Plerixafor, solution for subcutaneous injection, 20 mg per mL, 1.2 mL, Mozobil®
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Product: Plerixafor, solution for subcutaneous
injection, 20 mg per mL, 1.2 mL, Mozobil®
Sponsor: Genzyme Australasia Pty Ltd
Date of PBAC Consideration: November 2010
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drugs
Program) listing for use in combination with granulocyte-colony
stimulating factor (G-CSF), in mobilisation of haematopoietic stem
cells to the peripheral blood for collection and subsequent
autologous transplantation in patients with non-Hodgkin lymphoma
(NHL), Hodgkin lymphoma (HL) and multiple myeloma (MM) who meet
certain criteria.
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 drug had not previously been considered by the PBAC.
3. Registration Status
Plerixafor was TGA registered on 31 May 2010 for use in combination
with G-CSF to mobilise haematopoietic stem cells to the peripheral
blood for collection and subsequent autologous transplantation in
patients with lymphoma and multiple myeloma.
4. Listing Requested and PBAC’s View
Section 100 listing – Highly Specialised Drug program
Private Hospital Authority Required
- Patients with NHL who are undergoing ASCT and have not failed previous stem cell collections or collection attempts.
- Patients with MM who are undergoing ASCT, have not failed previous stem cell collections or collection attempts, and are predicted to be poor mobilisers.
- Patients with NHL/HL who are undergoing ASCT and have failed previous stem cell collections or collection attempts.
- Patients with MM who are undergoing ASCT and have failed previous stem cell collections or collection attempts.
‘Failure’ is defined as the inability to collect the minimum number of cells required
for transplantation (2 x 106 CD34+cells/kg).
For PBAC’s view, see Recommendations and Reasons.
5. Clinical Place for the Proposed Therapy
High dose chemotherapy with autologous stem cell transplantation is
an effective treatment for patients with haematological
malignancies who are fit enough to undergo this form of therapy.
Before transplantation can take place, patients must undergo stem
cell mobilisation to increase the number of peripheral blood stem
cells available for collection and subsequent autologous
transplantation.
Currently, most patients are mobilised with G-CSF alone, or G-CSF
with chemotherapy.
The submission claimed that plerixafor used in combination with
G-CSF would provide an alternative therapy to enhance mobilisation
of stem cells in patients with NHL, HL and MM who are undergoing
high dose chemotherapy plus autologous stem cell transplantation
(ASCT).
6. Comparator
The submission nominated G-CSF alone as the comparator in treating
patients with NHL and MM, who have not failed previous stem cell
collections or collection attempts. The PBAC did not accept G-CSF
alone as the appropriate comparator.
The submission nominated G-CSF in combination with chemotherapy
(ifosfamide plus carboplatin plus etoposide for NHL; and
cyclophosphamide for MM) as the comparator in treating patients
with NHL, HL and MM, who have failed previous mobilisation
attempts. The PBAC considered this appropriate.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
For use as first-line therapy in NHL, the submission presented one randomised trial
comparing first-line plerixafor plus G-CSF with placebo plus G-CSF in NHL patients
(Study 3101).
For use as first-line treatment in predicted poor mobilisers with MM, the submission
presented one randomised trial comparing first-line plerixafor 0.24 mg per kg plus
G-CSF with placebo plus G-CSF in MM patients, with post-hoc analyses in the subgroup defined as predicted poor mobilisers (i.e. MM patients with
a pre-apheresis peripheral blood CD34+ count less than 10 cells per microlitre) (Study
3102).
