Nilotinib, capsule, 200 mg, Tasigna, March 2008
Public summary document for Nilotinib, capsule, 200 mg, Tasigna, March 2008
Page last updated: 04 July 2008
Public Summary Documents
Product: Nilotinib, capsule, 200 mg, Tasigna
Sponsor: Novartis Pharmaceuticals Australia Pty Limited
Date of PBAC Consideration: March 2008
1. Purpose of Application
The submission sought a Section 85 Authority Required listing for the treatment of chronic phase (CP) and accelerated phase (AP) Philadelphia chromosome positive chronic myeloid leukaemia (CML) in adult patients intolerant of, or resistant to at least one prior therapy including imatinib.
2. Background
This was the first time nilotinib had been considered by the PBAC.
3. Registration Status
Nilotinib was registered by the TGA on 17 January 2008 for the treatment of adults with chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukaemia (CML) resistant to, or intolerant of, prior therapy including imatinib.
4. Listing Requested and PBAC’s View
NOTE:
Any queries concerning the arrangements to prescribe nilotinib may be directed to
Medicare Australia on 1800 700 270 (hours of operation 8 a.m. to 5 p.m. EST Monday
to Friday). Prescribing information (including Authority Application forms) is available
on the Medicare Australia website at www.medicareaustralia.gov.au.
Any queries concerning patients who are enrolled on the Nilotinib Compassionate Program
may be directed to Medicare Australia on 1800 700 270 (hours of operation 8 a.m. to
5 p.m. EST Monday to Friday).
Applications for authority to prescribe nilotinib should be forwarded to:
Medicare Australia
Prior Written Approval of Specialised Drugs
Reply Paid 9826
GPO Box 9826
HOBART TAS 7001
Authority Required
Initial treatment, as the sole PBS-subsidised therapy, of a patient with chronic myeloid
leukaemia in chronic or accelerated phase bearing the Philadelphia chromosome or expressing
the transcript, BCR-ABL, who has active leukaemia (as defined by presence on current
pathology assessments of either the Philadelphia chromosome on cytogenetic or FISH
analysis, or the presence of the transcript BCR-ABL and morphological evidence of
leukaemia) and who has failed an adequate trial of imatinib or has failed dasatinib
or other second-line therapy (after prior imatinib treatment).
Failure of an adequate trial of imatinib is defined as:
(i) Lack of response to initial imatinib therapy, defined as either:
- failure to achieve a haematological response after a minimum of 3 months therapy with imatinib for patients initially treated in chronic phase; o
- failure to achieve any cytogenetic response after a minimum of 6 months therapy with imatinib for patients initially treated in chronic phase as demonstrated on bone marrow biopsy by presence of greater than 95% Philadelphia chromosome positive cells; or
- failure to achieve a major cytogenetic response or a peripheral blood BCR-ABL level of less than 1% after a minimum of 12 months therapy with imatinib;
OR
(ii) Loss of a previously documented major cytogenetic response (demonstrated by the
presence of greater than 35% Ph positive cells on bone marrow biopsy), during ongoing
imatinib therapy;
OR
(iii) Development of accelerated phase in a patient previously prescribed imatinib
for the chronic phase of chronic myeloid leukaemia.
Accelerated phase is defined by the presence of 1 or more of the following:
(1) Percentage of blasts in the peripheral blood or bone marrow greater than or equal
to 15% but less than 30%; or
(2) Percentage of blasts plus promyelocytes in the peripheral blood or bone marrow
greater
than or equal to 30%; or
(3) Peripheral basophils greater than or equal to 20%; or
(4) Progressive splenomegaly to a size greater than or equal to 10 cm below the left
costal margin to be confirmed on 2 occasions at least 4 weeks apart, or a greater
than or equal to 50% increase in size below the left costal margin over 4 weeks; or
(5) Karyotypic evolution (chromosomal abnormalities in addition to a single Philadelphia
chromosome).
OR
(iv) Disease progression (defined as ≥ 50% increase in peripheral white blood cell
count, blast count, basophils or platelets) during first-line imatinib therapy in
patients with accelerated phase chronic myeloid leukaemia: or
(v) Detection of a mutation in BCR-ABL (L248V, G250E, Q252H/R, Y253H/F, E255K/V, H396P/R,
and D276G) that infers high level imatinib resistance. (Patients with these mutations
but without active leukaemia, will not be approved); or
(vi) Grade 3 or 4 toxicity that is imatinib related or Grade 2 adverse events related
to imatinib therapy that persisted for greater than 1 month or that recurred more
than three times despite optimal supportive care.
Failure of dasatinib therapy after imatinib is defined as:
(i) Lack of response to dasatinib therapy, defined as either:
- failure to achieve a haematological response after a minimum of 3 months therapy with dasatinib for patients initially treated in chronic phase; or
- failure to achieve any significant cytogenetic response after a minimum of 6 months therapy with dasatinib for patients initially treated in chronic phase or
OR
(ii) Loss of a previously documented major cytogenetic response (demonstrated by the
presence of greater than 35% Ph positive cells on bone marrow biopsy), during ongoing
dasatinib therapy;
OR
(iii) Development of accelerated phase in a patient previously prescribed dasatinib
for the chronic phase of chronic myeloid leukaemia.
