Imatinib mesylate, tablet, 100 mg and 400 mg (base), Glivec, July 2007
Public summary document for 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 acute lymphoblastic leukaemia (ALL) expressing the Philadelphia chromosome or the transcript, bcr-abl tyrosine kinase, in newly diagnosed patients or patients with relapsed or refractory disease.
2. Background
This drug has not previously been considered by the PBAC for this indication.
3. Registration Status
Imatinib is currently registered for:
- Treatment of patients with chronic myeloid leukaemia.
- Treatment of patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumours.
- Adult patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy
- Adult patients with relapsed or refractory Ph+ ALL as monotherapy
- Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene re-arrangements, where conventional therapies have failed
- Adult patients with aggressive systemic mastocytosis, where conventional therapies have failed
- Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukaemia
- Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.
4. Listing Requested and PBAC’s View
Authority Required
Treatment in combination with chemotherapy of adult patients with newly diagnosed
acute lymphoblastic leukaemia (ALL) expressing the Philadelphia chromosome or the
transcript, bcr-abl tyrosine kinase.
Treatment as monotherapy of adult patients with relapsed or refractory acute lymphoblastic
leukaemia (ALL) expressing the Philadelphia chromosome or the transcript, bcr-abl
tyrosine kinase.
The PBAC recommended listing for newly diagnosed patients only. Following a period
of initial treatment, prescriptions for further treatment should be dependent on achievement
of a complete response. Imatinib should not be subsidised for use post-stem cell transplant.
In patients who did not proceed to stem cell transplant, the total course of treatment
should not exceed 2 years.
5. Clinical Place for the Proposed Therapy
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) is an aggressive
form of acute leukaemia with extremely poor prognosis.
Current chemotherapy regimens for Ph+ ALL produce disappointing results with median
survival of less than one year in adults. Allogeneic stem cell transplantation remains
the only curative option so far. However, less than 30% of patients have a matched
sibling donor and patients aged 55 years or over, are generally not considered ideal
candidates for a transplant. Imatinib provides an additional treatment option for
some of these patients.
6. Comparator
Appropriately, the submission nominated chemotherapy as the main comparator for patients with newly diagnosed Ph+ ALL and for patients with relapsed/refractory Ph+ ALL.
7. Clinical Trials
Newly diagnosed Ph+ ALL:
The submission presented two single arm studies (imatinib +chemotherapy) versus separate
historical controls (chemotherapy alone):
- Lee et al (2005) – younger patients (median age 36, 35 years) who had a stem cell
transplant and
- Study AFR09 – older patients (median age 66, 61 years) who did not receive a stem
cell transplant.
Relapsed/refractory Ph+ ALL:
The submission presented three single arm studies – two imatinib studies (Study 109
and Study 114) vs one chemotherapy alone study (GIMEMA ALL).
The trials that had been published at the time of submission are as below:
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
Lee S et al |
The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia-chromosome positive acute lymphoblastic leukemia. |
Blood 2005; 105: 3449-57 |
|
Lee S et al |
Minimal residual disease-based role of imatinib as a first-line interim therapy prior to allogeneic stem cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia. |
Blood 2003; 102: (8): 3068-3070 |
|
Study AFR09 |
||
|
Delannoy A et al |
Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia: results of the GRALL AFR09 study. |
Leukemia 2006; 20: 1526-1532 |
|
Study 109 |
||
|
Ottman OG et al |
A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. |
Blood 2002; 100: 1965-1971 |
|
Study 114 (expansion of Study 109) |
||
|
Wassmann B et al |
Early prediction of response in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) treated with imatinib. |
Blood 2004; 103(4): 1495-1498 |
|
GIMEMA ALL |
||
|
Camera A et al |
GIMEMA ALL - Rescue 97: a salvage strategy for primary refractory or relapsed adult acute lymphoblastic leukemia. |
Haematologica 2004; 89: 145-153 |
8. Results of Trials
Comparative effectiveness
The results of the key studies are summarised below.
Newly diagnosed Ph+ ALL
|
Lee S et al (2005) with SCT |
Imatinib + chemotherapy (N=29) |
Chemotherapy |
p- value |
|---|---|---|---|
|
After consolidation therapy
|
22/23 (95.7%) |
16/27 (59.3%) |
0.003 |
|
|
|
|
|
|
Pre-transplantation status
|
25/29 (86.2%) |
17/33 (51.5%) |
0.004 |
|
|
|
|
|
|
Survival |
|||
|
Disease-free survival |
78.1% 11.6% |
38.7% 8.8% |
<0.01 |
|
Overall survival |
78.1% 11.6% |
38.7% 8.8% |
<0.001 |
|
Study AFR09 without SCT |
(N=30) |
(N=21) |
p-value |
|
Induction therapy |
21/29, 72% |
6/21, 29% |
0.003 |
|
Salvage therapy |
Imatinib + steroids |
Additional chemotherapy |
0.001 |
|
Survival |
|||
|
1-yr overall survival (95% CI) |
66% (49%, 83%) |
43% (24%, 62%) |
0.004 |
|
Median relapse-free survival |
20.1 months |
4.2 months |
0.0003 |
CR1 = first complete remission; CR2 = second complete remission; SCT = stem cell transplant
Survival curves for DFS and OS
Relapsed /refractory Ph+ ALL
|
Outcome |
Imatinib group |
Chemotherapy group |
||
|---|---|---|---|---|
|
|
Study 109 |
Study 114 (N=353) |
Wassmann et al (2004) (N=68) |
GIMEMA ALL (N=135) † |
|
Marrow CR rate |
10% |
NR |
29% |
12/22 (54.6%) |
|
Median OS |
4.9 months |
8.9 months |
6.2 months |
6.4 months |
Analysis based on 14 patients from Study 109 and 54 patients from Study 114
† n=22 Ph+ ALL patients; CR complete remission; OS overall survival; NR not reported
Lee S et al (2005) reported no detrimental effects of imatinib on engraftment, graft-versus-host
disease or transplant-related organ toxicity, compared to historical data but no tabulation
of comparative toxicity was provided.
