Imatinib, tablet, 100 mg and 400 mg (as mesylate), Glivec® - March 2011
Page last updated: 29 June 2011
PDF printable version to Imatinib, tablet, 100 mg and 400 mg (as mesylate), Glivec®
(PDF 39 KB)
Public Summary Document
Product: Imatinib, tablet, 100 mg and 400 mg (as
mesylate), Glivec®
Sponsor: Novartis Pharmaceuticals Australia Pty
Ltd
Date of PBAC Consideration: March 2011
1. Purpose of Application
To seek an Authority Required listing for the adjuvant treatment of
an adult patient at high risk of recurrence following complete
resection of primary gastrointestinal stromal tumour (GIST) who
meets certain criteria.
2. Background
This is the third submission seeking an Authority Required listing for adjuvant treatment
of GIST.
At the November 2009 meeting, the PBAC rejected a submission seeking an Authority
Required listing for adjuvant treatment of GIST on the basis uncertain clinical benefit
and a high and highly uncertain cost-effectiveness ratio.
A copy of the Public Summary Document from that meeting is available.
At the July 2010 meeting, the PBAC rejected a resubmission seeking an authority required
listing for adjuvant treatment of GIST on the basis of uncertain clinical benefit
and an unacceptably high and uncertain cost-effectiveness ratio.
A copy of the Public Summary Document from that meeting is available.
3. Registration Status
The TGA registration for imatinib was extended on 17 June 2009 to
include the adjuvant treatment of adult patients following complete
gross resection of KIT (CD117)-positive primary GIST.
4. Listing Requested and PBAC’s View
The requested listing was the same as that in the July 2010 submission.
NOTE:
Imatinib mesylate is not PBS-subsidised for the treatment of patients with resectable
malignant gastrointestinal stromal tumours.
Authority required
Adjuvant treatment of an adult patient at high risk of recurrence following complete
resection of primary gastrointestinal stromal tumour which has been histologically
confirmed by the detection of CD117 on immunohistochemical staining, at a dose not
exceeding 400 mg/day for a period of 12 months.
High risk of recurrence is defined as:
Primary GIST greater than 5 cm with a mitotic count of greater than 5/50 high power
fields (HPF); or
Primary GIST greater than 10 cm with any mitotic rate; or
Primary GIST with a mitotic count of greater than 10/50 HPF
(Prognosis definition based on the Australian and New Zealand consensus approach to
best practice management, see Zalcberg et al. Asia-Pacific Journal of Clinical Oncology
2008: 4.4: 188-98.)
Authority required (grandfathering)
Initial treatment of a patient who was receiving adjuvant imatinib mesylate for GIST
prior to [list date] and who meets the above PBS criteria. The patient is eligible
to receive sufficient imatinib at a dose of 400 mg/day to complete 12 months of combined
PBS-subsidised and non-PBS-subsidised therapy.
Applications for authorisation must be in writing and must include:
(1) a completed authority prescription form; and
(2) a completed Imatinib Mesylate (Glivec) PBS Authority Application for Use in Adjuvant
Treatment of Gastrointestinal Stromal Tumour - Supporting Information Form [may be
downloaded from the Medicare Australia website (www.medicareaustralia.gov.au)] which
includes the following:
(i) a copy of a pathology report from an Approved Pathology Authority supporting the
diagnosis of a gastrointestinal stromal tumour and confirming the presence of CD117
on immunohistochemical staining; and
(ii) a copy of the most recent (within 2 months of the application) computed tomography
(CT) scan, magnetic resonance imaging (MRI) or ultrasound assessment of the tumour(s),
including whether or not there is evidence of metastatic disease; and
(iii) a written statement indicating that the date of tumour resection was not more
than 3 months prior to the date of this application; and
(iv) a copy of the pathology report must include the size and mitotic rate of the
tumour
Change the NOTE in the current continuing treatment restriction for metastatic GIST
as follows:
Authority required
Continuing PBS-subsidised treatment, at a dose of up to 600 mg per day, of adult patients
with a metastatic or unresectable malignant gastrointestinal stromal tumour who have
previously been issued with an authority prescription for this drug.
NOTE:
Patients with metastatic/unresectable disease who achieve a response to treatment at an imatinib dose of 400 mg per day should
be continued at this dose and assessed for response at regular intervals. Patients
who fail to achieve a response to 400 mg per day may have their dose increased to
600 mg per day. Authority applications for doses higher than 600 mg per day will not
be approved.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Gastrointestinal stromal tumours (GIST) are rare and occur in the
muscular layer of the digestive tract. Surgery has been the sole
treatment for primary localised GIST and most patients after
surgery are observed (‘watchful waiting’). However,
surgery alone is not curative for the majority of patients and over
50% of patients will have disease recurrence within 2 years.
Recurrence can occur as a result of tumour rupture during surgery
or after “complete” resection due to unsuspected
microscopic tumour dissemination.
The submission proposed that adjuvant treatment with imatinib
following complete resection of the primary GIST will provide a
treatment option after surgery and may prevent disease recurrence
in those patients classified as being at high risk of metastatic
disease recurrence.