For second-line use in patients with NHL, HL and MM, the submission presented five
observational cohorts of patients receiving second-line plerixafor 0.24 mg per kg
plus
G-CSF in NHL, HL and MM patients (Calandra 2008, Fowler 2009, Micallef 2009, Pusic
2008 and Tricot 2010); and compared these to one observational cohort of patients
receiving second-line chemotherapy plus G-CSF (Pusic 2008). An independent search
located an additional observational cohort of NHL, HL and MM patients receiving second-line
plerixafor (Duarte 2010). Details these trials are presented in the following table.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| First-line therapy in NHL | ||
| plerixafor plus G-CSF vs. placebo plus G-CSF | ||
|
Study 3101 DiPersio et al. (2009a) DiPersio et al. (2007) |
Phase III prospective randomised double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilisation and transplantation for patients with non-Hodgkin's lymphoma A phase III, multicenter, randomised, double-blind, placebo-controlled, comparative trial of AMD3100 (Plerixafor)+G-CSF vs. placebo+G-CSF in non-Hodgkin's lymphoma (NHL) patients for autologous haematopoietic stem cell (aHSC) transplantation |
Journal of Clinical Oncology 27:4767-4773, 2009 Blood (ASH Annual Meeting Abstracts) 2007; 110: Abstract 601 |
| First-line therapy in MM | ||
| plerixafor plus G-CSF vs. placebo plus G-CSF | ||
|
Study 3102 DiPersio et al. (2009b) DiPersio et al. (2007) |
Plerixafor and G-CSF versus placebo and G-CSF to mobilise haematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. A Phase III, Multicenter, Randomised, Double-Blind, Placebo-Controlled, Comparative Trial of AMD3100 (Plerixafor)+G-CSF vs. G-CSF+Placebo for Mobilisation in Multiple Myeloma (MM) Patients for Autologous Haematopoietic Stem Cell (aHSC) Transplantation |
Blood 113:5720-5726, 2009 Blood (ASH Annual Meeting Abstracts) 2007; 110: Abstract 445 |
| Second-line NHL, HL and MM (failed mobilisers) | ||
| plerixafor plus G-CSF | ||
|
Calandra et al. Fowler et al. Micallef et al. Pusic et al. Tricot et al. Duarte et al. |
AMD3100 plus G-CSF can successfully mobilise CD34+ cells from non-Hodgkin's lymphoma, Hodgkin's disease and multiple myeloma patients previously failing mobilisation with chemotherapy and/or cytokine treatment: Compassionate use data Rescue from failed growth factor and/or chemotherapy HSC mobilisation with G-CSF and plerixafor (AMD3100): An institutional experience Successful Stem Cell Mobilisation Rescue by AMD3100 (Plerixafor)+G-CSF for Patients Who Failed Primary Mobilisation: Results from the Phase III (3101-NHL) Study Impact of Mobilisation and Remobilisation Strategies on Achieving Sufficient Stem Cell Yields for Autologous Transplantation Safety and efficacy assessment of plerixafor in patients with multiple myeloma proven or predicted to be poor mobilisers, including assessment of tumor cell mobilisation Plerixafor plus granulocyte CSF can mobilise hematopoietic stem cells from multiple myeloma and lymphoma patients failing previous mobilisation attempts: EU compassionate use data. |
Bone Marrow Transplantation , 41:331-338, 2008 Bone Marrow Transplantation 43:909-917, 2009 Blood (ASH Annual Meeting Abstracts) 2007; 110: Abstract 602 Biology of Blood and Marrow Transplantation 14:1045-1056, 2008 Bone Marrow Transplantation 45:63-68, 2008 Bone Marrow Transplantation , advance online publication 22 March 2010; doi:10.1038/bmt.2010.54 |
| chemotherapy plus G-CSF | ||
| Pusic et al. | Impact of Mobilisation and Remobilisation Strategies on Achieving Sufficient Stem Cell Yields for Autologous Transplantation | Biology of Blood and Marrow Transplantation 14:1045-1056, 2008 |
8. Results of Trials
First-line non-Hodgkin lymphoma (NHL):
The primary outcomes of Study 3101 were the percentage of patients able to mobilise
greater than or equal to 5 x 106 CD34+ cells per kg in less than or equal to 4 days of apheresis; and achieve greater
than or equal to 2 x 106 CD34+ cells per kg in less than or equal to 4 days of apheresis and have successful
polymorphonuclear and platelet engraftment (European Medicines Agency (EMA)-specific
composite endpoint).
The secondary outcomes and post-hoc analyses for Study 3101 were the proportions of patients achieving the optimum number
of CD34+ cells of greater than or equal to 2 x 106 CD34+ cells per kg within 2 and 4 days of apheresis, and the number of days of apheresis
required to reach greater than or equal to 2 x 106 CD34+ cells per kg.