Accelerated phase is defined by the presence of 1 or more of the following:
(1) Percentage of blasts in the peripheral blood or bone marrow greater than or equal
to 15% but less than 30%; or
(2) Percentage of blasts plus promyelocytes in the peripheral blood or bone marrow
greater
than or equal to 30%; or
(3) Peripheral basophils greater than or equal to 20%; or
(4) Progressive splenomegaly to a size greater than or equal to 10 cm below the left
costal margin to be confirmed on 2 occasions at least 4 weeks apart, or a greater
than or equal to 50% increase in size below the left costal margin over 4 weeks; or
(5) Karyotypic evolution (chromosomal abnormalities in addition to a single Philadelphia
chromosome).
OR
(iv) Disease progression (defined as ≥ 50% increase in peripheral white blood cell
count, blast count, basophils or platelets) during dasatinib therapy in patients with
accelerated phase chronic myeloid leukaemia: or
(vi) Grade 3 or 4 toxicity that is dasatinib related or Grade 2 adverse events related
to dasatinib therapy that persisted for >1 month or that recurred more than three
times despite optimal supportive care.
Applications for authorisation must be in writing and must include:
(a) a completed authority prescription form; and
(b) a completed Chronic Myeloid Leukaemia Nilotinib PBS Authority Application –Supporting
Information Form,
(c) a signed patient acknowledgement
(d) a bone marrow biopsy pathology report demonstrating the patient has active chronic
myeloid leukaemia, either manifest as cytogenetic evidence of the Philadelphia chromosome,
or morphological evidence of chronic myeloid leukaemia plus qualitative RT-PCR evidence
of BCR-ABL transcript. (The date of the relevant pathology report needs to be provided);
and
(e) a copy of the current confirming pathology report(s) from an Approved Pathology
Authority or details of the dates of assessment in the case of progressive splenomegaly
or extramedullary involvement or details of prolonged Grade 2, or Grade 3 or 4 imatinib
or dasatinib related toxicity.
NOTE:
Nilotinib will only be subsidised for patients with chronic myeloid leukaemia who
are not receiving concomitant PBS-subsidised imatinib mesylate, dasatinib or interferon
alfa therapy. Patients should be commenced on a dose of nilotinib of 400 mg twice
daily. Continuing therapy is dependent on patients demonstrating a major cytogenetic
response to nilotinib therapy or a peripheral blood BCR-ABL level of less than 1%
at 12 monthly intervals, irrespective of the daily nilotinib dose received.
Authority Required
Continuing treatment, as the sole PBS-subsidised therapy, of a patient who has received
initial treatment with nilotinib as a pharmaceutical benefit for chronic myeloid leukaemia,
and who has demonstrated either a major cytogenetic response, or less than 1% BCR-ABL
level in the blood, to nilotinib in the preceding 12 months.
Applications for authorisation must be in writing and must include:
(1) a completed authority prescription form; and
(2) a completed Chronic Myeloid Leukaemia Nilotinib Authority Application Form for
continuing treatment; and
(3) demonstration of continued response to treatment as evidenced by either:
(a) major cytogenetic response [see Note explaining definitions of response]. Where
this has been supplied within the previous 12 months, only the date of the relevant
pathology report need be provided; or
(b) a peripheral blood level of BCR-ABL of less than 1% on the international scale
[see Note explaining definitions of response]. Where this has been supplied within
the previous 12 months, only the date of the relevant pathology report need be provided.
NOTE:
Definitions of response.
A major cytogenetic response is defined as less than 35% Philadelphia positive bone
marrow cells.
A bone marrow or peripheral blood BCR-ABL level of less than 1% on the international
scale (Blood 108: 28-37, 2006) also indicates a response, at least the biological
equivalent of a major cytogenetic response.
Authority approval requirements.
For the purposes of assessing response to PBS-subsidised treatment with nilotinib,
either cytogenetic analysis indicating the number of Philadelphia positive [t (9;22)]
cells in the bone marrow measured by standard karyotyping, or quantitative PCR indicating
the relative level of BCR-ABL transcript in the peripheral blood using the international
scale, must be submitted. For bone marrow analyses, where the standard karyotyping
is not informative for technical reasons, a cytogenetic analysis performed on the
bone marrow by the use of fluorescence in situ hybridisation (FISH) with BCR-ABL specific
probe must be submitted. The cytogenetic or peripheral blood quantitative PCR analyses
must be submitted as follows:
(i) between 10 and 12 months of the commencement of treatment with nilotinib, at which
time patients in whom a major cytogenetic response or peripheral blood BCR-ABL level
of less than 1% has been demonstrated may receive authorisation for a further 12 months
of treatment; and
(ii) at no greater than 12 month intervals thereafter, to demonstrate that the major
cytogenetic response or peripheral blood BCR-ABL level of less than 1% has been sustained.