6. Comparator
The submission previously nominated placebo as the main comparator,
which was considered appropriate by the PBAC.
7. Clinical Trials
The submission did not provide any additional clinical data
compared to the July 2010 submission. See July 2010 Public Summary
Document (PSD) for details.
8. Summary of Submission
The submission stated that clinical data from the following
on-going trials will become available in 2015, which may help
address the PBAC’s concerns regarding the comparative effect
for overall survival:
1) Intergroup Study (EORTC 62024, EudraCT number 2004-001810-16):
“Intermediate and high risk localized, completely resected,
gastrointestinal stromal tumors (GIST) expressing KIT receptor: a
controlled randomized trial on adjuvant Imatinib mesylate (Glivec)
versus no further therapy after complete surgery”.
2) SSG XVIII/AIO Trial: “Short (12 months) versus long (36
months) duration of adjuvant treatment with imatinib of operable
GIST with a high risk for recurrence: a randomized phase III
study”.
To address the issue of whether imatinib affects the emergence of
resistance under imatinib therapy in the metastatic setting, the
submission outlined published results of treatment interruption in
patients with non-progressive disease after 3 years of imatinib in
a randomised trial, Le Cesne et al (2010).
The table below details the published trial presented in the
submission.
| Trial/First author | Protocol title/Publication title | Publication citation |
| Le Cesne et al | Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open -label multicentre randomised phase 3 trial. | The Lancet Oncology 2010 Oct; 11 (10): 942-9. |
Although this trial did not directly address the impact of
rechallenging with imatinib following use in the adjuvant setting,
the submission stated the authors of the study concluded that while
treatment interruption after 3 years in metastatic patients
resulted in tumour progression in most patients, there was further
tumour control in all cases after the reintroduction of imatinib.
Importantly the time to secondary resistance to imatinib was
similar in the continued treatment group vs interrupted treatment
group, which provided evidence that imatinib interruption neither
prevents nor promotes the emergence of imatinib resistance in GIST
cells.
9. Economic Analysis
The submission stated that in the absence of substantive clinical
data to address the overall survival issue raised by the PBAC, the
sponsor proposed to reduce the daily cost of imatinib (400 mg/day)
in the adjuvant setting to mitigate the PBAC concerns regarding the
high and uncertain cost-effectiveness ratio, and uncertain clinical
benefit of imatinib as adjuvant treatment for GIST over a range of
estimates of overall survival.
The submission presented a revised modelled economic analysis based
on the reduced price.
The incremental cost per QALY was estimated to be in the range of
$15,000 - $45,000.
In an attempt to address the PBAC’s concerns regarding
whether adjuvant treatment using imatinib offers an increase in
overall survival (OS) and whether recurrence-free survival (RFS)
would be a valid surrogate for OS in GIST patients, the submission
presented a series of scenarios to test and demonstrate that
imatinib represents a cost-effective option for the adjuvant
treatment of GIST.
The base case incremental cost per life year gained was estimated
to be in the range of
$15,000 - $45,000.
For PBAC’s view, see Recommendation and
Reasons.
10. Estimated PBS Usage and Financial Implications
The submission presented revised financial implications for
imatinib in adjuvant setting in patients at high risk of metastatic
GIST recurrence.
The submission estimated lees than 10,000 patients would be
eligible for imatinib in year 4 of listing.
The submission estimated the overall net costs to the PBS of
imatinib (adjuvant setting) to be less than $10 million in year 4
of listing.
11. Recommendation and Reasons
The PBAC recommended listing imatinib on the PBS as an Authority Required benefit
for the adjuvant treatment of GIST following complete resection of the primary tumour
on the basis of an acceptable cost-effectiveness ratio compared with placebo.
The PBAC noted that there were no new clinical data, but supportive evidence was provided
in relation to imatinib resistance and treatment interruption. A price decrease was
offered by the sponsor and a revised modelled economic analysis and financial implications
were presented.
The PBAC considered that the evidence provided from La Cesne (2010) addressed concerns
regarding treatment interruption in patients with non-progressive disease and the
emergence of resistance under imatinib therapy in the metastatic setting and agreed
with the authors’ conclusion that “interruption of treatment with imatinib neither
prevents nor promotes emergence of imatinib resistance in GIST cells”.
The PBAC noted that the revised ICER calculated using the same model and the price
decrease was estimated to be in the range of $15,000 - $45,000/QALY compared with
$45,000 - $75,000/QALY in the November 2010 submission. The PBAC considered the revised
ICER to be acceptable but in the higher range compared with other adjuvant treatments.
The PBAC noted that the impact of survival assumptions was calculated as LYG rather
than QALYs, to address PBAC's previous concerns about uncertainty in relation to the
QALY gains in the model. The PBAC also noted the sensitivity analysis in relation
to survival advantage showed that even with a 30% reduction in survival advantage,
the incremental cost per LYG was acceptable.
The PBAC agreed that there was a high clinical need for use of imatinib in the adjuvant
treatment of GIST, a rare disease, in a small population where patient numbers were
low (less than 10,000 per year in year 5), and that the financial cost to the PBS
was also relatively low.
