Pegfilgrastrim, injection 6 mg in 0.6 mL single use prefilled syringe and injection 6 mg in 0.6 mL single use prefilled pen, Neulasta and Neulasta Sureclick November 2006
Public summary document for Pegfilgrastrim, injection 6 mg in 0.6 mL single use prefilled syringe and injection 6 mg in 0.6 mL single use prefilled pen, Neulasta and Neulasta Sureclick
Page last updated: 02 March 2007
Public Summary Document
Product: Pegfilgrastrim, injection 6 mg in 0.6 mL single use prefilled syringe and
injection 6 mg in 0.6 mL single use prefilled pen, Neulasta and Neulasta Sureclick
Sponsor: Amgen Australia Pty Ltd
Date of PBAC Consideration: November 2006
1. Purpose of Application
The submission requested an extension to the current Section 100 (Highly Specialised
Drug) listing for pegfilgrastim to allow PBS subsidised treatment for primary prophylaxis
of chemotherapy induced neutropenia in patients with breast cancer who are undergoing
adjuvant chemotherapy with a docetaxel containing regimen.
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
At the September 2002 meeting, the PBAC recommended a section 100 (Highly Specialised
Drug) listing for pegfilgrastim for the same indications as filgrastim on a cost-minimisation
basis compared with filgrastim. Single dose pegfilgrastim 6 mg is 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.
Both filgrastim and pegfilgrastim are currently only PBS-subsidised for secondary
prophylaxis in breast cancer patients.
3. Registration Status
Pegfilgrastim (Neulasta 6 mg in 0.6 mL single dose syringe) is 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 (Highly Specialised Drug) Private hospital authority required
Patients being treated with aggressive chemotherapy with the intention of achieving
a cure or substantial remission in:
Breast cancer (adjuvant chemotherapy with a docetaxel containing regimen).
5. Clinical Place for the Proposed Therapy
Chemotherapy-induced neutropenia is the most common dose-limiting toxicity of chemotherapy
and may result in infection-related morbidity and mortality. Neutropenic events frequently
result in chemotherapy dose reductions or treatment delays. This may impact on the
success of treatment, particularly when treatment intent is either curative or to
prolong survival. The incidence, severity and duration of neutropenia or febrile neutropenia
(FN) are reduced by prophylactic use of granulocyte-colony stimulating factors (G-CSFs).
There have been recent advances in the management of breast cancer with newer more
aggressive regimens showing improved survival but at the expense of increased bone
marrow toxicity. One of these regimens is TAC (docetaxel, doxorubicin and cyclophosphamide),
which is used in the adjuvant treatment of operable node positive, breast cancer.
Clinical evidence has shown that TAC is associated with a high incidence of febrile
neutropenia and there is a clinical need of primary prophylaxis (use from the first
chemotherapy cycle) with granulocycte- colony stimulating factors (G-CSFs).
An extension to the listing for pegfilgrastim, a G-CSF, would allow use as primary
prophylaxis (use from the first chemotherapy cycle) to reduce the incidence of febrile
neutropenia and other neutropenic complications associated with docetaxel containing
regimens used for the adjuvant treatment of breast cancer.
6. Comparator
The submission nominated placebo plus secondary prophylactic use of pegfilgrastim
(in eligible patients only, as it is currently approved on the PBS after prior episodes
of febrile neutropenia or prolonged severe neutropenia).
The PBAC accepted this as appropriate. See Recommendations and Reasons.
7. Clinical Trials
The submission presented a single randomised trial (Vogel) comparing pegfilgrastim
for primary prophylaxis with placebo in both metastatic and non-metastatic breast
cancer patients who received docetaxel monotherapy over 12 weeks. Patients did not
receive TAC chemotherapy, as given in Australia and required by the PBS listing of
docetaxel. Also, in this study, the nodal status of the patient population was not
specified, and the eligibility for secondary prophylaxis only included prior febrile
neutropenia.
