Dasatinib, tablets, 20 mg, 50 mg, 70 mg and 100 mg, Sprycel® - July 2011
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Public Summary Document
Product: Dasatinib, tablets, 20 mg, 50 mg, 70 mg
and 100 mg, Sprycel®
Sponsor: Bristol-Myers Squibb Pty Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission sought to extend the current Authority required
listing to include treatment of newly diagnosed patients in the
chronic phase of chronic myeloid leukaemia (CML) expressing the
Philadelphia chromosome or the transcript, bcr-abl tyrosine kinase,
and who have a primary diagnosis of chronic myeloid
leukaemia.
2. Background
At the March 2007 meeting, the PBAC recommended listing dasatinib
as an Authority Required benefit for the treatment of all phases of
CML in patients not responding to imatinib because of resistance or
intolerance, on a cost-effectiveness basis against imatinib.
Listing was effective from 1 August 2007.
At the same meeting, the PBAC rejected a submission to list
dasatinib as a Section 100 (Highly Specialised Drugs Program)
benefit 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 therapy. The PBAC was unable to form a view on
the cost-effectiveness of the comparator, imatinib, in the
treatment of ALL because of the absence of adequate data.
At the July 2007 meeting, the PBAC recommended the listing of
dasatinib on the PBS for the treatment of patients with ALL,
expressing the Philadelphia chromosome or the transcript bcr-abl
kinase, who are resistant to, or whose disease has relapsed on,
prior therapy. The PBAC considered that the listing of dasatinib in
this small patient group was consistent with the intention of its
‘Rule of Rescue’ guidelines. Listing was effective from
1 December 2007.
3. Registration Status
Dasatinib is TGA registered for the following indications:
- Treatment of adults aged 18 years or over with newly diagnosed Ph+ CML in the chronic phase;
- Treatment of adults aged 18 years or over with chronic, accelerated or myeloid or lymphoid blast phase CML with resistance or intolerance to prior therapy including imatinib;
- Treatment of adults aged 18 years or over with Ph+ ALL with resistance or intolerance to prior therapy.
4. Listing Requested and PBAC’s View
The submission sought a listing consistent with imatinib’s
restriction for the chronic phase of CML and provided the following
abridged restriction:
Authority Required
Initial treatment of patients in the chronic phase of chronic
myeloid leukaemia expressing the Philadelphia chromosome or the
transcript, bcr-abl tyrosine kinase, and who have a primary
diagnosis of chronic myeloid leukaemia.
Continuing treatment of patients who have received initial
treatment with dasatinib mesylate as a pharmaceutical benefit for
the chronic phase of chronic myeloid leukaemia and who have
demonstrated either a major cytogenetic response or less than 1%
bcr-abl level in the blood in the preceding 12 months.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
CML is a rare, myeloproliferative disorder. The use of bone marrow
transplantation/stem cell transplantation is the only potential
curative option for patients with CML. However, this is an option
for very few patients due to patient age, the presence of
co-morbidities and the absence of suitably matched donors.
Currently, imatinib at a dose of 400 mg/day or 600 mg/day is first
line therapy for patients newly diagnosed with CML in the chronic
phase. For patients who are intolerant of imatinib, fail to achieve
a response or lose a previously obtained response with imatinib,
dasatinib and nilotinib are second-line treatment options.
The submission proposed that the place in therapy of dasatinib is
as a first line alternative therapy to imatinib (and possibly
nilotinib) in chronic phase CML.
The submission stated that if dasatinib (and possibly nilotinib)
becomes a first line therapy in chronic phase CML, the treatment
algorithm for patients who fail to achieve a response with
dasatinib is uncertain due to a paucity of evidence for using
imatinib following dasatinib (or nilotinib) treatment
failure.
For PBAC’s view, see Recommendation and
Reasons.
6. Comparator
The submission nominated imatinib 400 mg as the comparator and
imatinib 600 mg as a supportive comparator. Nilotinib 300 mg and
400 mg was also nominated as a supportive comparator (for efficacy
only). The use of imatinib at a dose of 400 mg as the main
comparator was considered appropriate by the PBAC.