The following table summarises the results of the primary efficacy outcomes for Study
3101 in NHL patients.
Results of primary efficacy outcomes for Study 3101 in NHL patients
| Trial ID | Plerixafor n/N (%) | Placebo n/N (%) | Risk Difference (95% CI) | Relative Risk (95% CI) | Odds Ratio (95% CI) |
| % of patients able to mobilise greater than or equal to 5 x 10 6 CD34+ cells/kg in less than or equal to 4 days of apheresis | |||||
| Study 3101 (NHL) | 89/150 (59.3) | 29/148 (19.6) | 0.40 (0.30, 0.50) | 3.03 (2.13, 4.31) | 5.99 (3.56, 10.07) |
| p-value | p<0.00001 | p<0.00001 | p<0.00001 | ||
| % of patients achieving greater than or equal to 2 x 10 6 CD34+ cells/kg in less than or equal to 4 days of apheresis and having successful polymorphonuclear and platelet engraftment (EMA-specific composite endpoint) | |||||
| Study 3101 (NHL) | 126/150 (84.0) | 64/148 (43.2) | 0.41 (0.31, 0.51) | 1.94 (1.59, 2.37) | 6.89 (4.00, 11.88) |
| p-value | p<0.00001 | p<0.00001 | p<0.00001 | ||
Abbreviations: CI, confidence interval; EMA, European Medicines Agency; NHL, non-Hodgkin
lymphoma
Statistically significantly more NHL patients treated with plerixafor achieved the
primary endpoint and the EMA-specific composite endpoint compared to patients in the
placebo arm. However, it was noted in DiPersio et al. (2009a) that the failure rate
in the placebo arm of the trial was higher than expected.
More plerixafor treated patients (90%; 135 of 150) proceeded to transplant compared
with 55.4% of patients (82 of 148) in the placebo arm. However, the magnitude of this
benefit remained uncertain due to the high unexplained rates of treatment failure
in placebo-treated patients.
For patients proceeding to transplant there were no statistically significant differences
in successful polymorphonuclear and platelet engraftment or graft durability between
plerixafor and placebo treated patients. For all patients, there was no evidence of
a difference in patient survival at 12 months between the two treatment groups, although
it was noted that there were few deaths in either plerixafor or placebo treated arms
at 12 months. Longer term data on progression-free survival and overall survival for
this trial will not be available until 2014.
The key outcomes differ from those chosen for use in the economic model. The key outcomes
of the trial related to the proportions of patients achieving the optimum number of
CD34+ cells within a specified number of days. The proportion of patients achieving
the minimum number of CD34+ cells (greater than or equal to 2 × 106 CD34+ cells per kg) was considered to be more important for this submission and to
reflect clinical practice. Post-hoc analyses were conducted to determine the proportion of patients achieving this minimum
target collection within two days, and the mean number of days of apheresis required
to achieve this minimum target collection.
The following table summarises the results the secondary outcomes and post-hoc analysis for Study 3101 in NHL patients.
Results of key secondary efficacy outcomes and post-hoc analysis for Study 3101 in NHL patients
| Trial ID | Plerixafor n/N (%) | Placebo n/N (%) | Risk Difference (95% CI) | Relative Risk (95% CI) | Odds Ratio (95% CI) |
| % of patients achieving greater than or equal to 2 x 10 6 CD34+ cells/kg in less than or equal to 4 days of apheresis | |||||
| Study 3101 (NHL) | 130/150 (86.7) | 70/148 (47.3) | 0.39 (0.30, 0.49) | 1.83 (1.53, 2.20) | 7.24 (4.09, 12.82) |
| p-value | p<0.00001 | p<0.00001 | p<0.00001 | ||
| Post-hoc analysis of the % of patients achieving greater than or equal to 2 x 10 6 CD34+ cells/kg in less than or equal to 2 days of apheresis | |||||
| Study 3101 (NHL) | 119/150 (79.3) | NR | NR | NR | NR |
Abbreviations: CI, confidence interval; EMA, European Medicines Agency; NHL, non-Hodgkin
lymphoma
A statistically significantly higher proportion of NHL patients receiving plerixafor
achieved a collection of greater than or equal to 2 × 106 CD34+ cells per kg in less than or equal to 4 days of apheresis compared to placebo
(86.7% versus 47.3%). The results of a post-hoc analysis of the proportion of plerixafor-treated patients achieving a collection
of greater than or equal to 2 × 106 CD34+ cells per kg in less than or equal to 2 days of apheresis showed that the proportions
achieving this minimum target in less than or equal to 2 days was only slightly lower
than that reported achieving this target in less than or equal to 4 days (79.3% versus
86.7%).