For each authority application where eligibility for continuing PBS-subsidised treatment
is to be demonstrated, a copy of the cytogenetic analysis indicating the number of
Philadelphia positive [t (9;22)] cells in the bone marrow measured by standard karyotyping,
or a copy of the quantitative PCR indicating the relative level of BCR-ABL transcript
in the peripheral blood using the international scale, must be submitted as described
in (i) and (ii) above. For bone marrow analyses, where the standard karyotyping conducted
at the time of application is not informative, a copy of a cytogenetic analysis conducted
on the bone marrow using FISH with BCR-ABL specific probe must be submitted with the
authority application. A copy of the non-informative standard karyotype analysis must
be included with the authority application. Where a patient has previously received
PBS-subsidised treatment with nilotinib, no approval will be granted for PBS-subsidised
re-treatment where that patient has at any time failed to meet the criteria for continuing
treatment.
See recommendations and Reasons for PBAC’s view.
5. Clinical Place for the Proposed Therapy
Nilotinib will provide a second-line treatment option for patients who are resistant or intolerant to imatinib mesylate.
6. Comparator
The submission nominated the main comparator as dasatinib 70 mg twice a day and high-dose imatinib (600 to 800 mg per day) as the comparator in the imatinib resistant population, as shown below.
|
Disease and patient setting |
Relevant comparator |
|---|---|
|
Chronic Phase CML |
|
|
- Imatinib resistant |
Dasatinib 70 mg bd and imatinib 800 mg/day |
|
- Imatinib intolerant |
Dasatinib 70 mg bd |
|
- Imatinib and dasatinib resistant or intolerant |
Placebo (or in reality remaining on previous ineffective therapy i.e. dasatinib) |
|
Accelerated Phase CML |
|
|
- Imatinib resistant |
Dasatinib 70 mg bd |
|
- Imatinib intolerant |
Dasatinib 70 mg bd |
|
- Imatinib and dasatinib resistant or intolerant |
Placebo (or in reality remaining on previous ineffective therapy i.e. dasatinib) |
This was accepted by the PBAC as appropriate.
7. Clinical Trials
CML-CP:
The comparison of nilotinib and dasatinib was based on data from imatinib resistant
patients of one single-arm open-label trial (Study 2101) with 120 days update for
nilotinib and one open-label single-arm trial with dasatinib (START C) with a similar
median duration and two supplementary single arms of randomised dasatinib trials (START
R and the 2 x 2 Study).
The comparison of nilotinib and high-dose imatinib was based on one single-arm open-label
trial with nilotinib and high-dose imatinib data collected during imatinib clinical
trials and published case series of the use of high-dose imatinib.
The treatment algorithm for nilotinib included use after failure of imatinib 800 mg.
In study 2101, 70% of patients enrolled were reported as imatinib resistant but as
fewer than 70% of all patients had the maximal imatinib dose the actual proportion
of patients in the study with imatinib resistance is unknown.
Characteristics of patients in the nilotinib and dasatinib studies are presented in
the table below.
Characteristics of patients in the nilotinib and dasatinib studies
|
Total |
Study 2101-CP |
Study 2101-CP |
START-C total33 |
START-C imatinib resistant3 |
START-C imatinib intolerant3 |
START-R4 (dasatinib patients) |
2x2 |
2x2 |
2x2 140 mg qd5 |
2x270 mg bd5 |
|
|---|---|---|---|---|---|---|---|---|---|---|---|
|
N |
2801 |
194 |
85 |
186 |
127 |
59 |
101 |
55 |
52 |
56 |
52 |
|
Median age |
58.01 |
58 |
59 |
59 (24-79) |
59 (24-79) |
59 (24-79) |
51 (24-85) |
NR |
NR |
NR |
NR |
|
Male gender (%) |
51.41 |
56 |
39 |
46 |
47 |
44 |
52 |
NR |
NR |
NR |
NR |
|
Median duration of CML (months) |
65.21 |
NR |
NR |
64 |
77 |
26 |
64 |
55 |
52 |
56 |
52 |
|
Proportion of imatinib resistance |
69.31 |
NR |
NR |
68% |
100 |
0 |
100 |
74 |
74 |
73 |
75 |
|
Prior highest imatinib dose |
|||||||||||
|
> 400 mg |
NR |
NR |
NR |
NR |
NR |
NR |
64 |
||||
|
< 600 mg |
27.51 |
NR |
NR |
48 |
27 |
93 |
NR |
64 |
66 |
66 |
66 |
|
≥ 600 mg- < 800 mg |
32.51 |
72.1 |
52 |
73 |
7 |
NR |
36 |
34 |
33 |
33 |
|
|
≥ 800 mg |
39.61 |
||||||||||
|
missing |
0.41 |
NR |
NR |
0 |
0 |
0 |
NR |
0 |
0 |
<1 |
<1 |
|
Prior therapy |
|||||||||||
|
Allogenic or stem cell transplant |
82 |
NR |
NR |
9 |
10 |
7 |
7 |
6 |
8 |
3 |
4 |
|
Hydroxyurea |
8322 |
NR |
NR |
42 |
50 |
25 |
96 |
||||
|
Cytarabine |
252 |
39 |
24 |
31 |
25 |
26 |
|||||
|
Interferon |
662 |
70 |
77 |
54 |
73 |
52 |
52 |
56 |
49 |
||
|
Baseline CHR yes |
33.91 |
NR |
NR |
NR |
50 |
NR |
NR |
NR |
NR |
||
NR: not reported
Source: 1: 120 day Efficacy Update of Study 2101, Table 4-1 and 4-2 p25-26., post-text
table 3.5-1.9B, 2. Kantarjian publication of Study 2101-CP 3. START-C, Table 1. 4.
