Lenalidomide, capsules, 5 mg and 10 mg, Revlimid® - March 2011
Page last updated: 15 July 2011
PDF printable version to Lenalidomide, capsules, 5 mg and 10 mg, Revlimid ® (PDF 88
KB)
Public Summary Document
Product: Lenalidomide, capsules, 5 mg and 10 mg,
Revlimid®
Sponsor: Celgene Pty Ltd
Date of PBAC Consideration: March 2011
1. Purpose of Application
The submission sought an extension to the Section 100 (Highly
Specialised Drug) Public and Private Authority Required listing to
include initial and continuing treatment of a patient with
myelodysplastic syndrome (MDS), defined as low or intermediate-1,
who has a 5q cytogenetic abnormality and who is red blood cell
transfusion dependent.
2. Background
This drug had not previously been considered by the PBAC for this
indication.
3. Registration Status
An extension to the TGA registration for lenalidomide was granted
on 15 April 2010 to include the treatment of patients with
transfusion-dependent anaemia due to low or imtermediate-1 risk
myelodysplastic syndromes associated with a deletion 5q cytogenetic
abnormality with or without additional cytogenetic
abnormalities.
Lenalidomide was TGA registered on 20 December 2007 for use in
combination with dexamethasone in patients with multiple myeloma
whose disease has progressed after one therapy.
4. Listing Requested and PBAC’s View
Section 100 (Highly Specialised Drug)
Public and Private Hospital Authority Required
Initial treatment for a period of up to 16 weeks of a patient with:
- MDS classified as low risk or Intermediate-1 according to the International Prognostic Scoring System (IPSS); and
- Who has a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities; and
- Who is red blood cell transfusion dependent.
Classification of a patient as low risk requires a score of 0 on
the IPSS, achieved with the following combination: < 5% marrow
blasts with good karyotypic status (normal, -Y alone, -5q alone,
-20q alone), and 0/1 cytopenias.
Classification of a patient as Intermediate-1 requires a score of
0.5 to 1 on the IPSS, achieved with the following possible
combinations:
1. 5%-10% marrow blasts with good karyotypic status (normal, -Y
alone, -5q alone, -20q alone), and 0/1 cytopenias; OR
2. < 5% marrow blasts with intermediate karyotypic status (other
abnormalities), and 0/1 cytopenias; OR
3. < 5% marrow blasts with good karyotypic status (normal, -Y
alone, -5q alone, -20q alone), and 2/3 cytopenias; OR
4. < 5% marrow blasts with intermediate karyotypic status (other
abnormalities) and 2/3 cytopenias; OR
5. 5%-10% marrow blasts with intermediate karyotypic status (other
abnormalities), and 0/1 cytopenias; OR
6. 5%-10% marrow blasts with good karyotypic status (normal, -Y
alone, -5q alone, -20q alone), and 2/3 cytopenias; OR
7. < 5% marrow blasts with poor karyotypic status (complex, >
3 abnormalities), and 0/1 cytopenias.
Public and Private Hospital Authority Required
Continuing treatment of a patient with:
- MDS classified as low risk or Intermediate-1 according to the International Prognostic Scoring System (IPSS); and
- Who has a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities; and
- Who is red blood cell transfusion dependent;
- Who has been previously issued with an authority prescription for lenalidomide and who achieved at least a 50% reduction in their red blood cell transfusion requirements during that treatment and remained free from disease progression.
Note:
Patients receiving lenalidomide under the PBS listing must be
registered in the i-access™ risk management program.
The requested maximum quantity is one pack of 21 capsules with two
repeats, allowing for three months of treatment.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
The myelodysplastic syndromes (MDS) are a group of disorders of
haematopoiesis (formation of blood cellular components), which
include refractory anaemia, chronic myelomonocytic leukaemia
(CMML), acute myeloid leukaemia (AML) and a specific subtype
characterised by the presence of a deletion of the 5q chromosome.
Presence of a 5q deletion occurs in approximately 10% of patients
with MDS. The 5q deletion subtype is typically associated with a
better prognosis for survival and freedom from progression to AML
than occurs in patients without a 5q deletion.
The incidence of MDS is highest among older persons, with the
median age of diagnosis being in the range of 65 to 70 years. There
are currently no curative options available for most patients with
MDS although a small percentage of younger and fitter patients may
achieve long-term disease control through allogeneic
transplantation. Almost all patients with MDS will receive
background supportive therapy. Active therapies will be used in
patients at higher risk of transforming to leukaemia.
The submission proposed that the place in therapy of lenalidomide
was to provide an alternative treatment option to best supportive
care for patients who are unable or not suitable to be treated with
active chemotherapy/stem cell transplantation.
6. Comparator
The submission nominated best supported care (BSC) comprising red
blood cell transfusions, treatment with granulocyte colony
stimulating factor, blood forming and iron chelation therapy as the
comparator, which was considered appropriate by the PBAC.