The results of a post-hoc analysis for Study 3101 in NHL patients showed that patients
in the plerixafor arm required fewer days of apheresis compared to the placebo arm
to achieve the target collection of greater than or equal to 2 × 106 CD34+ cell per kg: mean of 2.02 versus 3.29 days.
First-line predicted poor mobilisers with multiple myeloma (MM):
The submission presented the full trial population results however, there were not
directly relevant to the requested PBS listing, (i.e. MM patients who have not failed
previous stem cell collections or collection attempts, and are predicted to be poor
mobilisers) and are not represented here.
The submission presented data to establish that the clinical efficacy of plerixafor
would be more apparent in the subgroup of patients who are predicted to be poor mobilisers.
The results of the post-hoc subgroup analyses for these poor mobilisers incorporated in the economic model are
summarised in the following table.
Post-hoc analyses of outcomes for a subgroup of MM patients with a pre-apheresis peripheral
blood CD34+ count of <10cells/μL on Day 4 and the full trial population from Study
3102
| Population | Plerixafor | Placebo | Difference | p-value |
| % of patients able to mobilise greater than or equal to 2 x 10 6 CD34+ cells/kg in less than or equal to 4 days of apheresis, n/N (%) | ||||
| PB CD34+ less than 10 cells/mcL | 25/27 (92.6) | 21/30 (70.0) | 22.6% | 0.031 |
| Full population | 141/148 (95.3) | 136/154 (88.3) | 7.0% | 0.031 |
| Post-hoc analysis: % of patients able to mobilise greater than or equal to 2 x 10 6 CD34+ cells/kg in less than or equal to 2 days of apheresis, n/N (%) | ||||
| PB CD34+ less than 10 cells/mcL | 25/27 (92.6) | 13/30 (43.3) | 49.3% | <0.001 |
| Full population | 139/148 (93.9) | 121/154 (78.6) | 15.3% | <0.001 |
| Post-hoc analysis: Mean number of days of apheresis to mobilise greater than or equal to 2 x 10 6 CD34+ cells/kg (Range) | ||||
| PB CD34+ less than 10 cells/mcL | 1.33 (1, 4) | 2.70 (1, 4) | 1.02 days | <0.001 |
| Full population | 1.1 (1, 3) | 1.5 (1, 4) | 0.5 days | <0.0001 |
Abbreviations: MM, multiple myeloma; PB = peripheral blood;
There were substantial differences in the proportions of plerixafor-treated patients
achieving optimum cell targets (greater than or equal to 6 × 106 CD34+ cells per kg in less than or equal to 2 days) between the full population and
the subgroup of poor mobilisers (71.6% versus 40.7%).
For the more clinically relevant minimum cell collection target of greater than or
equal to 2 ×106 CD34+ cells per kg in less than or equal to 2 days, 92.6% in predicted poor mobilisers
achieved this target versus 93.9% in the full trial population.
Second-line NHL, HL and MM:
The following table summarises the number of patients achieving the optimum number
of CD34+ cells of greater than or equal to 2 x 106 CD34+ cells per kg, in the observational cohort studies.