START-R, Table 1. 5.2x2 presentation at ASCO 2007
CML-AP:
The submission presented one single-arm open-label trial (Study 2101) with 120 days
update for nilotinib and one single-arm open-label trial with dasatinib (START-A)
and supplementary single arms of one randomised dasatinib trial (Pasquini et al 2007)
Failure of imatinib and dasatinib:
The evidence for nilotinib after imatinib and dasatinib treatment is data from a single
arm open-label nilotinib study for both CML-CP and CML-AP patients (Study 2101).
The evidence available for nilotinib and dasatinib is briefly summarised in the table
below.
|
Nilotinib |
Dasatinib |
|
|---|---|---|
|
Chronic phase |
A phase II, single arm, open-label study with no comparator. |
A phase II, single arm, open-label study with no comparator. |
|
Accelerated phase |
A phase II, single arm, open-label study with no comparator. |
A series of phase II, single-arm, open-label studies with no common comparator. |
|
Blast Crisis |
Not TGA approved. |
A series of phase II, single-arm, open-label studies with no common comparator. |
|
Third-line |
A single arm, open label study with nilotinib in CML-CP and CML-AP patients. |
It was requested that the sponsor provide the PBAC with updates on the key trial data
as it becomes available.
The following table lists the published studies presented in the submission.
|
Trial/First author |
Protocol title/Publication title |
Publication citation |
|---|---|---|
|
Nilotinib |
||
|
Chronic phase – Non-randomised studies |
||
|
Study 2101-CP |
Nilotinib (formerly AMN107), a highly selective Bcr-Abl tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. |
Blood 2007 110:3540-46. |
|
Accelerated phase – Non-randomised studies |
||
|
Study 2101-AP |
Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated phase chronic myelogenous leukemia. |
Blood 2007, epubl ahead of print. |
|
Dasatanib |
||
|
Chronic phase – Single arms of randomised trials |
||
|
START-R Kantarjian HP (Dasatinib arm) |
Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: A randomized phase 2 trial. |
Blood 2007 Jun 15;109(12):1543-1550. |
|
Chronic phase – Non-ransomised studies |
||
|
START-C |
Dasatinib induces notable hematologic and cytogenetic responses in chronic phase chronic myeloid leukemia after failure of imatinib therapy. |
Blood 2007;109(6):2303-9. |
|
Accelerated phase – Non-randomised studies |
||
|
START-A |
Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. |
Blood 2007;109(10):4143-50. |
|
Imatinib dose escalation up to 800 mg |
||
|
Chronic phase – Single arms of randomised trials |
||
|
START-R |
Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: A randomized phase 2 trial. |
Blood 2007 Jun 15;109(12):1543-1550. |
|
Chronic phase – Non-randomised studies |
||
|
Kantarjian et al |
Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy
in patients with chronic myelogenous leukemia. |
Blood 2003 Jan 15;101(2):473-5. |
|
Chronic phase – Case Reports |
||
|
Marin et al |
Transient benefit only from increasing the imatinib dose in CML patients who do not achieve complete cytogenetic remissions on conventional doses. |
Blood 2003 Oct1;102(7): 2702-3. |
|
Sohn et al |
Efficacy of dose escalation of imatinib mesylate in patients with cytogenetic or hematologic resistance. |
Leukemia and Lymphoma2007; 48(8):1659-61. |
|
Zonder et al |
The Effect of Dose Increase of Imatinib Mesylate in Patients with Chronic or Accelerated Phase Chronic Myelogenous Leukemia with Inadequate Hematologic or Cytogenetic Response to Initial Treatment. |
Clin Cancer Res 2003 Jun 1;9(6):2092-7. |
8. Results of Trials
CML – Chronic Phase
The submission stated that the most appropriate comparison is between the 120 day
update to Study 2101-CP and the publication of START-C for imatinib resistant patients,
because this group is most comparable and the treatment duration was similar (8.6
and 8.3 months, respectively). The imatinib resistant patients in Study 2101-CP achieved
a rate of major cytogenetic response (MCR) of 50% (95% CI 38.8-60.1%); and the similar
patient group from START-C achieved a MCR rate of 39% (95% CI 30.8-48.4%). Different
definitions of imatinib intolerance were used in the nilotinib and dasatinib studies
preventing any comparison between studies in this patient group. The PBAC noted the
values reported in the publication of Study 2101 were lower than the values reported
in the Study 2101 Clinical Study Report. The submission explained this difference
by stating that in the publication patients with a MCR at baseline were excluded from
analysis. The dasatinib arm of the START-R study reported data from a longer median
treatment duration (14 months) and the rate of MCR was 52% for imatinib resistant
patients (95%CI 42.3-62.5%). The rate of MCR was not calculated for the conventional
ITT populations for imatinib resistant and imatinib intolerant patients in the 180
day update report to Study 2101, however, the MCR rate in the entire patient cohort
was 56% after a median of 10 months nilotinib treatment.
The results are presented in the table below.