The submission also provided four observational studies. GEICAM 9805 was a randomised
trial comparing TAC with 5-fluorouracil/doxorubicin/cyclophosphamide (FAC), for adjuvant
treatment of node-negative breast cancer patients. G-CSFs were not allowed as primary
prophylaxis in the original study protocol. The eligibility for secondary prophylaxis
was broader than the PBS criteria, including infection and myelosuppression. After
amendment of the study protocol, primary prophylaxis with G-CSF (filgrastim or lenograstim)
was allowed in the TAC arm. The submission compared incidence of febrile neutropenia
in the TAC arm before and after the protocol amendment.
The GEPARTRIO study was a single arm cohort study of TAC for neoadjuvant treatment
of breast cancer patients. Four methods to avoid neutropenic adverse events were used
sequentially over the course of the trial, thus patients fall into one of four groups.
Group A received primary prophylaxis with antibiotic (ciprofloxacin) plus secondary
prophylaxis with filgrastim or lenograstim, if required; Group B received primary
prophylaxis with filgrastim or lenograstim; Group C received primary prophylaxis with
pegfilgrastim, and Group D received primary prophylaxis with antibiotics and pegfilgrastim.
The comparison between Group A (secondary G-CSF prophylaxis) and each primary prophylaxis
group with G-CSFs was confounded by the use of prophylactic antibiotics and the type
of G-CSFs used.
BCIRG 001 was a randomised controlled trial comparing TAC with FAC in the adjuvant
treatment of node-positive breast cancer patients. The fourth study was Chellema,
a single arm cohort study of adjuvant TAC treatment of node-positive breast cancer
patient. Incidence of neutropenic complications associated with TAC for the adjuvant
treatment of breast cancer was obtained from both BCIRG 001 and the Chellema Study.
Neither study provided comparative efficacy and safety data for primary versus secondary
prophylaxis for any G-CSF.
These trials had been published at the time of submission as follows:
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
Vogel Study |
||
|
Vogel (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. |
|
Vogel (2005) |
First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. |
Journal of Clinical Oncology 2005; 23(6):1178-84. |
|
GEICAM 9805 study |
||
|
Martin (2006) |
Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin, cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen. |
Annals of Oncology Advance Access published June 9, 2006 |
|
GEPARTRIO study |
||
|
Von Minckwitz G et al. |
Primary prophylaxis with 3 weekly pegfilgrastim and ciprofloxacin effectively prevent (febrile) neutropenia and infection during neoadjuvant chemotherapy with docetaxel/doxorubicin/cyclophosphamide (TAC) in breast cancer patients. |
2005 ASCO meeting. Abstract 8008. |
|
Von Minckwitz et al |
In vivo chemosensitivity-adapted preoperative chemotherapy in patients with early-stage breast cancer: the GEPARTRIO pilot study. |
Annals of Oncology 2005;16:56-63. |
|
BCIRG 001 study |
||
|
Martin, et al. |
Adjuvant docetaxel for node-positive breast cancer. |
New England Journal of Medicine, 2005, 352:2302-13. |
|
Chellama study |
||
|
Chellama et al. |
Prevention of febrile neutropenia by prophylactic use of G-CSF with adjuvant TAC based on risk assessment-single institute study. |
Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 10711. |
8. Results of Trials
The results of the key trial, Vogel showed that there was a statistically significant
difference in the incidence of febrile neutropenia, favouring primary prophylaxis
with pegfilgrastim in the key trial’s primary analysis.
The adverse events with a higher subject incidence in the pegfilgrastim arm than that
in the placebo arm were bone pain, myalgia, headache not otherwise specified, arthralgia,
loss of body strength and constipation. The most frequently reported adverse events
that were considered by the investigator to be related to pegfilgrastim were bone
pain, arthralgia, and myalgia.