Patients achieving greater than or equal to 2 x 106 CD34+ cells/kg
| NHL | HL | MM | Total population | ||
| Plerixafor n/N (%) | Plerixafor n/N (%) | Plerixafor n/N (%) | Plerixafor n/N (%) | Chemotherapy n/N (%) | |
| Calandra (2008) | 38/63 (60) | 13/17 (77) | 25/35 (71) | 76/115 (66) | NA |
| Duarte (2010) | 15/24 (63) | 27/32 (84) | 42/56 (75) | NA | |
| Fowler (2009) | 10/10 (100) | 1/2 (50) | 4/6 (67)* | 17/20 (85) | NA |
| Micallef (2009) | 37/62 (60) | NA | NA | 37/62 (60) | NA |
| Pusic (2008) | NR | NR | NR | 13/18 (72) | 9/34 (26) |
| Tricot (2010) | NA | NA | 7/10 (70) | 7/10 (70) | NA |
Abbreviations: HL, Hodgkin lymphoma; MM, multiple myeloma; NA, not applicable;
NHL, non-Hodgkin lymphoma; NR = not reported
* Patient 1 and Patient 12 with MM failed mobilisation.
Note: Data for NHL/HL separated during the evaluation where possible. Some of the
data were corrected for transcription errors. Data from Duarte 2010 were extracted
during the evaluation
Duarte (2010) identified during the evaluation
NHL: In the pivotal trial Study 3101, 86.7% of NHL patients receiving plerixafor achieved
the minimum collection of greater than or equal to 2 × 106 CD34+ cells per kg in less than or equal to 4 days in the first-line setting. Data
from the subset of observational cohorts reporting this outcome suggested that 60%
to 100% of patients receiving plerixafor in the second-line setting achieved this
minimum target collection.
HL: The pivotal direct randomised trials presented in the submission did not recruit
HL patients. Based on small numbers of patients in the observational cohorts, 50%
to 77% of the patients successfully mobilised the minimum target collection. The PBAC
noted that the data for HL patients was very uncertain in that the data was non randomised
and was based on very small patient numbers (n=19).
MM: In the pivotal trial Study 3102, 95.3% of MM patients from the full trial population
receiving plerixafor achieved the minimum collection of greater than or equal to 2
× 106 CD34+ cells per kg in less than or equal to 4 days in the first-line setting. Data
from the observational cohorts indicated that 67% to 84% of MM patients receiving
plerixafor in the second-line setting achieved this minimum target collection.
There were limited data available to assess the impact of plerixafor in cell mobilisation
in the second-line setting. However, plerixafor-treatment appeared to produce quantitatively
similar results in achieving minimum cell targets (greater than or equal to 2 × 106 CD34+ cells per kg) in the first-line and second-line setting for NHL and MM.
Pusic et al (2008) was the only observational study to report cell collection for
chemotherapy plus G-CSF mobilisation. Data were reported for all disease groups combined.
Of 34 patients treated with chemotherapy-based mobilisation regimens, nine patients
(24%) achieved the minimum cell collection of greater than or equal to 2 × 106 CD34+ cells per kg. There were limited data presented to assess the effectiveness
of chemotherapy plus G-CSF in second-line mobilisation.
For PBAC’s view of these results, see Recommendations and Reasons.
Based on the short-term trials and studies, the majority of the adverse events associated
with plerixafor appeared to be mild to moderate; and included gastrointestinal disorders
(e.g. diarrhoea, nausea, vomiting, flatulence and abdominal pain), injection site
reactions (e.g. erythema and pruritis) and dizziness. There were no long term safety
data available. Concerns regarding potential risk of mobilising tumour cells have
been raised by regulatory agencies.
The PBAC noted the advice in the Pre-Subcommittee response that according to the TGA
clinical evaluator, mobilisation of tumour cells can result from “all methods of mobilisation
including G-CSF,” and that the sponsor was currently undertaking long term follow-up
studies of patients from the pivotal studies.
9. Clinical Claim
The submission claimed that plerixafor for first-line treatment is
superior in terms of comparative effectiveness over placebo. No
specific claim was made on the comparative safety of plerixafor
plus G-CSF over G-CSF.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a stepped economic evaluation which was a
cost-utility analysis.
The economic model was a decision analysis applied separately for
each of four requested listings (NHL and HL second-line listings
were considered together)
.
The results of Steps 1 to 3 of the economic evaluations for each of
the requested indications are summarised in the following table,
with incremental cost-effectiveness ratios shown in indicative
ranges only.
