Lenalidomide, capsules, 5 mg, 10 mg, 15 mg and 25 mg, Revlimid, March 2008
Public summary document for Lenalidomide, capsules, 5 mg, 10 mg, 15 mg and 25 mg, Revlimid, March 2008
Page last updated: 18 July 2008
Public Summary Documents
Product: Lenalidomide, capsules, 5 mg, 10 mg, 15 mg and 25 mg, Revlimid
Sponsor: Celgene Pty Ltd
Date of PBAC Consideration: March 2008
1. Purpose of Application
To seek a Section 100 (Highly Specialised Drug) listing for the treatment of patients
with relapsed/refractory multiple myeloma.
Highly specialised drugs are medicines for the treatment of chronic conditions, which,
because of their clinical use or other special features, are restricted to supply
to public and private hospitals having access to appropriate specialist facilities.
2. Background
This was the first time lenalidomide had been considered by the PBAC.
3. Registration Status
Lenalidomide was registered by the TGA on 20 December 2007 and is indicated 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 Private Hospital Authority Required
Relapsed/refractory multiple myeloma in combination with dexamethasone in a patient
who has undergone at least one other therapy.
A patient is considered to be refractory to treatment who:
- is unable to achieve a reduction (< 25% decrease in M-paraprotein levels), or at least control (no increase) in initial multiple myeloma activity despite receipt of at least two cycles of a treatment for multiple myeloma at therapeutic levels ; or
- is unable to receive therapeutic levels of a treatment for multiple myeloma due to reasons of treatment intolerance or contraindication.
A patient is considered to have relapsed multiple myeloma who has progressive disease
(> 25% increase in M-paraprotein levels, development of new lytic lesions, or progressive
of existing lesions) after having achieved a response to their prior therapy.
No repeats will be authorised for females of childbearing potential. Up to two repeats
will be authorised for all other patients.
Caution
Lenalidomide must not be given to pregnant women. Pregnancy in female patients, or
in the partners of male patients, must be avoided during treatment and for one month
after cessation of treatment with lenalidomide.
The PBAC noted that, if listed as requested, a restriction similar to that for thalidomide
would be appropriate.
5. Clinical Place for the Proposed Therapy
Multiple myeloma is a disorder in which malignant plasma cells accumulate in the bone marrow and produce immunoglobulin. It is a chronic and disabling condition with no cure. Lenalidomide would provide an alternative treatment option for patients with relapsed/refractory multiple myeloma.
6. Comparator
The submission nominated thalidomide as the main comparator and bortezomib as the secondary comparator. The PBAC accepted that when used in place of thalidomide, thalidomide is the appropriate comparator. However, lenalidomide may be used in patients who have previously failed thalidomide. In this patient population bortezomib is the appropriate comparator.
7. Clinical Trials
The basis of the submission for the comparison of lenalidomide versus thalidomide
were single arms of two direct randomised comparative trials with lenalidomide plus
dexamethasone vs. placebo plus dexamethasone and two cohort studies with thalidomide
plus dexamethasone. There was no common comparator for the lenalidomide and the thalidomide
trials.
The thalidomide trials were controlled cohort analyses and therefore were neither
randomised nor blinded. The PBAC was advised that the scientific basis of the comparison
is of a much lower quality than is usually required to sustain a case for superiority.
The basis of the comparison with bortezomib was an indirect comparison of two lenalidomide
plus dexamethasone vs. placebo plus dexamethasone trials (the same arms as in the
comparison with thalidomide) compared with one bortezomib and dexamethasone trial,
which had a randomised unblinded design, comparing bortezomib with high dose dexamethasone.
A list of the published trials and studies provided in the submission is presented
in table below.
|
Trial/First author |
Protocol title/Publication title |
Publication citation |
|---|---|---|
|
Lenalidomide |
||
|
Weber DM, et al |
Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. |
N Engl J Med 357 2133-2142, 2007 |
|
Dimopoulos M, |
Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. |
N Engl J Med 357 2123-2132, 2007 |
|
Thalidomide |
||
|
Palumbo A et al |
Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma. |
The Hematology Journal 2004; 5:318-324. |
|
Offidani M et al |
Thalidomide-dexamethasone plus pegylated liposomal doxorubicin vs. thalidomide-dexamethasone: A case-matched study in advanced multiple myeloma. |
European Journal of Haematology 2007; 78(4):297-302 |
|
Bortezomib |
||
|
Richardson PG et al |
Bortezomib or high dose dexamethasone for relapsed multiple myeloma. |
N Engl J Med 352(24): 2487-2498, 2005 |
8. Results of Trials
The primary outcome for the lenalidomide trials was time to progression. In both trials,
the median time to progression was significantly longer in the lenalidomide plus dexamethasone
arm compared with the dexamethasone only arm. The size of the difference was about
20 – 25 weeks.