7. Clinical Trials
The submission presented one randomised trial MDS-004, comparing 10
mg or 5 mg lenalidomide once daily for 21 days in every 28 day
cycle with best supported care in patients with transfusion
dependent low risk/INT-1 del(5q) myelodysplastic syndrome.
The key trials published at the time of submission are shown in the
table below:
Trial ID / First author | Protocol title / Publication title | Publication citation |
Direct randomised trial | ||
MDS-004 | ||
Fenaux, P. et al | Safety of lenalidomide (LEN) from a randomized phase III trial (MDS-004) in low-/int-1-risk myelodysplastic syndromes (MDS) with a del(5q) abnormality. | J Clin Oncol. 2010; 28:15s: 6598. |
Fenaux, P. et al | 4027 Prognostic Factors of Long-Term Outcomes In Low- or Int-1-Risk MDS with del5q Treated with Lenalidomide (LEN): Results From a Randomized Phase 3 Trial (MDS-004). | Abstract 52 nd American Society Hematology Meeting, December 2010. |
Supplementary non randomised trial | ||
CC-5013-MDS-003 | ||
List, A. et al | Lenalidomide in the myelodysplastic syndrome with chromosome del(5q). | New England Journal of Medicine 2006; 355(14): 1456-1465 |
Sekeres, M. A. et al | Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. | Journal of Clinical Oncology 2008; 26(36): 5943-5949 |
8. Results of Trials
The primary outcome of MDS-004 was the proportion of patients
achieving red blood cell (RBC) transfusion independence for ≥182
days (6 months) in the MITT (modified intention to treat)
population measured at 52 weeks. The secondary outcome of the
International Working Group for MDS (IWG) criteria was defined as
transfusion independence ≥56 days.
The results for the primary outcome and key secondary outcome are
summarised below:
The ITT (intention to treat) and MITT results from both the primary
(transfusion independence for ≥ 182 days) and key secondary
outcomes (IWG criteria transfusion dependence ≥56 days)
demonstrated that patients treated with lenalidomide had a
statistically significantly greater chance of becoming transfusion
independent than placebo treated patients.
The PBAC noted that a clinically meaningful change in
patients’ HRQoL (health related quality of life) was observed
after 24 weeks of treatment with lenalidomide and a worsening in
placebo patients. However, the results were confounded due to loss
to follow up.
No differences were found in either progression to acute myeloid
leukaemia (AML) or overall survival at the date of primary
analysis. Limited long term data on overall survival was provided
by the submission and rates were not provided for placebo due to
cross-over.
Serious adverse events were frequent with lenalidomide treatment
with 94% of subjects in the 10 mg arm having at least one Grade 3/4
adverse event. Lenalidomide was associated with statistically
significant higher rates of neutropenia (75.4% in the lenalidomide
10 mg group versus 14.9% in the placebo group); thrombocytopenia
(40.6% in the lenalidomide 10 mg group versus 1.5% in the placebo
group); leucopenia (not otherwise specified) (8.7% in the
lenalidomide 10 mg group versus 0% in the placebo group); and
non-statistically significant higher rates of vascular disorders:
deep vein thrombosis (5.8% in the lenalidomide 10 mg group versus
1.5% in the placebo group).
9. Clinical Claim
The submission described lenalidomide as superior in terms of
comparative effectiveness and associated with more toxicity over
best supported care, which was considered reasonable based on the
supporting data.
10. Economic Analysis
The submission presented a stepped economic evaluation, based on
the pivotal trial.
The model was a decision analytic model which compared the use of
lenalidomide (plus BSC) with BSC alone for the treatment of
patients with transfusion dependent low risk/INT-1 del(5q) MDS over
a time horizon of 12 months. Costs of treating Grade 3/4 adverse
events associated with lenalidomide treatment were estimated in the
model. The main drivers of the model were the proportion of
patients achieving transfusion independence and the cost of
lenalidomide. Utilities in the model were assigned for transfusion
dependence and independence, with no adjustment for a reduction of
50% RBC transfusion requirement. These patients were assigned
transfusion dependent utilities.
The re-specified base case incremental cost per extra QALY gained
was estimated to be between $45,000 – $75,000.
The result of the univariate sensitivity analyses indicated that
the model was highly sensitive to a number of parameters including
the price of lenalidomide, the pack usage of lenalidomide and the
utility values used in the model.
The model was also highly sensitive to the assumed use of iron
chelation therapy.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated the total net cost to the PBS to be less
than $10 million per year
in Year five after listing.
12. Recommendation and Reasons
The PBAC agreed that the appropriate comparator was best supportive
care.