7. Clinical Trials
The submission presented two randomised trials comparing dasatinib
100 mg with imatinib 400 mg in adult patients newly diagnosed with
CML in the chronic phase (Study 056, S0325). Additional trials were
presented, one comparing imatinib 400 mg with imatinib 600 mg
(SPIRIT) and one comparing imatinib 400 mg with nilotinib 300 mg
and nilotinib 400 mg twice daily (Saglio).
Patients within the trials were adults newly diagnosed with CML in
the chronic phase for which a transplant was not viable.
The key outcome measures from the trials used by the submission
were: complete cytogenetic response (CCyR), confirmed CCyR (cCCyR;
a CCyR confirmed at two separate occasions at least 28 days apart
by bone marrow cytogenetics); time to CCyR (the date of a CCyR is
the date of the first recorded CCyR); and safety outcomes.
The submission did not provide an assessment of what could be
considered a minimally clinically important difference in either
cCCyR or CCyR.
Details of the published trials presented in the submission are in
the table below.
| Trial ID/ First author | Protocol title / Publication title | Publication citation |
| Direct comparison: Dasatinib v Imatinib 400 mg | ||
| Study 056 | An open label, randomized, multi-centre phase III trial of dasatinib vs. standard dose imatinib (400mg) in the treatment of subjects with newly diagnosed chronic phase Philadelphia chromosome positive chronic myeloid leukaemia. | |
| Kantarijan et al. (2010) | Dasatinib versus imatinib in newly diagnosed chronic phase chronic myeloid leukaemia. | New England Journal of Medicine . 2010 362:2260-2270. |
| Study S0325 | Imatinib Mesylate or Dasatinib in Treating Patients With Chronic Phase Chronic Myelogenous Leukaemia | |
| Radich et al. (2010) | A randomized phase II trial of dasatinib 100 mg vs. imatinib 400 mg in newly diagnosed chronic myeloid leukaemia in chronic phase: the S0325 intergroup trial. | Blood . 2010 116 (Abstract LBA-6) |
| Trials used for indirect comparison: Imatinib 600 mg | ||
| SPIRIT | A Phase III Prospective Randomized Comparison of Imatinib at a Dose of 400mg in Combination With Peg-Interferon-alpha2a (Peg-IFNa2a) or Cytarabine (Ara-C)Versus Imatinib at a Dose of 600mg Versus Imatinib a Dose of 400mg for Previously Untreated Chronic Myelogenous Leukaemia (CML) in Chronic Phase | |
| Predhomme et al. (2010) | Imatinib plus Peginterferon Alfa-2a in Chronic Myeloid Leukaemia. | New England Journal of Medicine 2010 363(26): 2511-2521 |
| Trials used for indirect comparison: Nilotinib 300 mg or 400 mg | ||
| Saglio et al. (2010) | A Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukaemia in Chronic Phase (CML-CP) (ENESTnd). | |
| Nilotinib versus imatinib for newly diagnosed chronic myeloid leukaemia. | New England Journal of Medicine . 2010 362(24): 2251-2259. | |
8. Results of Trials
Dasatinib vs. imatinib 400 mg
For Study 056, the cCCyR (one of the primary outcomes) at 12 months for imatinib 400
mg was 66.2% and 76.8% for dasatinib 100 mg daily. The PBAC noted that from a meta-analysis
of the CCyR results from Study 056 and S0325 (using the modified ITT population),
dasatinib is associated with a statistically significant increase in the proportion
of those who achieve a CCyR when compared with imatinib 400 mg (RR = 1.19, 95% CI:
1.06, 1.33; p=0.002). However, progression free survival (PFS) and overall survival
(OS) outcomes were too immature in either trial to draw any meaningful comparisons
between dasatinib and imatinib 400 mg.
The following table provides the cCCyR by 12 months, by 18 months and the within 12
month results from Study 056. Additionally, results from the 056 and S0325 trials,
and the meta-analysis results for CCyR at 12 months, are also included.
