Dasatinib, tablets, 20 mg, 50 mg and 70 mg, Sprycel®, March 2007
Public summary document for Dasatinib, tablets, 20 mg, 50 mg and 70 mg, Sprycel®, March 2007
Page last updated: 13 July 2007
Public Summary Document
Product: Dasatinib, tablets, 20 mg, 50 mg and 70
Sponsor: Bristol-Myers Squibb Pharmaceuticals
Date of PBAC Consideration: March 2007
1. Purpose of Application
To seek Section 100 (Special Authority Program) listing for the
treatment of acute lymphoblastic leukaemia (ALL) in adult patients
expressing the Philadelphia chromosome or transcript, bcr-abl
tyrosine kinase, who are resistant or intolerant to prior
Dasatinib has not previously been considered by the PBAC.
3. Registration Status
Sprycel was registered by the TGA in January 2007 for:
Treatment of adults aged 18 years or over with chronic, accelerated or myeloid or lymphoid blast phase chronic myeloid leukaemia with resistance or intolerance to prior therapy including imatinib.
Treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia with resistance or intolerance to prior therapy.
4. Listing Requested and PBAC’s View
Section 100 – Authority Required (Special Authority
Initial treatment of acute lymphoblastic leukaemia in adult patients expressing the Philadelphia chromosome or the transcript, bcr-abl tyrosine kinase, who are resistant or intolerant to prior therapy.
Resistance to prior therapy may be manifested as progression or lack of response to therapy.
Applications for authorisation must be in writing and must include:
- a completed authority prescription form; and
- a completed dasatinib (Sprycel) PBS Authority Application for Use in the Treatment of Adult Philadelphia Positive Acute Lymphoblastic Leukaemia (Ph+ ALL) – Supporting Information form, which includes a statement asserting whether a patient is resistant or intolerant to prior therapy and a definition of prior therapy. In addition, a copy of the confirmatory pathology report from an Approved Pathology Authority must be provided in the case of resistance. For intolerance, details of the nature of the intolerance must be provided; and
- a pathology cytogenetic report conducted on peripheral blood or bone marrow supporting the diagnosis of Ph+ ALL to confirm eligibility for treatment, or a qualitative PCR report documenting the presence of the bcr-abl transcript in either peripheral blood or bone marrow.
Continuing treatment of adult patients with acute lymphoblastic leukaemia expressing the Philadelphia chromosome or the transcript, bcr-abl, where the patient has previously received PBS-subsidised treatment with dasatinib.
For the PBAC’s view see Recommendation and Reasons
5. Clinical Place for the Proposed Therapy
Dasatinib will provide a second-line treatment option for patients
who have failed chemotherapy for prior therapy.
The submission nominated imatinib as the comparator.
Although the Committee acknowledged that imatinib is used in this condition and is an appropriate comparator according to the 2006 PBAC Guidelines as the therapy likely to be replaced in practice, it is not subsidised by the PBS for this use, nor are there any data on the dose and cost-effectiveness of imatinib in ALL, and thus no basis upon which to determine if dasatinib is a cost-effective treatment.
7. Clinical Trials
The submission presented two phase II, single arm, open label, non
randomised studies: 140 mg/day dasatinib in imatinib resistant or
intolerant Ph+ ALL patients (follow up for 32 weeks) and imatinib
(400 mg/day or 600 mg/day to 800 mg/day) in relapsed or refractory
Ph+ ALL patients over 12 weeks.
The studies forming the basis of the submissions are tabulated below.
|Dasatinib||Bristol-Myers Squibb CA180-015 A phase II study of dasatinib in subjects with Lymphoid Blast phase Chronic Myeloid Leukaemia or Philadelphia Chromosome Positive Acute Lymphoblastic Leukaemia resistant to or intolerant of imatinib mesylate 2005 (12 week interim analysis) and 2006 (32 weeks safety update).|
|Imatinib||Ottman OG, Druker BJ, et al. (2002). A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukaemia. Blood; 100 (6): 1965-1971|
8. Results of Trials
The following table shows the effectiveness results from the studies.
|Outcomes||CA180-015 (N=36)||Ottmann (2002) (N=48)|
|12 weeks||32 weeks||All responses a||Sustained responses b|
|Major Haematological Response (MaHR) c||41.7% (15/36)||41.7% (15/36)||-||6%|
|Complete Haematological Response (CHR)||30.6% (11/36)||33.3% (12/36)||19% (9/48)||6% (3/48)|
|Major Cytogenetic Response (MCyR)||58.3% (21/36)||58.3% (21/36)||-||-|
|Complete Cytogenetic Response (CCyR)||44% (16/36)||58.3% (21/36)||17% (8/48)||NR|
|No evidence of Leukaemia||11.1% (4/36)||8.3% (3/36) d||-||0%|
|Progression free survival (95%CI) e||-||3.3 (1.1, 7.2) mo||-||2.2 (1.8, 2.8) mo|
|No response/not evaluable||-||55.6%||39.6% (19/48)||72.9% (35/48)|
a represents best response at any time during therapy
b footnote noted in table but not defined.
c “Only” 5/15 subjects who achieved a MaHR progressed with most of them in excess of 6 months: a progression free survival >8 months in >20% of subjects.
d reported as 4.8% in ‘sustained’ response in submission.
e This outcome could be time to progression as the submission states that “the imatinib group were also quicker to progress”.
