Imatinib mesylate, tablet, 100 mg and 400 mg (base), Glivec, July 2007
Imatinib mesylate, tablet, 100 mg and 400 mg (base), Glivec, July 2007
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Public Summary Document
Product: Imatinib mesylate, tablet, 100 mg and 400 mg (base), Glivec
Sponsor: Novartis Pharmaceuticals Australia Pty Ltd
Date of PBAC Consideration: July 2007
1. Purpose of Application
The submission sought to extend the current listing for imatinib to include the treatment of four rare diseases: dermatofibrosarcoma protuberans, hypereosinophilic syndrome, myelodysplastic/myeloproliferative diseases and aggressive systemic mastocytosis.
2. Background
This drug had not previously been considered by the PBAC for these indications.
3. Registration Status
Imatinib is currently registered for:
- Treatment of patients with chronic myeloid leukaemia (CML).
- Treatment of patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST).
- Adult patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy (10 May 2007)
- Adult patients with relapsed or refractory Ph+ ALL as monotherapy (10 May 2007)
- Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements, where conventional therapies have failed (10 May 2007)
- Adult patients with aggressive systemic mastocytosis (ASM), where conventional therapies have failed (10 May 2007)
- Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) (10 May 2007)
- Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP) (10 May 2007)
4.Listing Requested and PBAC’s View
Section 100 authority required (Special Authority Program)
Treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma
protuberans (DFSP).
Treatment of adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic
leukaemia (CEL).
Treatment, where conventional therapies have failed, in patients with
- myelodysplastic syndromes/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements; or
- aggressive systemic mastocytosis (SM) without the D816V c-kit mutation or with c-kit mutational status unknown.
The PBAC considered that the restriction requested for each of the uncommon haematological
malignancies did not accurately reflect the patient characteristics that predict a
response to imatinib.
The PBAC noted that responsiveness to imatinib is predicted by the molecular detection
of FIP1L1-PDGFRA transcript in HES, 5q33 abnormalities in MDS/MPD with PDGFR gene
rearrangement and the presence of the FIP1L1-PDGFRA transcript in patients with SM.
The PBAC was also concerned about the cost, availability and access to the molecular
testing, and the number of patients who will need to be screened.
5. Clinical Place for the Proposed Therapy
Dermatofibrosarcoma protuberans (DFSP):
Dermatofibrosarcoma protuberans is a locally aggressive, highly invasive soft tissue
sarcoma with ulceration, bleeding and pain at the lesion sites commonly occurring
in the skin of the trunk, proximal extremities, head and neck. As this malignancy
is dependent on a genetic rearrangement of the platelet-derived growth factor (PDGF)
and Collagen 1A1 genes it may be sensitive to imatinib.
Hypereosinophilic syndrome (HES) / Chronic eosinophilic leukemia (CEL):Hypereosinophilic syndrome / chronic eosinophilic leukemia is a rare haematological
disorder characterised by chronic overproduction of eosinophils, tissue infiltration
and organ damage. The disease is thought to have multiple genetic origins with a high
frequency of PDGFR rearrangements, and therefore may be highly sensitive to imatinib.
Nearly any organ system may be involved. The most common and often serious are the
cardiovascular complications which are often life-threatening in patients with HES.
Myelodysplastic(MDS) / myeloproliferative disorders (MPS):
Myelodysplastic / myeloproliferative disorders are a group of myeloid disorders with
dysplastic and proliferative characteristics. Three major disorders are identified:
chronic myelomonocytic leukemia (CMML), atypical chronic myelogenous leukemia (aCML),
and juvenile myelomonocytic leukemia (JMML). A subgroup of these patients exhibit
disease that is dependent on genetic rearrangement of PDGFR and therefore may be highly
sensitive to imatinib. Patients experience anaemia, thrombocytopenia, and splenomegaly
with frequent lymph node, skin and other organ involvements. This disease can progress
much like an acute leukaemia with similar complications, morbidity and mortality.
Systemic Mastocytosis (SM):
Systemic mastocytosis involves infiltration of mast cells into multiple organs resulting
in many different clinical manifestations in the patient including peptic ulcers,
malabsorption deficiency, increased liver enzymes, osteoporosis, anaemia, thrombocytopenia,
leukaemia and angina. The disease is commonly dependent on over-activity of KIT and
may therefore be sensitive to imatinib. However, it is thought that a majority of
cases are dependent on a particular mutant form of KIT (D816V) that is resistant to
imatinib and in whom the drug is unlikely to be effective.
6. Comparator
Appropriately, the submission nominated standard medical management as the comparator.
7. Clinical Trials
The submission presented a case series study (B2225) of imatinib following failure
of standard therapeutic options in patients with dermatofibrosarcoma protuberans (N=12),
hypereosinophilic syndrome / chronic eosinophilic leukemia (N=14), myelodysplastic
/ myeloproliferative disorders (N=7) and systemic mastocytosis (N=5).
The submission also presented a number of additional case series for each disease
with and without imatinib.
The case series trial, B2225, had been published at the time of submission as follows:
|
Trial/First author |
Protocol title/Publication title |
Publication citation |
|---|---|---|
|
McArthur G, Demetri G, van Oosterom A, et al. |
Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans
treated with imatinib: Imatinib Target Exploration Consortium Study B2225. |
J Clin Oncol 2005; 23: 866-873 |
|
Apperley J, Dimitrijevic S, Browne P et al. |
Imatinib (STI571, Glivec) for chronic Ph-negative myeloproliferative disorders associated with eosinophilia. |
Br J Haematol 2003; 121(Suppl.1): 41-86 [abstract 213] |
|
Apperley J, Gardembas M, Melo J et al. |
Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. |
N Engl J Med 2002; 347: 481-487 |
8. Results of Trials
Comparative effectiveness
The results of the case series study are summarised in the table below.