Results across the direct randomised trials
| Trial | Dasatinib(%) | Imatinib 400 mg(%) | RR (95% CI) | OR (95% CI) | RD(95% CI) |
| cCCyR | |||||
| 056 12 mth a | 199/259 (76.8%) | 172/260 (66.2%) | 1.16 (1.04, 1.30) | 1.70 (1.15, 2.50) | 0.11 (0.03, 0.18) |
| 056 12 mth b | 199/259 (76.8%) | 177/260 (68%) | 1.13 (1.01, 1.26) | 1.56 (1.05, 2.29) | 0.09 (0.01, 0.16) |
| 056 18 mth c | 202/259 (78.0%) | 182/260 (70.0%) | 1.11 (1.01, 1.24) | 1.52 (1.02, 2.26) | 0.08 (0.01, 0.16) |
| CCyR at 12 mths | |||||
| 056 | 216/259 (83.4%) | 186/260 (71.5%) | 1.17 (1.06, 1.28) | 2.00 (1.31, 3.05) | 0.12 (0.05, 0.19) |
| S0325 d | 55/123 (45%) | 40/123 (33%) | 1.34 (1.00,1.90) | 1.68 (1.00, 2.82) | 0.12 (0.00, 0.24) |
| Pooled e result | 271/382 (70.9%) | 226/383 (59.0%) | 1.19 (1.06, 1.33) | 1.86 (1.34, 2.59) | 0.12 (0.6, 0.18) |
| Chi-square heterogeneity (P) I 2 statistic | 1.09 (0.30) 8.4% | 0.26 (0.61) 0% | 0.00 (0.96) 0% | ||
| S0325 f | 55/67 (82%) | 40/58 (69%) | 1.19 (0.97, 1.46) | 2.06 (0.89, 4.76) | 0.13 (-0.02, 0.28) |
Dasat = Dasatinib; Imat 400 mg = Imatinib 400 mg; RR = relative risk; OR = odds ratio;
RD = relative difference; cCCyR = confirmed complete cytogenetic response; CCyR =
complete cytogenetic response; mth = months
a results by 12 months
b results for achieving response within 12 months, note confirmation of response via
2nd test performed at any time including > 12mths
c results by 18 months
dmodified intention to treat population, disregards 7 patients randomised but not treated
e pooled results of CCyR at 12 months from Studies 056 and S0325 (modified intention
to treat population)
f results for evaluable patients i.e. those for which cytogenetic data available
Statistically significant results are shown in bold text.
The dasatinib arm within Study 056 had a higher proportion of Asians and females compared
with the imatinib 400 mg arm. The PBAC noted that a subgroup analysis conducted by
Ogura et al (Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 4484) for Study 056 of Japanese
patients treated with dasatinib or imatinib 400 mg achieved a greater cCCyR (90% for
dasatinib and 70% for imatinib) than that observed in the overall patient group (77%
for dasatinib and 66% for imatinib). The higher proportion of Asians within the dasatinib
arm may have biased the results in favour of dasatinib.
Study 056 found no statistically significant differences in the number of patients
who achieve an MCyR (defined as the sum of patients who achieve a CCyR or partial
CyR). Furthermore, both Study 056 and S0325 reported that imatinib 400 mg is associated
with a non-statistically significant increase in the number of patients with a complete
haematological response compared with dasatinib.
The median time to response for dasatinib was reported within Study 056 as 3.1 months
(95% CI: 3.0, 3.1) and 5.5 months (95% CI: 3.3, 5.7) for imatinib 400 mg. Patients
receiving dasatinib were associated with a statistically significant faster rate (2.4
months earlier) of achieving a cCCyR than those receiving imatinib 400 mg (HR 1.5,
p<0.0001).
An independent search conducted during the evaluation retrieved no relevant studies
that have explored the clinical significance or the impact on PFS or OS for achieving
CCyR 2.4 months earlier.
Indirect comparisons:
The table below summarises the main results from the indirect comparisons of dasatinib
100 mg once daily versus imatinib 600 mg once daily and versus nilotinib 300 mg twice
daily and nilotinib 400 mg twice daily for CCyR within 12 months.