Major cytogenetic response (MCR) in the nilotinib, dasatinib and imatinib studies in CML-Chronic Phase
|
Study |
Median time on drug |
MCR (% and 95% CI) |
||
|---|---|---|---|---|
|
Entire cohort |
Imatinib resistant |
Imatinib intolerant |
||
|
Nilotinib |
||||
|
Study 2101-CP |
8.6 months (0 – 16.5) |
52 (46-58) |
50 (39-60) |
49 (33-65) |
|
reported in publication |
48 (42-54)a |
47 (36-58) |
48 (41-56) |
|
|
10.4 months (0-20.5)b |
56.3 |
NRc |
NRc |
|
|
Dasatinib |
||||
|
START-C |
8.3 months (0.03-11.0) |
52 |
39 |
80 |
|
START-R (dasatinib arm) |
13.7 months (0.2 – 19.3) |
NA |
52 |
NA |
|
High-dose imatinib |
||||
|
Total high-dose imatinib |
35.0 % (69/197) |
|||
Notes: NR, not reported; MCR, major cytogenetic response
a note the results of the MCR reported in the paper differ from that reported in the
Study report as the Kantarjian analysis excluded patients who already had a response
at baseline, a true ITT analysis should have included these patients in the calculation
of the rate of response
b values extracted from 180 day update report to Study 2101 for EMEA
c The conventional ITT values for imatinib resistant and imatinib intolerant populations
was not presented in the 180 day update report to Study 2101
CML – Accelerated Phase
The rate of MCR was similar in nilotinib and dasatinib treated CML-AP patients; 30%
in nilotinib treated CML-AP patients, and 31-41% in patients treated with dasatinib
in the various studies. More patients treated with dasatinib achieved a complete cytogenetic
response than patients treated with nilotinib for a similar amount of time (22% in
START-A patients at 6 months compared to 16% in nilotinib treated patients in Study
2101-AP).
The results are presented in the table below.
Cytogenetic response rates in the nilotinib and dasatinib studies in CML-Accelerated
Phase
|
Study 2101-AP |
START-A |
|||
|---|---|---|---|---|
|
120 day update |
180 day update |
6 months |
8 months |
|
|
n (%) |
n (%) |
n (%) |
n (%) |
|
|
Major response (complete |
29 (30.2) |
35 (29) |
33 (31) |
35 (33) |
|
95% CI |
21.3-40.4 |
21-39 |
NR |
NR |
|
Complete |
15 (15.6) |
19 (16) |
23 (22) |
26 (24) |
|
Partial |
14 (14.6) |
16 (13) |
10 (9) |
9 (8) |
|
Minor |
12 (12.5) |
16 (13) |
6 (6) |
6 (6) |
|
Minimal |
20 (20.8) |
28 (24) |
19 (18) |
20 (19) |
|
None |
16 (16.7) |
19 (16) |
37 (35) |
33 (31) |
|
Undetermined |
NR |
NR |
12 (11) |
13 (12) |
NR: not reported
The submission stated that patients who have failed both imatinib and dasatinib treatment
are still able to show a response with nilotinib treatment.The PBAC noted that weak
evidence was presented for third-line treatment with nilotinib, after failure of both
imatinib and dasatinib.
With regard to adverse events (AEs), in CML-CP patients, the submission stated that
almost every adverse event noted occurred at a greater frequency in dasatinib treated
patients than patients receiving nilotinib.
Results are presented in the table below.
Adverse events suspected to be related to nilotinib and dasatinib at 8 months
|
Study 2101-CP (n = 318) |
START-C (n = 186) |
|||
|---|---|---|---|---|
|
All grades |
Grade 3-4 (%) |
All Grades† (%) |
Grade 3-4† (%) |
|
|
Headache |
18 |
2 |
34 |
1 |
|
Diarrhoea |
10 |
2 |
30 |
2 |
|
Fatigue |
20 |
1 |
28 |
1 |
|
Dyspnoea |
4 |
1 |
27 |
3 |
|
Rash |
28 |
2 |
22 |
0.5 |
|
Pruritus |
24 |
1 |
NR |
NR |
|
Asthenia |
6 |
0 |
20 |
2 |
|
Nausea |
22 |
1 |
19 |
1 |
|
Pleural Effusion |
1 |
0 |
19 |
3 |
|
Peripheral oedema |
5 |
0 |
18 |
0 |
|
Constipation |
11 |
0 |
NR |
NR |
|
Vomiting |
10 |
1 |
NR |
NR |
|
Pancreatitis |
1 |
0 |
NR |
NR |
|
Cytopenias |
||||
|
Leukocytopenia |
3 |
2 |
NR |
25 |
|
Neutropenia |
14 |
13 |
NR |
49 |
|
Febrile neutropenia |
1 |
1 |
NR |
NR |
|
Thrombocytopenia |
26 |
19 |
NR |
47 |
|
Anaemia |
12 |
4 |
NR |
22 |
|
Serum Chemistry |
||||
|
Elevated bilirubin |
6 |
2 |
14 |
0 |
|
Elevated ALAT |
9 |
2 |
52 |
2 |
|
Elevated ASAT |
4 |
0 |
60 |
2 |
|
Elevated lipase |
12 |
7 |
NR |
NR |
† investigator judged as related to study treatment
NR – not reported
In CML-AP patients, the submission stated that the rates of adverse events reported
with dasatinib were consistently higher than those reported for nilotinib with the
exception of rash and pruritus which occurred at a higher frequency in nilotinib treated
patients.