The submission presented one randomised trial MDS-004, comparing
10mg or 5mg lenalidomide once daily for 21 days in every 28 day
cycle with best supportive care in patients with transfusion
dependent low risk/INT-1 del(5q) myelodysplastic syndrome. The PBAC
agreed that the ITT and MITT (modified intention to treat) results
from both the primary (transfusion independence for ≥ 182 days)
and key secondary outcomes (IWG criteria transfusion dependence
≥56 days) demonstrate that patients treated with lenalidomide
had a statistically significantly greater chance of becoming
transfusion independent than placebo treated patients. The PBAC
noted that a clinically meaningful change in patients’ HRQoL
was observed after 24 weeks of treatment with lenalidomide and a
worsening in placebo patients. However, the results were confounded
due to loss to follow up.
The submission claimed that lenalidomide is superior in terms of
comparative effectiveness and associated with more toxicity over
best supported care. The PBAC considered that for the primary
outcome of transfusion independence this is reasonable based on the
supporting data.
The PBAC noted that the requested restriction did not provide a
definition of transfusion dependence. The PBAC considered that a
definition could be based on the criteria used in the trial or
alternatively “at least 8 units of RBC in last 6
months”, which is similar to the description of transfusion
dependence described by the clinician at the sponsor’s
Hearing. However, this may still be difficult for Medicare
Australia to implement, as there is some difficulty in accurately
recording the information. This was reflected in the exclusion of a
significant minority of patients from the mITT because transfusion
data were not able to be verified. There is also potential for
manipulation of transfusion regimens to artificially meet any
arbitrary definition within a certain time period. The PBAC also
noted that the restriction specified a 50% reduction in
transfusions for continuing therapy implying that reduced
transfusion dependence is a relevant state. However, this was not
modelled in the modelled economic evaluation. The 50% reduction was
consistent with the 16 week continuation criteria in trial and
whilst this may be a reasonable clinical indicator for ongoing use,
it would be difficult for Medicare Australia to administer. It is
also possible that at any given time, the requirement for a red
cell transfusion would not exclusively reflect failure of
lenalidomide, but rather that an intercurrent and correctable
medical issue had arisen which required transfusion. The PBAC
considered that the requirement of a 50% transfusion reduction may
be best handled by inclusion of this in the economic model or by a
risk share arrangement.
The submission presented a stepped economic evaluation, based on
the pivotal trial.
The PBAC noted that the model is highly sensitive to a number of
parameters including the price of lenalidomide, the pack usage of
lenalidomide and the utility values used in the model. The model is
also highly sensitive to the assumed use of iron chelation therapy.
The PBAC did not consider that the assumed 51% rate of use prior to
transfusion independence, reducing to 19% for transfusion
independence, is likely to be an overestimate if the
truly-transfusion dependent low risk myelodysplasia population
alone was included.
The PBAC noted that the cost of deferasirox was incorrect and the
costs of weekly blood tests and reviews for the first two months
were omitted from the lenalidomide arm. The base case was
re-specified and estimated to be in the range $45,000 –
$75,000 per QALY but was considered to be very uncertain, due to
various concerns with the assumptions made in the model, such
as:
- no inclusion of transition to AML or death;
- no modelling of the continuation rule, which required 50%
reduction in transfusions;
- uncertainty in relation to the likely numbers of packs used per
patient; and
- use of utility values taken from literature which reported the
greatest difference in values for transfusion independent and
dependent patients.
The PBAC noted that no QoL parameters were reported in the clinical
trials presented that could be converted to QALY weights. Of the
two available literature studies (Szende et al 2010 and Buckstein
et al 2009), the model used the values from Szende, which were more
favourable to lenalidomide. Sensitivity analyses using Buckstein
increased the ICER from $45,000 – $75,000in the respecified
base case to $75,000 – $105,000. The PBAC noted the Szende
study, which included three health states, transfusion
independence, reduced transfusion burden and transfusion
dependence. The vignette for reduced transfusion burden was not
included in the published study. The PBAC considered that this
intermediary state of reduced transfusion dependence may have been
a useful health state to be included in the model for those
patients eligible to continue treatment but not reaching
transfusion independence. The PBAC noted that by not including this
health state there was some potential for the utility gain to be
overstated (given that patients not achieving transfusion
independence were assigned the utility for transfusion dependence)
particularly as the vignettes for the transfusion independent ,
reduced transfusion burden state and dependent state differed
substantially on all aspects of the health state, for example
social and role function and anxiety, and may not be truly
representative of those states in myelodysplasia patients.
The PBAC noted that the definition of transfusion independence used
in the model is based on 56 days (secondary outcome) rather than
182 days (primary outcome). However, 182 days may be a more
appropriate outcome to extrapolate to one year.
The PBAC considered that although lenalidomide was an effective
drug, neither the restriction nor the model adequately reflected
the likely place in clinical practice.
The PBAC therefore rejected the submission on the basis of a high
and uncertain cost-effectiveness ratio.
Recommendation:
Reject
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Celgene will continue to work with the PBAC to achieve a positive
recommendation for lenalidomide for patients with myelodysplastic
syndrome (MDS), defined as low or intermediate-1, who have a 5q
cytogenetic abnormality and who are red blood cell transfusion
dependent.