Summary of results of the indirect comparison, based on the proportion achieving CCyR within 12 months
| Trial ID | Trials of Dasatinib | Trial of Imatinib 600 mg | Indirect RR c (95% CI) | ||||
| RR a (95% CI) | Dasat n/N (%) | Imat 400 n/N (%) | Imat 400 n/N (%) | Imat 600 n/N (%) | RR b (95% CI) | ||
| 056 | 1.17 (1.06, 1.28) | 216/259 (83%) | 186/260 (72%) | – | |||
| S0325 | 1.34 (1.00, 2.82) | 55/123 (45%) | 40/123 (33%) | – | |||
| Pooled d | 1.19 (1.06,1.33) | 261/382 (68%) | 226/383 (59%) | – | – | ||
| SPIRIT Imat 600 | 92/159 (58%) | 104/160 (65%) | 1.12 (0.94, 1.34) | ||||
| Indirect comparison dasatinib vs. Imatinib 600 mg | 1.06 (0.86, 1.31) | ||||||
| Trial ID | Trials of Dasatinib | Trial of Nilotinib 300 mg | Indirect RR c (95% CI) | ||||
| RR a (95% CI) | Dasat n/N (%) | Imat 400 n/N (%) | Imat 400 n/N (%) | Nilot 300 n/N (%) | RR b (95% CI) | ||
| Saglio Nilot 300 | 184/283 (55%) | 226/282 (80%) | 1.23 (1.11, 1.37) | ||||
| Indirect comparison dasatinib vs. nilotinib 300 mg e | 0.95 (0.83, 1.10) | ||||||
| Trial ID | Trials of Dasatinib | Trial of Nilotinib 400 mg | Indirect RR c (95% CI) | ||||
| RR a (95% CI) | Dasat n/N (%) | Imat 400 n/N (%) | Imat 400 n/N (%) | Nilot 400 n/N (%) | RR b (95% CI) | ||
| Saglio Nilot 400 | 184/283 (55%) | 219/281 (78%) | 1.20 (1.08, 1.33) | ||||
| Indirect comparison dasatinib vs. nilotinib 400 mg e | 0.98 (0.85, 1.12) | ||||||
CI = confidence interval; RR = relative risk; Dasat = dasatinib; Imat = Imatinib;
Nilot = Nilotinib; Bold = statistically significant; CCyR = complete cytogenetic response
a dasatinib over imatinib 400 mg
b comparator over imatinib 400mg
c inferred as comparator over dasatinib
d pooled using the random effects model
e S0325 was excluded from this indirect comparison
The PBAC noted that no statistically significant differences were found in the indirect
comparisons for CCyR when comparing dasatinib versus imatinib 600 mg (RR 1.06, 95%CI:
0.86, 1.31) and for the comparison of dasatinib versus nilotinib 300 mg (RR 0.95,
95%CI: 0.83, 1.10) and nilotinib 400 mg (RR 0.98, 95%CI: 0.85, 1.12). Again, the rates
of PFS and OS were too immature to interpret with any meaning and no claim was made
regarding the comparative efficacy of dasatinib compared with imatinib 600 mg or nilotinib
on these outcomes.
The results of the indirect comparisons may have been biased in favour of dasatinib
from the disproportional representation of Asian patients in the included trials.
As previously discussed, the Asian subgroup within Study 056 showed a greater cCCYR
response compared to the overall population. There was a higher proportion of Asian
patients in Study 056 compared to the Saglio trial, and in particular, a greater disproportion
of Asians within the dasatinib group compared to the common reference (imatinib 400
mg), within Study 056.
The table below presents a summary of the adverse events in Study 056 and S0325.
Summary of select adverse events in the direct randomised trials at 12 months
| Trial | Dasatinib (%) | Imatinib 400 (%) | RR (95% CI) |
| 056 | n = 258 | n = 258 | |
| All Drug-related grade 3/4 AEs | 78 (30%) | 61 (24%) | 1.28 (0.96, 1.70) |
| Thrombocytopenia (grade 3/4) | 34 (13%) | 21 (8%) | 1.62 (0.97, 2.71) |
| Pleural effusion any grade | 26 (10%) | 0 | 52.0 (3.14, 849) a |
| Drug-related AEs any grade leading to discontinuation | 13 (5%) | 11 (4%) | 1.18 (0.54, 2.59) |
| All deaths | 10 (4%) | 6 (2%) | 1.67 (0.62, 4.52) |
| S0325 | n = 123 | n = 123 | |
| Pleural effusion any grade | 14 (11%) | 2 (2) | 7.00 (1.63, 30.15) |
| Non-haematological (grade 3/4) | 44 (36%) | 21 (17) | 2.10 (1.33, 3.31) |
| Thrombocytopenia (grade 3/4) | 22 (18%) | 10 (8) | 2.20 (1.09, 4.45) |
| Drug related AEs any grade leading to discontinuation | 18 (15%) | 13 (11%) | 1.39 (0.71, 2.70) |
| Number died | 3 (2%) | 4 (3%) | 0.75 (0.17, 3.28) |
AE = adverse event; SAE = severe adverse event; Bold = statistically significant
a imputing 0.5 case for both treatment arms
Overall, dasatinib was associated with a statistically significant increase in the
incidence of grade 3/4 thrombocytopenia and pleural effusion (any grade) compared
to imatinib 400 mg. Comparatively, imatinib 400 mg appeared to be associated with
an increase in adverse events (AEs) any grade, with a statistically significant increase
in any grade nausea, myalgia, vomiting, muscle spasms, eyelid oedema, drug-related
fluid retention, superficial oedema and generalised oedema.