The primary outcome for the APEX trial was time to progression, similar to the primary
outcome of the lenalidomide trials. The results of lenalidomide and bortezomib on
time to progression across the direct randomised trials are shown in the table below.
|
Study 009 |
Study 010 |
APEX |
||||
|---|---|---|---|---|---|---|
|
LEN + DEX |
DEX |
LEN + DEX |
DEX |
BORT |
DEX |
|
|
N |
170 |
171 |
176 |
175 |
315 |
312 |
|
Progressed n (%) |
44 (25.9) |
98 (57.3) |
39 (22.2) |
99 (56.6) |
n.r. |
n.r. |
|
TTP (weeks)a |
26.8 |
15.2 |
||||
|
Median (published)b |
48.1 |
20.4 |
49.0 |
20.4 |
||
|
Min, Max |
0.0, 60.1 |
0.0, 57.0 |
0.0, 44.7 |
0.3, 48.1 |
||
|
Hazard rate ratioa |
||||||
|
As published |
2.86 |
2.85 |
||||
|
Hazard ratio |
(0.27 to 0.47) |
(0.27 to 0.46) |
0.55 |
|||
|
Log-rank test |
<0.001 |
<0.001 |
<0.001 |
|||
Notes: n.e., not estimable; CI, confidence interval; HR, hazard ratio.
aresults for the APEX study were reported as months, converted to weeks by multiplying
by 4.33. HR is for risk of progression with bortezomib over that for dexamethasone
alone, and is the reverse for lenalidomide.
bThe time of analysis was when the study was unblended. This was after a median treatment
period of 17 months in both studies.
**the trial abstracts and published reports used the alpha for the placebo arm in
the numerator of the calculation of HR, which is the inverse to the standard reporting
of HR. The usual method applied to the published results is shown in italics.
The pooled median time to progression was 41 weeks for lenalidomide plus DEX compared
with 20 weeks for DEX treatment only.
The PBAC noted time to progression was not available for the thalidomide studies,
neither of which included a DEX alone arm to serve as a common reference. The Offidani
study was not informative for assessing the effect of thalidomide, since both arms
of the study included thalidomide and the difference between them was the addition
of conventional chemotherapy in one arm.
In the APEX trial the time to progression was 26 weeks for bortezomib and 15 weeks
for DEX.
The PBAC noted that progression-free survival was similar between lenalidomide and
thalidomide.
The secondary outcome in the lenalidomide studies, which was used in the economic
evaluation, was overall survival. The submission presented updated results from the
most recent analysis for Study 009 and Study 010.
The submission stated that the data suggest that the median survival for lenalidomide
treated patients is above that of thalidomide: based on differences with the Palumbo
study and the Offidani study.
The PBAC had concerns with this extrapolation for several reasons:
- direct comparison of survival times cannot be made reliably across studies without a common reference;
- the difference in median survival with thalidomide plus DEX compared with conventional chemotherapy (i.e. possibly attributable to thalidomide) is about 6 months (Palumbo); and
- the Offidani did not compare a thalidomide-treated group with a non-thalidomide-treated group, and therefore the survival advantage in this study should be attributed to the addition of conventional chemotherapy, not to thalidomide itself.
The overall survival for bortezomib was shorter compared with lenalidomide plus DEX.
The hazard ratios for overall survival relative to DEX do not differ between the lenalidomide
plus DEX and bortezomib trials, and are 0.77 vs. dexamethasone.
With regard to comparative toxicity, an indirect comparison between lenalidomide and
thalidomide with a common comparator could not be made. The table below presents the
grade 3 and 4 adverse effects observed in the lenalidomide trials, which were notably
different between the two treatment arms.