Results of the economic evaluation
| Indication | ICER |
| Step 1: Incremental cost per additional patient achieving successful mobilisation | |
| NHL (first-line and second-line) | $15,000 - $45,000 |
| MM (first-line in predicted poor mobilisers and second-line) | $15,000 - $45,000 |
| NHL/HL (second-line) | $15,000 - $45,000 |
| MM (second-line) | < $15,000 |
| Step 2: Incremental cost per life year gained | |
| NHL (first-line and second-line) | <$15,000 |
| MM (first-line in predicted poor mobilisers and second-line) | $15,000 - $45,000 |
| NHL/HL (second-line) | <$15,000 |
| MM (second-line) | $15,000 - $45,000 |
| Step 3: Incremental cost per QALY gained | |
| NHL (first-line and second-line) | $15,000 - $45,000 |
| MM (first-line in predicted poor mobilisers and second-line) NHL/HL (second-line) | $45,000 - $75,000 |
| $15,000 - $45,00 | |
| MM (second-line) | $15,000 - $45,000 |
Abbreviations: HL, Hodgkin lymphoma; ICER, incremental
cost-effectiveness ratio; MM, multiple myeloma; NHL, non-Hodgkin
lymphoma; QALY, quality adjusted life year
The submission claimed that plerixafor was more cost-effective in
second-line only, than first- and second-line use; and in both
first- and second-line use, and second-line only use, plerixafor
was more cost-effective in NHL than in MM.
The economic model was most sensitive to the assumed event-free and
overall survival; cost per vial of plerixafor; mobilisation success
rate of plerixafor; and the rates of febrile neutropenia. The model
was also sensitive to mobilisation success rate and survival
estimates varied simultaneously.
The PBAC agreed that there was considerable uncertainty with the
submission’s economic evaluation. See Recommendations and
Reasons.
11. Estimated PBS Usage and Financial Implications
The financial costs per year to the PBS (inclusive of patient
co-payments) for the requested listings were all estimated in the
submission to be less than $10 million.
The PBAC considered the submission’s estimates
uncertain.
12. Recommendation and Reasons
The PBAC noted that the submission nominated G-CSF alone as the
comparator in treating patients with NHL and MM, who have not
failed previous stem cell collections or collection attempts.
However, the PBAC considered that the appropriate comparator for
this indication was chemotherapy plus G-CSF as this was considered
the most common clinical practice for mobilisation in Australia.
The PBAC noted that increased stem cell mobilisation can be
obtained in combination with chemotherapy compared with G-CSF
alone. In addition, chemotherapy is required as salvage for
lymphoma and is commonly used routinely in myeloma patients, and
therefore stem cell collection is incorporated with anti-lymphoma
therapy and anti-myeloma therapy. The PBAC also noted that
cyclophosphamide, when used for mobilisation in patients with
multiple myeloma, is also a potent anti-myeloma therapy.
The PBAC thus agreed that G-CSF in combination with chemotherapy
was the appropriate comparator for the treatment of patients with
NHL, HL and MM, who have failed previous mobilisation
attempts.
The PBAC noted that for use as first-line therapy in NHL, the
submission presented one randomised trial comparing first-line
plerixafor plus G-CSF with placebo plus G-CSF in NHL patients
(Study 3101). Statistically significantly more NHL patients treated
with plerixafor achieved the primary endpoint (59.3% versus 19.6%)
and the EMA-specific composite endpoint (84.0% versus 43.2%)
compared to patients in the placebo arm. The PBAC also noted that
more plerixafor-treated patients (90%) proceeded to transplant
compared with (55.4%) of patients in the placebo arm. However, the
magnitude of this benefit remains uncertain due to the high
unexplained rates of treatment failure in placebo-treated
patients.