The PBAC noted that there appeared to be no statistically significant difference in
grade 3/4 adverse events between dasatinib and imatinib 600 mg.
Dasatinib appeared to be associated with statistically significantly more grade 3/4
haematological adverse events and any grade non-haematological adverse events compared
to nilotinib 300 mg and 400 mg.
9. Clinical Claim
Dasatinib vs. Imatinib 400 mg
The submission described dasatinib as superior in terms of
comparative effectiveness and having a different safety profile
compared with imatinib 400 mg/day.
The PBAC accepted that although dasatinib is superior to imatinib
400 mg daily based on CCyR, the Committee did not accept that this
predicts superiority for progression free survival or overall
survival. The PBAC also did not accept the claim regarding the
safety profile. The PBAC noted that imatinib 400 mg is associated
with more drug related AEs of any grade, but that dasatinib is
associated with a greater proportion of Grade 3 or 4 AEs,
indicating that dasatinib might be inferior in terms of safety
compared with imatinib 400 mg.
Dasatinib vs. Imatinib 600 mg
The submission described dasatinib as similar and at least no worse
in terms of comparative effectiveness and having an equivalent
safety profile compared with imatinib 600 mg.
Dasatinib vs. Nilotinib 300 mg or 400 mg
The submission described dasatinib as no worse in terms of
comparative effectiveness and having a different safety profile
compared with nilotinib 300 mg or 400 mg.
The PBAC accepted that dasatinib is no worse in terms of
comparative effectiveness compared with imatinib 600 mg or
nilotinib 300 mg or 400 mg as the results of the indirect
comparisons support the claim for non-inferior efficacy with
respect to surrogate outcomes but noted that the point estimate for
dasatinib, 1.17 (1.06, 1.28) is less than nilotinib 1.23 (1.11,
1.37).
The PBAC considered the claim of equivalent safety of dasatinib
over imatinib 600 mg was uncertain as there was no pre-specified
inferiority margin and the comparison was indirect. The claim of a
different safety profile compared with nilotinib 300 mg or 400 mg
was not considered appropriate, as dasatinib was associated with
more adverse events.
10. Economic Analysis
Dasatinib versus Imatinib 400 mg
A trial-based economic evaluation was presented, based on the
direct randomised trial (Study 056).
The patient population in the economic model presented in the
submission was adult patients newly diagnosed with CML in the
chronic phase, and this was directly derived from the Trial 056.
The submission did not modify the patient data, because it stated
that the patients in the trial are likely to be similar to the
proposed PBS population. This may not have been appropriate given
the exclusion of patients with cardiovascular or other significant
co-morbidities, the lower mean age of participants and the
potential over-representation of Asians within Study 056 who may
have better CCyR outcomes compared to the general population.
A stepped analysis was presented in which health outcomes were
first presented as additional patients with a cCCyR within 13
months (Step 1), additional time with cCCyR (Step 2) and then as
quality-adjusted life years gained (Step 3). The results for
additional time with response and time with experiencing an AE were
directly estimated from Trial 056, while the quality-adjusted life
years (QALY) gained uses transformation steps relying on quality of
life estimates derived from the literature.
The time horizon in the modelled economic evaluation was 13 months.
The analysis did not consider longer term costs or outcomes since
it was assumed that the rates of progression to the accelerated
blast phases of disease, loss of response or survival did not
differ between the treatment groups. This may not have been
appropriate as drug treatment is over a patient’s remaining
lifetime as well as the differing safety profiles of dasatinib and
imatinib 400 mg with the potential for associated adverse event
treatment costs to differ over the course of drug treatment.
The PBAC considered that there was no basis for the
cost-effectiveness analysis based on its findings regarding
comparative effectiveness and safety.
