all second-line therapy after doublet therapy is
gefitinib, and (c) all patients receiving doublet therapy received
second-line therapy. This last assumption was acknowledged as an
unintended error in the pre-subcommittee response and the corrected
incremental cost per extra quality-adjusted life-year (QALY) gained
was estimated to be in the range $75,000 - $105,000 using the
deterministic model compared with the original estimate in the
range of $15,000 - $45,000 in the submission. The PBAC noted that
this corrected ratio was still favourable to first-line gefitinib
for all the reasons it had already identified. For example,
increasing the unit cost per test from $400 to $606 increased this
ratio to be in the range of $105,000 - $200,000.
The PBAC considered that the estimates of financial implications to
the government for both the PBS and the MBS (less than $10 million
in the fifth year of listing) were likely underestimates because of
the sensitivity of these estimates to the prevalence of EGFR M+ in
NSCLC. The PBAC considered the estimate of 9.5% may be an
overestimate which was most affected by uncertainties regarding the
prevalence in non-Asians and the proportion of Asians in the
Australian population.
The PBAC therefore rejected the submission on the basis of
unacceptably high and uncertain cost-effectiveness. The main
uncertainties related to the prevalence of EGFR M+ in unselected
Australian NSCLC patients, EGFR testing performance and cost, the
effect of these on the comparative treatment effect of first-line
gefitinib, and the extent of the incremental QALY gain based on
quality of life advantages without any overall survival
advantage.
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
AstraZeneca commit to continue working with both the PBAC and MSAC
to ensure Australian patients with non-small cell lung cancer are
able to identify and access the most effective and appropriate
treatments for their disease.