There was limited safety data on high-dose imatinib. From START-R the most commonly
reported AEs were superficial oedema (42%), nausea (33%), diarrhoea (29%) and fatigue
(22%). These events were similar to what was reported in patients on the standard
imatinib dose of 400 mg/day. The data from the IRIS dose escalation report that GI
bleeding was more prevalent when the dose of imatinib was escalated (3% compared to
1% on the standard dose); otherwise the safety of higher doses of imatinib was similar
to that seen with imatinib 400 mg/day.
The submission stated that the pattern of adverse events in the sub-group of patients
who have failed both imatinib and dasatinib therapy appears generally similar to the
adverse events reported in CML-CP and CML-AP patients in Study 2101 who have only
failed imatinib.
Overall, the PBAC considered nilotinib to have a different safety profile to both
high dose imatinib and dasatinib.
9. Clinical Claim
Chronic phase
Versus dasatinib
The submission described nilotinib as non-inferior in terms of comparative effectiveness
and superior in terms of comparative safety over dasatinib.
Versus high-dose imatinib
The submission described nilotinib as superior in terms of comparative effectiveness
and non-inferior in terms of comparative safety over imatinib.
With respect to effectiveness in the chronic phase, the PBAC considered that both
nilotinib and dasatinib are highly active against truly imatinib-resistant disease
with approximately 30% complete cytogenetic response rate at 6-8 months. However,
as the trials forming the basis of the comparison included a mix of imatinib resistant
and imatinib intolerant patients and used different definitions of intolerance it
was considered that current data do not indicate whether one is superior to the other.
Accelerated phase
The submission described nilotinib as non-inferior in terms of comparative effectiveness
and superior in terms of comparative safety over dasatinib.
The PBAC considered that while nilotinib is active against imatinib failure, the data
provided are insufficient to conclude that it is non-inferior to dasatinib in this
setting. It was considered that the significant uncertainty around this issue would
be best addressed with a randomised study, but might be informed by longer follow-up
of Study 2101-AP.
After imatinib and dasatinib failure
The submission described that some patients treated with nilotinib who have failed
imatinib and dasatinib treatment are able to achieve a response and the safety profile
in this patient population is similar to the other nilotinib patient groups.
The PBAC considered that insufficient data had been provided to determine what the
true rate of response was to nilotinib as a third-line agent.
See also Recommendations and Reasons.
10. Economic Analysis
The submission presented a cost analysis. The equi-effective doses were estimated
as nilotinib 697.5 mg per day over 8.3 months (based on trial data) and dasatinib
128.5 mg per day (based on market data). For pricing the submission used the recommended
doses for nilotinib and dasatinib as the equi-effective dose, i.e. nilotinib 800 mg
to dasatinib 140 mg.
The variables used in the economic evaluation are the costs of drug treatment and
the cost of treating adverse events.
The PBAC did not accept the submission’s claim that the equi-effective doses are nilotinib
687.3 mg per day and dasatinib 128.5mg per day.
For PBAC’s view, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated to be less than 10,000 in Year 5. The PBAC considered this to be an underestimate. The estimated net cost per year of nilotinib on the PBS was less than $10 million. This was also considered to be an underestimate by the PBAC.
12. Recommendation and Reasons
The PBAC recommended the listing of nilotinib on the PBS for the treatment of chronic
and accelerated phase Philadelphia positive chronic myeloid leukaemia in patients
who have failed imatinib and meet certain criteria on a cost-minimisation basis compared
with dasatinib.
The PBAC considered that the average doses from the nilotinib trial (687.3 mg) and
from the pivotal randomised dasatinib trial in imatinib resistant patients CA180-017
(START-R) would be more appropriate for determining the equi-effective doses at the
time of listing. However, the PBAC noted that the average daily dose of dasatinib
from this trial was not available as the START-R study report provides only the median
dose (111 mg) and that this is not known to the nilotinib sponsor (the publication
of the START-R trial cites a median dose of 103 mg/day). Thus, the equi-effective
doses should be nilotinib 792.1mg (the median dose from trial 2101 – 180 day update)
and dasatinib 111 mg.
With respect to effectiveness in the chronic phase, the PBAC considered that both
nilotinib and dasatinib are highly active against truly imatinib-resistant disease
with approximately 30% complete cytogenetic response rate at 6-8 months. However,
as the trials forming the basis of the comparison included a mix of imatinib resistant
and imatinib intolerant patients and used different definitions of intolerance it
was considered that current data do not indicate whether one is superior to the other.
With respect to the accelerated phase, the PBAC considered that while nilotinib is
active against imatinib failure, the data provided are insufficient to conclude that
it is non-inferior to dasatinib in this setting. It was considered that the significant
uncertainty around this issue would be best addressed with a randomised study, but
might be informed by longer follow up of Study 2101-AP.
