Pegfilgrastim, single dose pre-filled syringe, 6 mg in 0.6 mL, Neulasta, March 2008
Public summary document for Pegfilgrastim, single dose pre-filled syringe, 6 mg in 0.6 mL, Neulasta, March 2008
Page last updated: 18 July 2008
Public Summary Documents
Product: Pegfilgrastim, single dose pre-filled syringe, 6 mg in 0.6 mL, Neulasta
Sponsor: Amgen Australia Pty Ltd
Date of PBAC Consideration: March 2008
1. Purpose of Application
The submission requested an extension to the current Section 100 listing for use as primary prophylaxis for chemotherapy induced neutropenia (CIN) in all patients with breast cancer treated with docetaxel by replacing the words “breast cancer (adjuvant chemotherapy with docetaxel in combination with an anthracycline and cyclophosphamide)” with “breast cancer treated with docetaxel”.
2. Background
At the September 2002 meeting, the PBAC recommended a Section 100 listing for pegfilgrastim
for the same indications as filgrastim on a cost-minimisation basis compared with
filgrastim. Single dose pegfilgrastim 6 mg was considered to be of similar efficacy
and safety to filgrastim 5 micrograms/kg per day (as used on the PBS) for an average
of 11.25 days.
At its November 2006 meeting the PBAC recommended extending the pegfilgrastim listing
to include the primary prophylaxis of chemotherapy induced neutropenia in patients
with breast cancer who are undergoing adjuvant chemotherapy with docetaxel in combination
with an anthracycline and cyclophosphamide. In November 2007 the PBAC also recommended
that this recommendation should apply to filgrastim.
3. Registration Status
Pegfilgrastim is TGA-registered for the treatment of patients with cancer following chemotherapy to decrease the duration of severe neutropenia, and so reduce the incidence of infection, as manifested by febrile neutropenia.
4. Listing Requested and PBAC’s View
Section 100 private hospital authority required
Patients being treated with aggressive chemotherapy with the intention of achieving
a cure or substantial remission in:
(a) acute lymphoblastic leukaemia; or
Amend part (b) of the current listing to read:
(b) breast cancer treated with docetaxel; or
(c) ....
The PBAC did not comment on the requested restriction.
5. Clinical Place for the Proposed Therapy
Pegfilgrastim is a granulocyte colony stimulating factor (G-CSF) used to prevent CIN.
6. Comparator
The comparator for patients with advanced breast cancer treated with docetaxel was no granulocyte colony stimulating factor (G-CSF); pegfilgrastim used as secondary prophylaxis was the comparator in patients with early breast cancer treated with docetaxel plus trastuzumab. The PBAC accepted these were the appropriate comparators.
7. Clinical Trials
The submission presented one randomised trial (Vogel) comparing primary prophylaxis
of pegfilgrastim with placebo (secondary prophylaxis) in patients with breast cancer
(both metastatic and non-metastatic) receiving docetaxel monotherapy 100 mg/m2 over
12 weeks. The submission further presented pre-specified subgroup analyses for metastatic
and non-metastatic breast cancer, under the assumption that the metastatic group represents
advanced breast cancer and the non-metastatic group represents early breast cancer.
The trial has been published as follows:
|
Trial ID |
Protocol title/ Publication title |
Publication citation |
|---|---|---|
|
Vogel, Rader et al 2005 |
Pegfilgrastim nearly abrogates occurrence of neutropenic events early in the course
of chemotherapy: Results of a phase III, randomised, double-blind, placebo-controlled
study of patients with breast cancer receiving docetaxel. |
The Journal of Supportive Oncology 2005;3(2 SUPPL 1):58-59. |
8. Results of Trials
The results of the Vogel randomised controlled trial are summarised in the table below.
Results of the Vogel trial – primary endpoint defined FN
|
Outcome |
ITT population |
|
|---|---|---|
|
1 Prophy. |
2 Prophy. |
|
|
Yes |
6 (1%) |
78 (17%) |
|
No |
456 (98%) |
386 (83%) |
|
Unknowna |
1 (0%) |
1 (0%) |
|
Difference |
-15.5% |
|
|
95% CI |
-19.0%,-11.9% |
|
|
Relative risk (95% CI) |
0.077 |
(0.034, 0.175) |
Notes: aSubject withdrew prior to first on-study lab assessment.
1 Prophy. = primary prophylaxis; 2 Prophy. = secondary prophylaxis; FN = febrile neutropenia;
CI = confidence interval; ITT = intention to treat.
There was a statistically significant and clinically important difference in the incidence
of febrile neutropenia (FN), favouring primary prophylaxis with pegfilgrastim in the
trial’s primary analysis.
The PBAC noted that the applicability of this result to the intended early breast
cancer PBS population was uncertain as both the population and chemotherapy regimen
in the non-metastatic stratum are not consistent with the requested PBS listing. The
intended PBS population is HER2 positive early breast cancer treated with docetaxel
plus trastuzumab, while the population in the Vogel trial was non-metastatic breast
cancer patients treated with docetaxel monotherapy. The sponsor has stated “it is
unlikely that the HER2 status of a patient would impact on either baseline risk of
FN or the efficacy or safety of pegfilgrastim.” In addition, the Sponsor presented
evidence to show that the addition of trastuzumab to docetaxel increases the risk
of FN and therefore these patients have a higher clinical need for pegfilgrastim as
compared to the clinical trial population.