Haematological response (HR): § major (MHR), complete (CHR), overall (OHR)
- White Blood Cells = institutional ULN (upper limit of normal)
- Platelets <450,000/mm3
- No blasts of promyelocytes in peripheral blood
- <5% myelocytes plus metamyelocytes in peripheral blood
- Basophils <20% in peripheral blood
- No extramedullary involvement (including no hepatomegaly or splenomegaly)
- Maintained at least 4 weeks after the first documented at =day 14
Cytogenetic response (CyR): Defined as prevalence of Ph+ metaphases on a bone marrow biopsy/aspirate. Major (MCyR)
is defined as having =35% Ph+ cells - divided into two components: 1) a complete cytogenetic
response (CCyR) which is the complete elimination of Ph+ cells (or 0% Ph+ cells),
and 2) a partial cytogenetic response (PCyR [1% to 35% Ph+ cells]).
§ This definition is for complete HR .
The submission asserted that the patients treated with dasatinib showed a greater response than those treated with imatinib. The PBAC was advised that direct comparison of results from the respective studies was not possible as this is a comparison of phase II, single arm, open label, non randomised studies with no common comparator and dissimilar patient populations.
The toxicity results at 12 weeks are shown in the following table.
|Results, % (n/N)||CA180-015 (N=36)||Ottmann (2002) (N=56 )|
|SAE’s (>Grade 2 nonhaematological toxicity)||78% (28/36)||-|
|Pleural Effusion||14% (5/36)||-|
|Febrile Neutropenia||14% (5/36)||8% (4/56)|
|Nausea, Vomiting||-||4% (2/56) 77%, 63% a|
|Elevated liver aminotransferases||-||2% (1/56)|
|Fever, Headache||-||4% (2/56)|
|Cerebral Oedema||-||2% (1/56)|
|Generalised Rash||-||2% (1/56)|
|Lower limb oedema a||-||29%|
|Periorbital oedema a||-||27%|
|Face oedema a||-||11%|
|Muscle cramps a||-||14%|
|Skin rash a||-||11%|
|Myelosuppression (Grade 3-4)|
|Leukopenia||64% (23/36)||68% (38/56)|
|Neutropenia||74% (26/36)||66% (37/56)|
|Anaemia b||44% (16/36)||38% (21/56)|
|Thrombocytopenia||75% (27/36)||48% (27/56)|
|Within 30 days of treatment||86.7% (13/15)|
|Disease progression||26.7% (4/15)|
|Other c||13.3% (2/15)|
|>30 days after treatment||13.3% (2/15)|
|Disease Progression||100% (2/2)|
a Treatment related adverse events with >10% frequency and >grade 2 toxicity reported
only in the text on p200 of the submission (nausea 77%, vomiting 66%)
b anaemia of any grade
c respiratory failure/damaged general status)
SAE = serious adverse events; NR = not reported
Both treatments showed considerable toxicity including myelosuppression. Thrombocytopenia occurred more often with dasatinib patients than imatinib patients.
9. Clinical Claim
The submission claimed that dasatinib had significant clinical
advantages over imatinib but had more toxicity.
See Recommendation and Reasons for PBAC’s views
10. Economic Analysis
A preliminary economic evaluation was not presented.
A modelled economic evaluation was not presented.
The drug costs/patient/year were estimated to be between $75,000 – $105,000
for 140 mg/day for dasatinib and were estimated to be between $ 45,000 – $75,000 for imatinib 400 mg/day and between $75,000 - $105,000 for 600mg to 800mg/day.
11. Estimated PBS Usage and Financial Implications
The cost was estimated to be < $10 million per year.
12. Recommendation and Reasons
The PBAC is sympathetic to the needs of people with Philadelphia
chromosome positive acute lymphoblastic leukaemia (ALL) and
acknowledged that, with some caveats as described below, treatment
with dasatinib may result in clinically meaningful benefits in this
rare condition. However, the Committee rejected the application on
the basis of uncertain cost-effectiveness against the comparator,
imatinib. Although the Committee acknowledges that imatinib is used
in this condition and is an appropriate comparator according to the
2006 PBAC Guidelines as the therapy likely to be replaced in
practice, it is not subsidised by the PBS for this use, nor are
there any data on the dose and cost-effectiveness of imatinib in
ALL, and thus no basis upon which to determine if dasatinib is a
The Committee was unable to confidently conclude that dasatinib is more effective than imatinib in the treatment of adult patients with Philadelphia chromosome positive ALL, who are resistant to, or intolerant of, prior therapy, although the submitted data show this may be the case. A conclusion of superior effectiveness was hampered by the submission’s use of an indirect comparison of two phase II, single arm, open label, non randomised studies (dasatinib: CA1890-015; imatinib: Ottmann et al, 2002). Although the Committee generally accepted the Pre-PBAC Response arguments that the groups in the two studies are adequately comparable in the context of this disease, residual uncertainty about the comparative clinical effectiveness of the two agents remained because of the lack of a common reference.
Although the validity of the primary outcome in the dasatinib trial, major haematological response, as a surrogate for progression of disease is unknown, and the submission did not attempt to quantify the deferred time to progression of disease, which is the aim of therapy – the proportion of patients remaining on treatment at 32 weeks was high, which tends to support the clinical relevance of the surrogate outcomes.
The PBAC considered that the rule of rescue cannot apply to the use of dasatinib in ALL as there are a number of other treatment options available including bone marrow transplant, and salvage chemotherapy, as well as imatinib.
The PBAC considered that the dose of dasatinib was unlikely to exceed 140 mg/day in the majority of patients as the use of higher doses is limited by toxicity.
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 is continuing to work with the PBAC to achieve a suitable listing.