The PBAC also noted that whilst nilotinib has a different safety profile to both high
dose imatinib and dasatinib, there is considerable uncertainty around the claims that
nilotinib has significant activity after failure of both imatinib and dasatinib and
that nilotinib has a superior safety profile to dasatinib.
Furthermore, the Committee, while recognising the clinical need of patients who have
failed both imatinib and dasatinib, considered that there are insufficient data to
provide any certainty about the clinical benefit of either nilotinib (or dasatinib)
as third-line tyrosine kinase inhibitor (TKI) therapy and that nilotinib should be
restricted to use in patients who are resistant to imatinib only i.e. second-line
use after imatinib failure and not after imatinib and dasatinib failure as requested
in the submission. The PBAC recommended the restriction include a NOTE stating that
nilotinib is not PBS-listed for third-line therapy. The PBAC noted that this recommendation
also means that dasatinib-intolerant but sensitive patients would not have access
to nilotinib via the PBS. However, the PBAC considered it likely that such patients
would continue to be picked up by the Novartis compassionate access program.
The PBAC deferred a final decision for nilotinib for the treatment of chronic and
accelerated phase Philadelphia chromosome positive chronic myeloid leukaemia (CML)
for patients who are intolerant of at least one prior therapy including imatinib.
The PBAC considered that a Stakeholder meeting was necessary prior to further consideration
of this matter to discuss issues such as the intolerance to imatinib rules in the
current restrictions; the use of bone marrow biopsy as the marker for loss of major
cytogenetic response and imatinib resistance, rather than rising BCR-ABL transcript
levels in blood; and to discuss ground rules for assessment of tyrosine kinase inhibitors
in third-line management of CML.
Recommendation
NILOTINIB, capsule, 200 mg
Restriction: NILOTINIB
NOTE:
Any queries concerning the arrangements to prescribe nilotinib may be directed to
Medicare Australia on 1800 700 270 (hours of operation 8 a.m. to 5 p.m. EST Monday
to Friday). Prescribing information (including Authority Application forms) is available
on the Medicare Australia website at www.medicareaustralia.gov.au.
Any queries concerning patients who are enrolled on the Nilotinib Compassionate Program
may be directed to Medicare Australia on 1800 700 270 (hours of operation 8 a.m. to
5 p.m. EST Monday to Friday).
Applications for authority to prescribe nilotinib should be forwarded to:
Medicare Australia
Prior Written Approval of Specialised Drugs
Reply Paid 9826
GPO Box 9826
HOBART TAS 7001
Authority Required
Initial treatment, as the sole PBS-subsidised therapy, of a patient with chronic myeloid
leukaemia in chronic or accelerated phase bearing the Philadelphia chromosome or expressing
the transcript, BCR-ABL, who has active leukaemia (as defined by presence on current
pathology assessments of either the Philadelphia chromosome on cytogenetic or FISH
analysis, or the presence of the transcript BCR-ABL and morphological evidence of
leukaemia in sites other than peripheral blood) and who has failed an adequate trial
of imatinib.
Failure of an adequate trial of imatinib is defined as:
(i) Lack of response to initial imatinib therapy, defined as either:
- failure to achieve a haematological response after a minimum of 3 months therapy with imatinib for patients initially treated in chronic phase; or
- failure to achieve any cytogenetic response after a minimum of 6 months therapy with imatinib for patients initially treated in chronic phase as demonstrated on bone marrow biopsy by presence of greater than 95% Philadelphia chromosome positive cells; or
- failure to achieve a major cytogenetic response or a peripheral blood BCR-ABL level of less than 1% after a minimum of 12 months therapy with imatinib; or
(ii) Loss of a previously documented major cytogenetic response (demonstrated by the
presence of greater than 35% Ph positive cells on bone marrow biopsy), during ongoing
imatinib therapy (Note: a BCR/ABL qPCR >1% alone is not evidence of loss of response);
or
(iii) Development of accelerated phase in a patient previously prescribed imatinib
for the chronic phase of chronic myeloid leukaemia.
Accelerated phase is defined by the presence of 1 or more of the following:
(1) Percentage of blasts in the peripheral blood or bone marrow greater than or equal
to 15% but less than 30%; or
(2) Percentage of blasts plus promyelocytes in the peripheral blood or bone marrow
greater than or equal to 30%, provided that blast count is less than 30%; or
(3) Peripheral basophils greater than or equal to 20%; or
(4) Progressive splenomegaly to a size greater than or equal to 10 cm below the left
costal margin to be confirmed on 2 occasions at least 4 weeks apart, or a greater
than or equal to 50% increase in size below the left costal margin over 4 weeks; or
(5) Karyotypic evolution (chromosomal abnormalities in addition to a single Philadelphia
chromosome); or
(iv) Disease progression (defined as ≥ 50% increase in peripheral white blood cell
count, blast count, basophils or platelets) during first-line imatinib therapy in
patients with accelerated phase chronic myeloid leukaemia, provided that blast crisis
has been excluded on bone marrow biopsy: or
(v) Detection of a mutation in BCR-ABL (L248V, G250E, Q252H/R, Y253H/F, E255K/V, H396P/R,
and D276G) that infers high level imatinib resistance. (Patients with these mutations
but without active leukaemia, will not be approved); or
(vi) Grade 3 or 4 non-haematological toxicity that is imatinib related
Applications for authorisation must be in writing and must include:
(a) a completed authority prescription form; and
(b) a completed Chronic Myeloid Leukaemia Nilotinib PBS Authority Application –Supporting
Information Form,
(c) a signed patient acknowledgement
(d) a bone marrow biopsy pathology report demonstrating the patient has active chronic
myeloid leukaemia, either manifest as cytogenetic evidence of the Philadelphia chromosome,
or morphological evidence of chronic myeloid leukaemia in bone marrow plus qualitative
RT-PCR evidence of BCR-ABL transcript. (The date of the relevant pathology report
needs to be provided); and
(e) details of Grade 3 or 4 non-haematological imatinib related toxicity.