The submission stated that the use of dasatinib in place of
imatinib in the treatment of patients with CML in chronic phase is
associated with an incremental cost-effectiveness ratio (ICER) in
the range of $15,000 - $45,000 per QALY gained. The ICER was
uncertain as there were uncertainties about the use of dasatinib
and imatinib within the Australian PBS population, the estimated
utility values in both treatment groups for with and without
response, the disutility estimates for adverse events, the costs of
treating pleural effusion within Australia, the future costs of
drug therapy post 13 months and the cost of treating AEs post 13
months.
Sensitivity analyses indicated that the model was most sensitive to
definition of response (with the attached utility), choice of AEs
included within the model, the time horizon of the model, and
uncertainty in the actual dose of dasatinib and imatinib.
For the sensitivity analyses assessing the impact of the time
horizon on the ICER, a mortality rate was not applied and there was
no change in the incremental QALY gain. As such, these were not
genuine sensitivity analyses as only the drug cost changed.
Indirect comparison of Dasatinib versus Imatinib 600 mg
In addition to the cost effectiveness analysis presented against
imatinib 400 mg, the submission also presented a cost-minimisation
analysis to imatinib 600 mg, based on the claim of non-inferiority
of dasatinib to imatinib 600 mg.
Equi-effective doses of dasatinib 100 mg to imatinib 600 mg were
assumed.
The resulting annual cost difference between dasatinib treatment
and imatinib 600 mg treatment was very sensitive to the assumed
equi-effective doses. The point where dasatinib 100 mg/day becomes
more expensive annually compared with imatinib is at an average
daily dose of imatinib of just under 599 mg, which is higher than
the 590 mg/day median imatinib dose reported in the SPIRIT trial.
Including the costs for treating pleural effusion would add
additional costs for dasatinib, resulting in imatinib being less
expensive than dasatinib (based on the price to pharmacist).
The rationale for presenting the cost minimisation of dasatinib
versus imatinib 600 mg was based on the premise that Australian
patients are initiated on a dose of either 400 mg or 600 mg. This
may not have been appropriate, as the recommended starting dose in
the Australian PI for patients with chronic phase CML is imatinib
400 mg.
The PBAC accepted that dasatinib is non-inferior to imatinib 400 mg
and nilotinib 300 mg or 400 mg and considered that a listing based
on cost-minimisation with imatinib 400 mg was more appropriate with
the inclusion of cost-offsets for managing the increased adverse
effects, particularly the pleural effusions which are associated
with dasatinib.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely total number of patients
treated to be less than 10,000 in year 5.
The submission estimated a total net cost to the PBS of less than
$10 million in year 5.
12. Recommendation and Reasons
The PBAC recommended listing dasatinib on the PBS as an Authority
Required benefit for first-line treatment of chronic phase
Philadelphia positive chronic myeloid leukaemia on a
cost-minimisation basis compared with imatinib 400 mg. The PBAC
considered the equi-effective doses to be dasatinib 93.88 mg and
imatinib 395.77 mg based on the average doses from Study 056.
The PBAC noted that the availability of dasatinib as first-line
therapy for CML would change the current treatment algorithm. The
PBAC considered that it was unlikely that imatinib would be used
after failure of dasatinib due to resistance as there is little
evidence for this use. It is possible that imatinib might be used
after dasatinib in cases of intolerance to dasatinib but the most
likely scenario after failure of dasatinib is second-line
nilotinib. The PBAC considered that the PBS listings for TKIs in
second-line setting would need reviewing due to the change in the
treatment algorithm. In future, it will be critical to distinguish
between the need to change TKI because of intolerance and because
of inadequate response. Second-line therapy after dasatinib should
refer to the situation where there has been failure of response and
should not include failure due to toxicity. Changes between TKIs
should be possible in first–line therapy where there is
intolerance to the first initiated TKI. The PBAC noted that further
discussion will be needed with the sponsor and Stakeholders before
finalisation of the restrictions for first and second-line
treatment settings.