Grade 3/ 4 adverse events in Studies 009 and 010*
|
Study 009 |
Study 010 |
|||||||
|---|---|---|---|---|---|---|---|---|
|
Event |
Len+Dex |
Dex |
Len + Dex (N=176) |
Dex |
||||
|
Grade 3 |
Grade 4 |
Grade 3 |
Grade 4 |
Grade 3 |
Grade 4 |
Grade 3 |
Grade 4 |
|
|
number (percent) |
||||||||
|
Hematologic disorder |
||||||||
|
Neutropenia |
62 (35) |
11 (6.2) |
6 (3.4) |
2 (1.1) |
44 (25) |
8 (4.5) |
4 (2.3) |
0 |
|
Anaemia |
19 (10.7) |
4 (2.3) |
6 (3.4) |
3 (1.7) |
14 (8.0) |
1 (0.6) |
12 (6.9) |
0 |
|
Thrombocytopenia |
24 (13.6) |
2 (1.1) |
12 (6.9) |
0 |
17 (9.7) |
3 (1.7) |
7 (4.0) |
3 (1.7) |
|
Febrile neutropenia |
5 (2.8) |
1 (0.6) |
0 |
0 |
5 (2.8) |
1 (0.6) |
0 |
0 |
|
Infection |
||||||||
|
Pneumonia |
19 (10.7) |
3 (1.7) |
10 (5.7) |
5 (2.9) |
||||
|
All other infection† |
33 (18.6) |
5 (2.8) |
16 (9.1) |
5 (2.9) |
15 (8.5) |
2 (1.1) |
9 (5.1) |
0 |
|
Vascular disorder |
||||||||
|
Deep-vein thrombosis |
21 (11.9) |
0 |
6 (3.4) |
0 |
6 (3.4) |
1 (0.6) |
5 (2.9) |
1 (0.6) |
|
Pulmonary embolism |
1 (0.6) |
5 (2.8) |
0 |
1 (0.6) |
2 (1.1) |
6 (3.4) |
1 (0.6) |
1 (0.6) |
|
Venous thromboembolism‡ |
21 (11.9) |
5 (2.8) |
5 (2.9) |
1 (0.6) |
13 (7.4) |
7 (4.0) |
6 (3.5) |
2 (1.1) |
Notes: * Listed are data that were available on December 31, 2005. Percentages may
not total 100 because of rounding.
† This condition was also described in the following terms: infections not otherwise
specified, pneumonia, upper respiratory tract infection, upper respiratory viral infection,
sepsis, bacterial infection, urinary tract infection, pharyngitis, nasopharyngitis,
febrile neutropenia, oral candidiasis, oral fungal infection, primary atypical pneumonia,
fungal sinusitis, herpes simplex, herpes zoster, herpes encephalitis, herpes viral
infection, cytomegalovirus pneumonia, and viral infection.
‡ This condition was also described in the following terms: deep-vein thrombosis,
pulmonary embolism, pulmonary infarction, thrombosis, phlebothrombosis, thrombophlebitis,
superficial thrombophlebitis, venous thrombosis, thromboembolism, splenic-vein thrombosis,
phlebitis, and superficial phlebitis.
The submission stated that based on trial data, the incidence of neuropathy appears
lower with lenalidomide than thalidomide.
The comparison of the lenalidomide and bortezomib treatments indicates that the overall
incidence of adverse events did not differ between them. However, the pattern of those
events is different: lenalidomide treatment appears to be associated with significantly
more neutropenia, insomnia and muscle cramps; bortezomib treatment appears to be associated
with significantly more diarrhoea, nausea, peripheral neuropathy, vomiting, pyrexia,
thrombocytopenia, cough, paraesthesia and bone pain.
9. Clinical Claim
The submission described lenalidomide as superior to thalidomide in terms of comparative
effectiveness with a different safety profile.
The submission described lenalidomide as a more effective and well tolerated treatment
than bortezomib.
Overall, the PBAC concluded there is great uncertainty about the relative clinical
benefits of lenalidomide in comparison with either thalidomide or bortezomib, and
that the three drugs have different toxicities.
With respect to the comparison between lenalidomide and thalidomide, the lack of a
common reference precluded direct comparison of time to progression or overall survival,
and this, together with the poor quality of the thalidomide studies makes any conclusions
of superiority of one treatment over the other extremely unreliable.
With respect to the comparison between lenalidomide and bortezomib, while no differences
were observed in the hazard rates for overall survival, a formal comparison had not
been carried out.
10. Economic Analysis
A modelled economic evaluation was presented. The model calculated years of life lived
and progression-free years of life lived for lenalidomide and thalidomide, using the
survival data from the trials (three years), extrapolated for another three years
for a total time horizon of six years. Most of the difference in years of life lived
was from the within-trial data. Health benefits were based on the years of life lived,
while the treatment costs are driven by the progression free years of life lived.