The PBAC noted that there seems to be little additional toxicity of imatinib in addition
to the adverse events caused by chemotherapy regimens.
For PBAC’s view of these results, see Recommendations and Reasons.
9. Clinical Claim
Newly diagnosed Ph+ ALL
The submission claimed that imatinib when used in combination with chemotherapy is
significantly more effective than, and has similar toxicity to, chemotherapy alone.
The PBAC accepted this claim.
Relapsed/refractory disease
The submission claimed that imatinib monotherapy is significantly more effective than,
and has similar toxicity to, standard chemotherapy. The PBAC did not accept this claim.
See also Recommendation and Reasons.
10. Economic Analysis
The submission presented a preliminary economic evaluation. The resources included
were cost of drug treatment, chemotherapy and stem cell transplants (and septicaemia
in newly diagnosed patients with no stem cell transplant).
The trial-based incremental cost per extra complete responder was estimated to be
in the range $45,000 - $75,000 for newly diagnosed patients who either go on to have
a stem cell transplant or do not go on to have a stem cell transplant, and greater
than $200,000 for relapsed/refractory patients.
The submission presented a modelled economic evaluation. The choice of the cost-effectiveness
approach was considered valid. The resources included were cost of drug treatment,
chemotherapy and stem cell transplants (and septicaemia in newly diagnosed patients
with no stem cell transplant). A stem cell transplant rate of 30% was assumed.
The base case modelled incremental cost/extra discounted life year gained was estimated
to be <$15,000 for newly diagnosed patients who go on to have a stem cell transplant;
between $15,000 - $45,000 for newly diagnosed patients who do not go on to a stem
cell transplant; and between $15,000 - $45,000 for relapsed/refractory patients. In
the relapsed/refractory patients, the sensitivity analysis for the incremental cost
per extra complete responder was as high as $100,000 to $200,000. The incremental
cost/extra discounted life year gained was as high as $100,000 in the sensitivity
analysis.
For PBAC’s view, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients/year to be <10,000 in Year 4 at an estimated financial cost/year to the PBS (excluding co-payments) of less than $10 million.
12. Recommendation and Reasons
The PBAC recommended the listing of imatinib for the treatment of acute lymphoblastic
leukaemia (ALL) expressing the Philadelphia chromosome or transcript, bcr-abl tyrosine
kinase (Ph +ve) in newly diagnosed patients in combination with chemotherapy on the
basis of an acceptable cost-effectiveness ratio compared to chemotherapy alone.
The PBAC considered the studies in newly diagnosed Ph +ve ALL patients who go on to
have a stem cell transplant, demonstrated that imatinib in combination with chemotherapy
had significant advantages in effectiveness over chemotherapy alone, and was of similar,
or less toxicity. The PBAC noted that, in some patients, these benefits translated
into a major survival benefit post stem cell transplant. The PBAC noted there was
some uncertainty associated with the benefits in patients who did not proceed to a
stem cell transplant as the active and comparator studies were not completely comparable.
The PBAC agreed the incremental costs per life-year gained in these patient groups
were acceptable overall, though in the case of those patients who do not progress
to a stem cell transplant, the incremental cost effectiveness ratio was noted to be
high. While the economic evaluation did not model quality adjusted life years gained,
the PBAC accepted that significant utility improvements would be achieved in patients
who responded.
The PBAC noted that the optimum duration of treatment with imatinib in both patient
groups is unknown, and that without some limitations, the use of imatinib would not
remain cost-effective. The Committee took account of the data as well as opinions
about current clinical practice provided by the sponsor to determine this aspect of
its recommendation. The PBAC requested the Pharmaceutical Benefits Pricing Authority
consider entering into a risk sharing arrangement taking account of imatinib use in
this patient group.
The PBAC rejected the application for use of imatinib as monotherapy in relapsed or
refractory patients who are resistant or intolerant to prior the therapy, on the basis
of an unacceptably high and uncertain cost-effectiveness ratio.
The PBAC was of the view that many current patients and the great majority of all
future patients with relapsed or refractory Ph+ve ALL will have received and hence
failed imatinib, either alone or in combination with chemotherapy. As no data were
provided in the submission to demonstrate efficacy in this clinical situation, the
Committee could not support its use in patients previously treated with imatinib.
The PBAC noted the data provided related to imatinib-naﶥ patients, and demonstrated
modest clinical efficacy, with significant uncertainty about the durability of responses.
Significant uncertainty also existed about the incremental cost effectiveness ratio
because of the low quality of the clinical data, the uncertainty of durability of
clinical responses and the lack of an appropriate Ph+ve control group for the chemotherapy
comparator. In the face of an incremental cost effectiveness ratio potentially as
high as $105,000 - $200,000, which is outside the usual range that the committee considers
acceptable, the “rule of rescue” could not be considered appropriate as another treatment,
dasatinib, is available for this situation.
Recommendation
IMATINIB MESYLATE, tablet, 100 mg and 400 mg (base)
To be finalised
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 welcomes the decision by the PBAC to recommend listing of imatinib in
newly diagnosed Ph+ ALL patients.
Further data will be submitted to the PBAC to support the clinical benefits of continued
treatment with imatinib for more than 2 years in newly diagnosed Ph+ ALL patients
without a stem cell transplant as well as for treatment in post-stem cell transplant
patients.