For the advanced breast cancer patients, the PBAC noted that although it was unclear
the extent of overlap between the proposed PBS population and the patients in the
metastatic subgroup, the intention-to-treat (ITT) population are likely to be representative
of advanced breast cancer patients, as over 80% of the ITT population had Stage III
or IV diseases (defined as advanced breast cancer according to NHMRC Clinical Practice
Guidelines for the Management of Advanced Breast Cancer). Therefore, it was likely
that the results observed from the ITT population could be generalised to patients
with advanced breast cancer.
The full dose of chemotherapy as scheduled in the primary prophylaxis group did not
differ significantly from that in the secondary prophylaxis group. The PBAC noted
that maintaining and/or improving compliance with chemotherapy, as one of the primary
objectives of prophylaxis, did not seem to have been achieved. Therefore, primary
prophylaxis may not have survival benefit compared with secondary prophylaxis.
9. Clinical Claim
The submission described pegfilgrastim primary prophylaxis as superior in terms of
comparative effectiveness and similar in terms of comparative safety to pegfilgrastim
secondary prophylaxis.
The evaluation commented that based on supporting data, this description may be reasonable,
but advised the applicability of the results to the proposed PBS population is uncertain.
The extent of overlap between the patients in the non-metastatic subgroup in the Vogel
trial and the population for whom PBS listing is sought (HER2 positive early breast
cancer) was unclear. The stratified study population results were not representative
of either the advanced breast cancer or early breast cancer patient groups, although
the ITT population has a considerable overlap with advanced breast cancer population.
The proposed comparator for the advanced breast cancer setting was no G-CSF, while
the Vogel trial compared pegfilgrastim primary prophylaxis with pegfilgrastim secondary
prophylaxis. The chemotherapy regimen administered in the Vogel trial was docetaxel
monotherapy, which may have a different safety profile to that of docetaxel plus trastuzumab,
which is used in HER2 positive early breast cancer patients.
For PBAC's views see Recommendations and Reasons.
10. Economic Analysis
The submission conducted separate premodelling studies for pegfilgrastim primary prophylaxis
in settings of advanced breast cancer treated with docetaxel and of early breast cancer
treated with docetaxel plus trastuzumab.
The submission extrapolated the relative risk of FN of primary prophylaxis vs. secondary
prophylaxis in the first cycle to the remaining cycles to derive the estimated number
of FN events without prophylaxis over the course of chemotherapy. This may not be
reasonable, given that the relative risk of FN in later cycles may be different from
that in Cycle 1, due to patient-relevant and time-dependent factors such as chemotherapy
and G-CSF dosage and cycle length, modification in response to adverse events, and
patient co-morbidities.
The submission presented separate stepped economic evaluations for (i) advanced breast
cancer treated with docetaxel, and (ii) early breast cancer treated with docetaxel
plus trastuzumab. Both economic evaluations were cost-effectiveness analyses over
a time horizon of four chemotherapy cycles (4 נ21 days/cycle). The outcome of the
cost-effectiveness analysis is the incremental cost per FN event avoided.
(i) Advanced breast cancer treated with docetaxel
In the model for advanced breast cancer treated with docetaxel, the efficacy of pegfilgrastim
versus no pegfilgrastim as observed in cycle 1 of the clinical trials was extrapolated
to the subsequent cycles.
The incremental cost per FN event avoided was between $15,000 and $45,000. This was
most sensitive to the relative risk of FN in primary prophylaxis vs. no G-CSF prophylaxis
as well as the number of chemotherapy cycles.
The PBAC did not consider the extrapolation of the relative risk of FN for primary
versus secondary prophylaxis in Cycle 1 to Cycles 2 to 4 to derive the estimated number
of FN events without prophylaxis over the course of chemotherapy was reasonable, given
that the risk of FN reduces in later cycles from that in Cycle 1, due to patient-relevant
and time-dependent factors such as chemotherapy and G-CSF dosage and cycle length,
modification in response to adverse events, and patient co-morbidities. The PBAC recalled
that this means that because the increase in costs remains constant but the extent
of FN reduction decreases as the number of cycles of chemotherapy increases, the cost-effectiveness
ratio becomes less favourable. In the setting proposed, the number of cycles could
be as large as 20, which is greater than the number of cycles considered for other
listed situations with a similar risk of FN in Cycle 1. The PBAC also noted that when
the lower confidence interval for the relative risk of FN in Cycle 1 is applied to
cycles 2-4, or the average number of cycles is increased to 6, the incremental cost
per FN event avoided is greater.
(ii) Early breast cancer treated with docetaxel plus trastuzumab
The risk of FN associated with docetaxel plus trastuzumab and the efficacy of primary
versus secondary prophylaxis observed in the Vogel trial drive the model for early
breast cancer treated with docetaxel plus trastuzumab.