For use as first-line treatment in patients with MM who are
predicted poor mobilisers, the submission presented Study 3102
comparing plerixafor plus G-CSF with placebo plus
G-CSF, with post-hoc analyses in the subgroup defined as predicted
poor mobilisers, (i.e. MM patients with a pre-apheresis peripheral
blood CD34+ count of less than 10 cells per microlitre). The PBAC
noted that there were only small differences in proportions of
plerixafor-treated patients achieving the more clinically relevant
minimum cell collection target of greater than or equal to 2
×106 CD34+ cells per kg in less than or equal to 2
days (92.6% in predicted poor mobilisers versus 93.9% in the full
trial population) which suggested that plerixafor is as effective
in poor mobilisers at achieving minimum target cell
collections.
For second-line use in patients with NHL, HL and MM, the submission
presented five observational cohorts of patients receiving
second-line plerixafor. The PBAC agreed that plerixafor treatment
appeared to produce quantitatively similar results in achieving
minimum cell targets (greater than or equal to 2 × 106 CD34+
cells per kg) in the first-line and second-line setting for NHL and
MM. However, the PBAC noted that this was an uncontrolled series
and as such there is a lack of comparator data and that the
comparator data that do exist may not be representative as a
consequence of reporting bias.
Regarding the clinical claim, the PBAC agreed that in the
first-line mobilisation setting plerixafor plus G-CSF is superior
in terms of comparative effectiveness over G-CSF alone but the
clinical importance of this is uncertain in Australian practice as
the submission did not provide a comparison with chemotherapy plus
G-CSF. No specific claim was made on the comparative safety of
plerixafor plus G-CSF over G-CSF.
For second-line treatment, the PBAC also agreed that plerixafor
plus G-CSF could be an effective means to mobilise patients who
have previously failed to mobilise, but noted that the submission
did not specifically make a claim regarding the comparative
efficacy and safety over chemotherapy plus G-CSF.
The PBAC considered that as the submission did not provide any
evidence of benefit over chemotherapy plus G-CSF in the first-line
setting there was no basis for a cost-effectiveness
comparison.
However, the PBAC noted that the submission presented a stepped
economic evaluation which was a cost-utility analysis. The PBAC
agreed that there is considerable uncertainty with the
submission’s economic evaluation, given the number of issues
with the model and inputs as identified by its Economics
Sub-Committee, such as the response rate of the comparator arms,
risk of febrile neutropenia associated with chemotherapy-based
mobilisation regimens, survival benefit associated with downstream
treatment, and utilities/disutilities values.
The PBAC noted that the overall survival benefit modelled for
plerixafor patients depended on an increased proportion of patients
mobilising sufficiently to undergo autologous stem cell transplant
(ASCT) and high dose chemotherapy (HDT), and the assumption that
ASCT and HDT will improve overall survival compared to standard
chemotherapy. The key trials presented in the submission reported
survival data at 12 months, at which stage no difference in
survival was apparent. The PBAC agreed that the extrapolation of
the surrogate outcomes measured in the trials to a survival benefit
in the economic model was highly uncertain. The PBAC also noted
that the survival benefit studies considered in the submission
would not have included patients who were poor mobilisers. There
was also concern whether the economic model presented reflects
likely clinical practice or outcomes in the Australian context and
whether a comparison of survival benefit of chemotherapy plus G-CSF
would be needed, as the incremental benefit of this combination may
not be the same as G-CSF alone. The PBAC noted that longer term
data on progression-free survival and overall survival for both
these trials will not be available until 2014.
The PBAC therefore rejected the submission on the basis of an
inappropriate comparator for the first-line indications, uncertain
clinical benefit in second-line setting relating to the lack of
comparative data, and uncertainty regarding the economic
model.
The PBAC agreed that any future submission should provide a
comparison with chemotherapy plus G-CSF in the first-line setting.
A simple and conservative comparison of costs of mobilisation on a
per patient basis should also be provided, rather than a claim of
highly uncertain transplant benefits.
The PBAC noted the advice of the Highly Specialised Drugs Working
Party which concluded that plerixafor meets all the criteria for
listing under the Highly Specialised Drugs Program.
The PBAC also noted the consumer comments received for this
item.
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
Genzyme Australasia is committed to working to address the
PBAC’s issues and demonstrating, what Genzyme Australasia
considers to be, the significant benefits of Mozobil for patients
with lymphoma and multiple myeloma.