NOTE:
Nilotinib will only be subsidised for patients with chronic myeloid leukaemia who
are not receiving concomitant PBS-subsidised imatinib mesylate, dasatinib or interferon
alfa therapy. Patients should be commenced on a dose of nilotinib of 400 mg twice
daily. Continuing therapy is dependent on patients demonstrating a major cytogenetic
response to nilotinib therapy or a peripheral blood BCR-ABL level of less than 1%
at 12 monthly intervals, irrespective of the daily nilotinib dose received.
Nilotinib is not PBS-subsidised for patients with CML that is resistant to dasatinib.
Nilotinib is not TGA-registered and not PBS-subsidised for patients with CML in blast
crisis.
Requests for doses of greater than nilotinib 400mg twice daily will not be approved.
Authority Required
Continuing treatment, as the sole PBS-subsidised therapy, of a patient who has received
initial treatment with nilotinib as a pharmaceutical benefit for chronic myeloid leukaemia,
and who has demonstrated either a major cytogenetic response, or less than 1% BCR-ABL
level in the blood, to nilotinib in the preceding 12 months.
Applications for authorisation must be in writing and must include:
(1) a completed authority prescription form; and
(2) a completed Chronic Myeloid Leukaemia Nilotinib Authority Application Form for
continuing treatment; and
(3) demonstration of continued response to treatment as evidenced by either:
(a) major cytogenetic response [see Note explaining definitions of response]. Where
this has been supplied within the previous 12 months, only the date of the relevant
pathology report need be provided; or
(b) a peripheral blood level of BCR-ABL of less than 1% on the international scale
[see Note explaining definitions of response]. Where this has been supplied within
the previous 12 months, only the date of the relevant pathology report need be provided.
NOTE:
Definitions of response.
A major cytogenetic response is defined as less than 35% Philadelphia positive bone
marrow cells.
A bone marrow or peripheral blood BCR-ABL level of less than 1% on the international
scale (Blood 108: 28-37, 2006) also indicates a response, at least the biological
equivalent of a major cytogenetic response.
Authority approval requirements.
For the purposes of assessing response to PBS-subsidised treatment with nilotinib,
either cytogenetic analysis indicating the number of Philadelphia positive [t (9;22)]
cells in the bone marrow measured by standard karyotyping, or quantitative PCR indicating
the relative level of BCR-ABL transcript in the peripheral blood using the international
scale, must be submitted. For bone marrow analyses, where the standard karyotyping
is not informative for technical reasons, a cytogenetic analysis performed on the
bone marrow by the use of fluorescence in situ hybridisation (FISH) with BCR-ABL specific
probe must be submitted. The cytogenetic or peripheral blood quantitative PCR analyses
must be submitted as follows:
(i) between 10 and 12 months of the commencement of treatment with nilotinib, at which
time patients in whom a major cytogenetic response or peripheral blood BCR-ABL level
of less than 1% has been demonstrated may receive authorisation for a further 12 months
of treatment; and
(ii) at no greater than 12 month intervals thereafter, to demonstrate that the major
cytogenetic response or peripheral blood BCR-ABL level of less than 1% has been sustained.
For each authority application where eligibility for continuing PBS-subsidised treatment
is to be demonstrated, a copy of the cytogenetic analysis indicating the number of
Philadelphia positive [t (9;22)] cells in the bone marrow measured by standard karyotyping,
or a copy of the quantitative PCR indicating the relative level of BCR-ABL transcript
in the peripheral blood using the international scale, must be submitted as described
in (i) and (ii) above. For bone marrow analyses, where the standard karyotyping conducted
at the time of application is not informative, a copy of a cytogenetic analysis conducted
on the bone marrow using FISH with BCR-ABL specific probe must be submitted with the
authority application. A copy of the non-informative standard karyotype analysis must
be included with the authority application. Where a patient has previously received
PBS-subsidised treatment with nilotinib, no approval will be granted for PBS-subsidised
re-treatment where that patient has at any time failed to meet the criteria for continuing
treatment.
Maximum quantity: 112
Repeats: 5
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
Novartis Pharmaceuticals Australia thank the PBAC for recommending the use of nilotinib
in patients who are intolerant of, or resistant to imatinib. We look forward to working
with the PBAC and other Stakeholders to further streamline the listing of the Tyrosine
Kinase Inhibitors and to permit patients who have failed both imatinib and dasatinib
access to nilotinib on the PBS.