The model structure was considered appropriate.
The incremental cost per life year gained (as calculated in the submission) for lenalidomide
in place of thalidomide for the treatment of patients with relapsed/refractory multiple
myeloma was between $45,000 and $75,000 (discounted). This increased using the updated
base case but remained within the same range.
The submission calculated an incremental cost per Quality-Adjusted Life-Year (QALY)
gained of between $75,000 and $105,000 (discounted).
11. Estimated PBS Usage and Financial Implications
The financial cost per year to the PBS was estimated to be between $30 and $60 million
in Year 5. The submission proposed a risk sharing agreement.
The PBAC noted that costings for the use of granulocyte colony-stimulating factors
(g-CSF), as per the guidelines used in the clinical studies, were not included in
financial estimates.
12. Recommendation and Reasons
The PBAC noted that, if listed as requested, a restriction similar to that for thalidomide
would be appropriate.
The PBAC considered that where used instead of thalidomide, thalidomide is the appropriate
comparator. However, lenalidomide may be used in patients who have previously failed
thalidomide. In this patient population bortezomib is the appropriate comparator.
The PBAC noted that the basis of the comparison of lenalidomide versus thalidomide
was the single arms of two direct randomised comparative trials with lenalidomide
plus dexamethasone versus placebo plus dexamethasone and two cohort studies with thalidomide
plus dexamethasone. The cohort studies with thalidomide were considered to be of very
poor quality, and the scientific basis of the comparison was therefore of a much lower
quality than is usually required to sustain a case for superiority.
The PBAC noted that there was no evidence of superiority of lenalidomide over thalidomide
in progression-free survival, and considered a comparison of overall survival to be
un-interpretable because of time biases (i.e. because the lenalidomide trials were
conducted more recently). Other improvements in managing these patients may explain
some or all of the claimed survival gains. On the data provided, even the case for
the non-inferiority of lenalidomide and thalidomide is uncertain. Furthermore it cannot
be anticipated that a randomised trial directly comparing thalidomide plus dexamethasone
with lenalidomide plus dexamethasone will be done.
Although the Committee considered that better evidence exists to support a comparison
between lenalidomide and bortezomib, with both superior to dexamethasone alone, there
remain uncertainties inherent in any indirect comparison.
Additionally, although the lenalidomide trials included subjects who had relapsed
after thalidomide (42.5% in 009 and 33.9% in 010) or bortezomib (10.6% in trial 090
and 4.5% in trial 010), the impact of prior treatment with bortezomib or thalidomide
remained uncertain.
With respect to comparative toxicity, no indirect comparison could be made between
lenalidomide and thalidomide using a common comparator. Based on trial data it appeared
the incidence of neuropathy is lower with lenalidomide compared to thalidomide. A
comparison between lenalidomide and bortezomib indicates that the overall incidence
of adverse events does not differ between them. However, the pattern of those events
is different: lenalidomide treatment appears to be associated with significantly more
neutropenia, insomnia and muscle cramps; bortezomib treatment appears to be associated
with significantly more diarrhoea, nausea, peripheral neuropathy, vomiting, pyrexia,
thrombocytopenia, cough, paraesthesia and bone pain.
Overall, the PBAC concluded there is great uncertainty about the relative clinical
benefits of lenalidomide in comparison with either thalidomide or bortezomib.
The PBAC also considered there was uncertainty in the modelled economic evaluation.
The inclusion of only the thalidomide naﶥ lenalidomide patients was inappropriate
because the requested listing did not exclude patients who have received prior treatment
with thalidomide. The total population of the lenalidomide trials was more appropriate
for inclusion in the model as using only the thalidomide naﶥ patients would favour
lenalidomide. There was also considerable uncertainty around the utility weights used
and these utilities used did not incorporate the different safety profiles of lenalidomide
and thalidomide.
The PBAC considered the incremental cost effectiveness ratios per life year gained
and per QALY to be unacceptably high and uncertain.
The PBAC therefore rejected the application based on the quality of the data, the
uncertainty of the clinical claim and the resulting unacceptably high and uncertain
cost effectiveness ratios.
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 believes that lenalidomide is an important therapeutic option for the treatment
of Multiple Myeloma patients in Australia. Celgene is therefore committed to working
with the PBAC to address any areas of uncertainty and ensure that patients are able
to access lenalidomide through the PBS.