There was a large difference in the incremental cost per FN avoided using the two
different scenarios to estimate the risk of FN associated with docetaxel plus trastuzumab.
The model is most sensitive to the efficacy of primary prophylaxis (relative risk
reduction in FN of primary versus secondary prophylaxis), the risk of FN associated
with docetaxel plus trastuzumab, the FN risk in the secondary prophylaxis group, and
the extent of secondary prophylaxis use. The base case result from Step 2 analysis
is an incremental cost per FN event avoided between $15,000 and $45,000. The incremental
cost per FN event avoided would be much higher if the alternative values of these
sensitive variables were applied to the model.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of pegfilgrastim units dispensed per year as less than 10,000 in year 5, at a net cost to the PBS of less than $10 million. The PBAC noted the estimates were uncertain in relation to the proportion of eligible patients who are likely to be treated with pegfilgrastim as primary prophylaxis, but the cost to government was likely to be an underestimate.
12. Recommendation and Reasons
The PBAC noted that, in the Vogel trial, the full dose of chemotherapy as scheduled
in the primary prophylaxis group did not differ significantly from that in the secondary
prophylaxis group i.e. the reduction in febrile neutropenia (FN) was not relevant
clinically in terms of chemotherapy dose intensity. Therefore, primary prophylaxis
would not be expected to have a survival benefit compared with secondary prophylaxis
in terms of better chemotherapy effect.
The PBAC noted that the pre-specified subgroup analyses for metastatic and non-metastatic
breast cancer assumed that the metastatic group represented advanced breast cancer
and the non-metastatic group, early breast cancer. However, the PBAC considered that
the applicability of this result to the intended early breast cancer PBS population
was uncertain as both the population and the chemotherapy regimen in the non-metastatic
stratum were inconsistent with the requested PBS listing. The intended PBS population
is HER2 positive early breast cancer treated with docetaxel plus trastuzumab, while
the population in the Vogel trial was non-metastatic breast cancer patients treated
with docetaxel monotherapy.
In addition, the PBAC noted that the dose of docetaxel monotherapy in the Vogel trial
was 100mg/m2. However, in clinical practice, a proportion of patients would receive
75mg/m2 docetaxel monotherapy which is not as myelotoxic. The PBAC considered that
the submission failed to identify the applicability of the trial results to the chemotherapy
regimen containing docetaxel 75mg/m2.
The PBAC did not consider the extrapolation of the relative risk of FN for primary
versus secondary prophylaxis in Cycle 1 to Cycles 2 to 4 to derive the estimated number
of FN events without prophylaxis over the course of chemotherapy was reasonable, given
that the risk of FN reduces in later cycles from that in Cycle 1, due to patient-relevant
and time-dependent factors such as chemotherapy and G-CSF dosage and cycle length,
modification in response to adverse events, and patient co-morbidities. The PBAC recalled
that this means that because the increase in costs remains constant but the extent
of FN reduction decreases as the number of cycles of chemotherapy increases, the cost-effectiveness
ratio becomes less favourable. In the setting proposed, the number of cycles could
be as large as 20, which is greater than the number of cycles considered for other
listed situations with a similar risk of FN in Cycle 1. The PBAC also noted that when
the lower confidence interval for the relative risk of FN in Cycle 1 is applied to
cycles 2-4, or the average number of cycles is increased to 6, the incremental cost
per FN event avoided was increased and within the range $15,000 to $45,000.
Therefore, the PBAC rejected the submission based on uncertain clinical benefit and
uncertain cost-effectiveness.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.
14. Sponsor’s Comment
The PBAC has questioned the applicability of the pivotal clinical trial (Vogel 2005).
The study represents the best available evidence supporting the proposed listing and
there is overlap between the proposed patient population and the clinical trial population.
Vogel is a large (n=946), randomised controlled trial (RCT) assessing the safety and
efficacy of pegfilgrastim in breast cancer patients across all stages of disease (advanced
and early) who were treated with docetaxel. The study was commenced in 2002 and the
design reflects clinical practice at that time.
The sponsor does not agree with the PBAC’s statement that primary prophylaxis may
not have survival benefit compared with secondary prophylaxis, which is speculative.
No survival benefit was observed in the clinical trial due to study design. For ethical
reasons control patients were permitted access to pegfilgrastim as secondary prophylaxis
thus it is likely that patients in the control arm achieved similar levels of compliance
with chemotherapy as compared to the treatment arm due to the availability of pegfilgrastim
in subsequent cycles.
Treatment regimens of choice in oncology are dynamic and constantly evolving. It would
be impractical to conduct an efficacy trial specifically in each of tumour type and
with each chemotherapy regimen, particularly in light of continually changing clinical
practice.
Pegfilgrastim has a broad registration label i.e. treatment of cancer patients following
chemotherapy, and was TGA registered in 2002. In clinical practice it is used across
a wide range of tumour types in combination with a range of different chemotherapy
regimens. Pegfilgrastim is an important component of supportive care for myletoxic
chemotherapy regimens.