The PBAC noted that there was an ongoing trial which will report at a future date
on progression free survival versus overall survival for this indication. The PBAC
requested that the sponsor provide the PBAC with an update on the results of this
trial when available.
The PBAC recommended that imatinib is not suitable for inclusion in the PBS medicines
for prescribing by nurse practitioners within collaborative arrangements.
Recommendation:
IMATINIB, tablet, 100 mg and 400 mg (as mesylate), Glivec®
Extend the current restriction to include:
Restriction:
NOTE:Imatinib mesylate is not PBS-subsidised for the treatment of patients with resectable
malignant gastrointestinal stromal tumours.
Authority required
Adjuvant treatment of a patient at high risk of recurrence following complete resection of primary gastrointestinal stromal tumour which has been histologically confirmed by the detection of CD117 on immunohistochemical staining, at a dose not exceeding 400 mg/day for a period of 12 months.
High risk of recurrence is defined as:
Primary GIST greater than 5 cm with a mitotic count of greater than 5/50 high power fields (HPF); or
Primary GIST greater than 10 cm with any mitotic rate; or
Primary GIST with a mitotic count of greater than 10/50 HPF
(Prognosis definition based on the Australian and New Zealand consensus approach to best practice management, see Zalcberg et al. Asia-Pacific Journal of Clinical Oncology 2008: 4.4: 188-98.)
Authority required (grandfathering)
Initial treatment of a patient who was receiving adjuvant imatinib mesylate for GIST prior to [list date] and who meets the above PBS criteria. The patient is eligible to receive sufficient imatinib at a dose of 400 mg/day to complete 12 months of combined PBS-subsidised and non-PBS-subsidised therapy.
Applications for authorisation must be in writing and must include:
(1) a completed authority prescription form; and
(2) a completed Imatinib Mesylate (Glivec) PBS Authority Application for Use in Adjuvant Treatment of Gastrointestinal Stromal Tumour - Supporting Information Form [may be downloaded from the Medicare Australia website (www.medicareaustralia.gov.au)] which includes the following:
(i) a copy of a pathology report from an Approved Pathology Authority supporting the diagnosis of a gastrointestinal stromal tumour and confirming the presence of CD117 on immunohistochemical staining; and
(ii) a copy of the pathology report must include the size and mitotic rate of the tumour, and the date of tumour resection must be documented, which must not be more than 3 months prior to the date of this application.
Max qty: 60 (100 mg), 30 (400 mg)
Repeats: 5
Amend the current listing for imatinib use in metastatic or unresetcable GIST to read as follows as highlighted by italics and strikethrough:
Authority Required
Initial PBS-subsidised treatment, for up to 3 months, of a adult patients with a metastatic or unresectable malignant gastrointestinal stromal tumour which has been histologically confirmed by the detection of CD117 on immunohistochemical staining.
Patients must commence treatment at a dose not exceeding 400 mg per day for at least 3 months. Authority prescriptions for a higher dose will not be approved during this initial 3 month treatment period.
Applications for authorisation must be in writing and must include:
(1) a completed authority prescription form; and
(2) a completed Imatinib Mesylate (Glivec) PBS Authority Application for Use in the Treatment of Metastatic or Unresectable Gastrointestinal Stromal Tumour - Supporting Information Form [may be downloaded from the Medicare Australia website (www.medicareaustralia.gov.au)] which includes the following:
(i) a copy of a pathology report from an Approved Pathology Authority supporting the diagnosis of a gastrointestinal stromal tumour and confirming the presence of CD117 on immunohistochemical staining; and
(ii) a copy of the most recent (within 2 months of the application) computed tomography (CT) scan, magnetic resonance imaging (MRI) or ultrasound assessment of the tumour(s), including whether or not there is evidence of metastatic disease; and
(iii) where the application for authority to prescribe is being sought on the basis of an unresectable tumour, written evidence in support of that claim must be provided.
Authority Required
Continuing PBS-subsidised treatment, at a dose of up to 600 mg per day, of a adult patients with a metastatic or unresectable malignant gastrointestinal stromal tumour who have
previously been issued with an authority prescription for this drug.
Applications for continuing treatment may be made by telephone (1800 700 270, hours of operation 8 a.m. to 5 p.m. EST Monday to Friday).
Patients who have failed to respond or are intolerant to imatinib are no longer eligible to receive PBS-subsidised imatinib.
NOTE:
Patients with metastatic/unresectable disease who achieve a response to treatment at an imatinib dose of 400 mg per day should be continued at this dose and assessed for response at regular intervals. Patients who fail to achieve a response to 400 mg per day may have their dose increased to 600 mg per day. Authority applications for doses higher than 600 mg per day will not be approved.
A response to treatment is defined as a decrease from baseline in the sum of the products of the perpendicular diameters of all measurable lesions of 50% or greater. (Response definition based on the Southwest Oncology Group standard criteria, see Demetri et al. N Engl J Med 2002; 347: 472-80.)
NOTE:
No applications for increased repeats will be authorised.
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 has no comments.