9. Clinical Claim
The submission described pegfilgrastim as having significant advantages in effectiveness
over placebo and having similar toxicity. Based on the supporting data, the PBAC agreed
that this description might be reasonable, but the chemotherapy regimen given in the
Vogel study was docetaxel monotherapy (not TAC), which might have a different safety
profile from that of TAC in terms of the incidence of febrile neutropenia. See Recommendations
and Reasons.
10. Economic Analysis
Multiple preliminary economic evaluations were presented; one based on the GEICAM
study and four using the Vogel study, and all used a cost-effectiveness approach.
The resources included are drug costs and hospitalisation costs.
The trial-based incremental discounted cost/extra febrile neutropenic event avoided
in the GEICAM study was estimated to be < $15,000 and in the Vogel study, $45,000
– $75,000.
A modelled economic evaluation was presented which was a cost-effectiveness analysis.
The resources included were drug costs and the cost of hospitalisation for febrile
neutropenia.
The base case modelled incremental discounted cost/extra febrile neutropenic event
avoided was estimated to be < $15,000 (re-calculated during the evaluation as $15,000
- $45,000).
11. Estimated PBS Usage and Financial Implications
The likely number of packs dispensed/year was estimated to be < 10,000 in Year 4.
The PBAC considered this to be a likely under-estimate in the submission.
The financial cost/year to the PBS was estimated to be < $10 million in Year 4. This
was also likely to be an under-estimate in the submission.
12. Recommendation and Reasons
The PBAC recommended extending the Section 100 (Highly Specialised Drug) listing for
pegfilgrastim to include the prophylaxis of chemotherapy induced neutropenia in patients
with breast cancer who are undergoing adjuvant chemotherapy with docetaxel in combination
with an anthracyline and cyclophosphamide. This recommendation is on a cost-effectiveness
basis over the comparators, placebo plus secondary prophylactic use of pegfilgrastin.
The PBAC accepted that there is a clear clinical need for prophylaxis against neutropenia
in patients undergoing adjuvant treatment with docetaxel in combination with an anthracyline
and cyclophosphamide. The BCIRG 001 trial of TAC (docetaxel, doxorubicin, cyclophosphamide,
Martin et al, 2005) showed a significant risk of febrile neutropenia of up to 25%,
a figure which the PBAC considered is likely to be higher when TAC is used in Australian
practice.
The Committee agreed that the benefit of treatment with pegfilgrastim is probably
underestimated in the main clinical trial presented in support of the listing application
(Vogel et al, 2005) which used docetaxel monotherapy. The reverse situation, ie the
possibility that Vogel might overestimate the treatment effect because the study did
not specify nodal status or because the addition of an anthracycline and cyclophosphamide
might reduce the efficacy of pegfilgrastim, was not considered probable by the Committee.
The PBAC considered that the most appropriate relative risk reduction (RRR) for febrile
neutropenia to apply in the economic analysis is that from the Vogel trial for the
non-metastatic patient subgroup (0.74). The Committee noted that in the GEICAM 9805
trial which compared filgrastim with placebo for prophylaxis of febrile neutropenia
in patients receiving adjuvant chemotherapy with TAC, the RRR was 0.73 which lends
further support to the use of the 0.74 figure in the economic analysis. The PBAC agreed
that the base case incremental discounted cost per extra febrile neutropenia event
avoided of $30,030 calculated using the RRR of 0.74, represented acceptable cost-effectiveness
and was consistent with previous recommendations for filgrastim/pegfilgrastim.
Recommendation
PEGFILGRASTRIM, injection 6 mg in 0.6 mL single use prefilled syringe and injection
6 mg in 0.6 mL single use prefilled pen
Add to the current restriction:
(Highly Specialised Drug) Private hospital authority required
A patient being treated with aggressive chemotherapy with the intention of achieving
a cure or substantial remission in:
Breast cancer (adjuvant chemotherapy with docetaxel in combination with an anthracyline
and cyclophosphamide)
Pack: 1
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
Amgen is pleased that Neulasta (pegfilgrastim) will be PBS listed for primary prophylaxis in this group of breast cancer patients and thanks the PBAC for this recommendation.