Treatment effectiveness:
|
Outcome |
DFSP |
HES |
MDS/MPD |
SM |
|---|---|---|---|---|
|
Complete response |
1 (8%) |
– |
3 (43%) |
– |
|
Partial response |
8 (67%) |
4 (29%) |
1 (14%) |
1 (20%) |
|
Stable disease |
– |
2 (14%) |
– |
1 (20%) |
|
Progressive disease |
– |
2 (14%) |
1 (14%) |
– |
|
Unknown a |
3 (25%) |
6 (43%) |
2 (29%) |
3 (60%) |
|
Overall response rate |
9/12 (75%) |
4/14 (29%) |
4/7 (57%)b |
1/5 (20%) |
|
Duration response (median), days |
112; n=9 |
266; n=4 |
400; n=4 |
127; n=1 |
a Only confirmed responses were included, all unconfirmed PR or SD or patients who
are ongoing at the time of cut-off date and have only the baseline assessment at the
time of cut-off or patients with assessments not done are listed as unknown.
b Of the four patients with PDGFR gene-rearrangements, 2 had CR and 1 had PR for an
overall response rate in this subgroup of 75%
Flow of participants through the case series study
|
Study B2225 |
DFSP |
HES |
MDS/MPD |
SM |
|---|---|---|---|---|
|
Completed |
1 (8%) |
3 (21%) |
3 (43%) |
1 (20%) |
See Recommendation and Reasons for PBAC’s view.
Comparative toxicity
Gastrointestinal disorders, general disorders, skin complaints and oedema at various
sites were the most frequently reported adverse events in study B2225. No patients
died during the study.
9. Clinical Claim
The submission suggested that imatinib produced good response rates with an acceptable
safety profile. The submission also argued that patients with these rare diseases
who have failed conventional therapies face a poor prognosis, with unmet clinical
need.
The PBAC acknowledged that effective treatments are limited and that because of the
rarity of these conditions, any data to support a PBS listing will have limitations.
However, the Committee considered that there was only very weak evidence of greater
efficacy of imatinib over standard care, particularly with regards durable benefit.
The PBAC also considered there was uncertainty regarding the dose, the duration of
response and the appropriate duration of treatment in all the rare diseases in the
submission.
10. Economic Analysis
The PBAC noted that the submission stated that the trial based economic evaluation presented was a cost-consequence analysis. However, there was only one outcome and no comparator, hence there was no incremental cost or benefit, nor was there a comparison across outcomes. The data provided were the average cost per treatment response. The PBAC was therefore unable to form a judgement based on an average cost per treatment response estimate about the true cost-effectiveness of this drug for these chronic conditions.
11. Estimated PBS Usage and Financial Implications
The financial cost/year to the PBS (excluding co-payments) was estimated by the submission to be less than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC expressed its sympathy for patients with these rare conditions acknowledging
that effective treatments are limited. The PBAC further accepted that because of the
rarity of these conditions, any data to support a PBS listing will have limitations.
However, the PBAC considered that there was only very weak evidence of greater efficacy
of imatinib over standard care, particularly with regards durable benefit. The data
were limited to response rates in case series, with and without imatinib, and with
no controlled data, and very minimal long term follow up. The data were very sparse
with considerable residual statistical uncertainty and the PBAC considered that the
effects of imatinib appeared moderate, at best. The clinical benefits of observed
responses were also uncertain because of a lack of follow up data.
The PBAC noted that in study B2225, there was a low level of response in dermatofibrosarcoma
protuberans with a complete response observed in 1 out of 12 patients. In myelodysplastic
/ myeloproliferative, 3 out of 7 patients had a complete response of which 2 had the
platelet derived growth factor receptor (PDGFR) gene re-arrangements specified in
the proposed restriction. In patients with myelodysplastic / myeloproliferative with
PDGFR rearrangement, the PBAC noted that the detection of 5q33 abnormalities would
allow diagnosis with a high degree of confidence and also target those patients more
likely to respond to imatinib.
The PBAC considered that the data on efficacy in all patients with hypereosinophilic
syndrome / chronic eosinophilic leukemia were modest and associated with considerable
uncertainty. However, there was a high level of efficacy in a genotypically defined
subset in the series reporting outcomes according to FIP1L1-PDGFRA status. The PBAC
noted that the restriction proposed by the submission does not limit treatment to
patients with this transcript. There was also uncertainty about the magnitude of the
long term clinical benefits.
The PBAC considered that the case series for SM were informative and indicated that
responsiveness to imatinib was predicted by the presence of FIP1L1-PDGFRA, with 13/13
patients having this gene rearrangement achieving an apparently durable complete response
(CR). It was noted that the presence of D816V predicted no or minimal response; and
that lack of D816V was not predictive of a response in the absence of FIP1L1-PDGFRA.
Furthermore, there was uncertainty regarding the dose, the duration of response and
the appropriate duration of treatment in all the rare diseases in the submission.
The PBAC was unable on the basis of the data provided to form a judgement based on
an average cost per treatment response estimate about the true cost-effectiveness
of this drug for these chronic conditions.
The PBAC was concerned about the cost, availability and access to the molecular testing,
and the number of patients who will need to be screened.
The PBAC therefore rejected the submission on the basis of uncertain clinical benefit
and uncertain cost-effectiveness.
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
The sponsor intends to provide further data to demonstrate the value of imatinib in
patients with either of these rare diseases.