The PBAC noted that the submission presented two randomised trials
comparing dasatinib 100 mg with imatinib 400 mg in adult patients
newly diagnosed with CML in the chronic phase (Study 056, S0325)
and described dasatinib as superior in terms of comparative
effectiveness and having a different safety profile compared with
imatinib 400 mg. For Study 056, the cCCyR (one of the primary
outcomes) by 12 months for imatinib 400 mg was 66.2% and 76.8% for
dasatinib 100 mg daily. The PBAC noted that from a meta-analysis of
the CCyR results from Study 056 and S0325 (using the modified ITT
population), dasatinib is associated with a statistically
significant increase in the proportion of those who achieve a CCyR
when compared with imatinib 400 mg (RR = 1.19, 95% CI: 1.06, 1.33;
p=0.002). However, progression free survival (PFS) and overall
survival (OS) outcomes were too immature in either trial to draw
any meaningful comparisons between dasatinib and imatinib 400
mg.
The PBAC noted that there was no statistically significant
difference between dasatinib and imatinib 400 mg with regards to
complete haematological response and it is uncertain whether the
increase in CCyR (a surrogate outcome) found for dasatinib versus
imatinib 400 mg, without a difference in MCyR, would result in an
improvement in final outcomes, PFS and OS. Based on this, the PBAC
accepted that although dasatinib was superior to imatinib 400 mg
daily based on CCyR, the Committee did not accept that this
predicts superiority for PFS or OS. The PBAC also did not accept
the claim regarding the safety profile. The PBAC noted that
imatinib 400 mg was associated with more drug related AEs of any
grade, but that dasatinib was associated with a greater proportion
of Grade 3 or 4 AEs, indicating that dasatinib might be inferior in
terms of safety compared with imatinib 400 mg. Consequently, the
PBAC was not prepared to recommend the listing of dasatinib on a
cost effectiveness basis compared with imatinib 400 mg.
Indirect comparisons of dasatinib 100 mg once daily versus imatinib
600 mg once daily and versus nilotinib 300 mg twice daily and
nilotinib 400 mg twice daily for CCyR within 12 months were
presented in the submission. The PBAC noted that no statistically
significant differences were found in the indirect comparisons for
CCyR when comparing dasatinib versus imatinib 600 mg (RR 1.06,
95%CI: 0.86, 1.31) and for the comparison of dasatinib versus
nilotinib 300 mg (RR 0.95, 95%CI: 0.83, 1.10) and nilotinib 400 mg
(RR 0.98, 95%CI: 0.85, 1.12). Again, the rates of PFS and OS were
too immature to interpret with any meaning and no claim was made
regarding the comparative efficacy of dasatinib compared with
imatinib 600 mg or nilotinib on these outcomes.
The PBAC accepted that dasatinib is no worse in terms of
comparative effectiveness compared with imatinib 600 mg or
nilotinib 300 mg or 400 mg as the results of the indirect
comparisons support the claim for non-inferior efficacy with
respect to surrogate outcomes but noted that the point estimate for
dasatinib, 1.17 (1.06, 1.28) is less than nilotinib 1.23 (1.11,
1.37). However, dasatinib appears to be associated with
statistically significantly more grade 3/4 haematological adverse
events and any grade non-haematological adverse events compared to
nilotinib 300 mg and 400 mg. Therefore, the claim of a different
safety profile compared with nilotinib 300 mg or 400 mg was not
considered appropriate, as dasatinib is associated with more
adverse events.
The PBAC noted that there appears to be no statistically
significant difference in grade 3/4 adverse events between
dasatinib and imatinib 600 mg. However, the claim of equivalent
safety of dasatinib over imatinib 600 mg is uncertain as there is
no pre-specified inferiority margin and the comparison is
indirect.
The PBAC considered that there was no basis for the
cost-effectiveness analysis based on the above conclusions.
However, the PBAC accepted that dasatinib is non-inferior to
imatinib 400 mg and nilotinib 300 mg or 400 mg and considered that
a listing based on cost-minimisation with imatinib 400 mg was more
appropriate with the inclusion of cost-offsets for managing the
increased adverse effects, particularly the pleural effusions which
are associated with dasatinib.
The PBAC acknowledged and noted the consumer comments received in
its consideration of dasatinib.
Dasatinib is not included on the PBS medicines for prescribing by
nurse practitioners.
Recommendation: DASATINIB, tablet, 20 mg,
50 mg, 70 mg, 100 mg
Amend the current restriction as follows:
Restriction: To be finalised
Maximum quantity: 60 (20 mg, 50 mg, 70 mg)
30 (100 mg)
Repeats: 5 (all strengths)
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 comment.
