Paclitaxel, powder for I.V. infusion (suspension), 100 mg, Abraxane®, November 2008
Public summary document for Paclitaxel, powder for I.V. infusion (suspension), 100 mg, Abraxane® November 2008
Page last updated: 19 March 2009
Public Summary Document
Product: Paclitaxel, powder for I.V. infusion
(suspension), 100 mg, Abraxane®
Sponsor: Specialised Therapeutics Australia Pty
Ltd.
Date of PBAC Consideration: November 2008
1. Purpose of Application
The submission sought an Authority Required listing for advanced
breast cancer after failure of prior therapy which includes an
anthracycline.
2. Background
This formulation of paclitaxel had not previously been considered
by the PBAC.
Paclitaxel solution concentrate for I.V. infusion has been listed
on the PBS since 1 October 1994.
3. Registration Status
Nanoparticle albumin-bound (nab) paclitaxel
(Abraxane®) 100mg powder for injection (suspension)
was registered by the TGA on 17 October 2008 for the treatment of
metastatic carcinoma of the breast after failure of anthracycline
therapy.
4. Listing Requested and PBAC’s View
Authority Required
Advanced breast cancer after failure of prior therapy which
includes an anthracycline.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Breast cancer is the most common invasive cancer and the most
common cause of cancer-related death among Australian women. This
formulation of paclitaxel provides a treatment alternative for
patients with metastatic breast cancer following failure of prior
therapy which includes an anthracycline.
Existing paclitaxel products have been formulated with Cremophor to
improve water solubility. However, Cremophor is associated with
hypersensitivity reactions. Paclitaxel powder for I.V. infusion
contains paclitaxel bound to albumin to overcome the solubility and
hypersensitivity problems. The albumin-bound formulation allows
shorter infusion times and avoids the use of in-line filters and
special tubing.
6. Comparator
The submission nominated the current PBS listings of solvent-based
paclitaxel as the main comparator. Docetaxel was nominated as
secondary comparator. This was accepted as appropriate by the
PBAC.
7. Clinical Trials
The submission presented two key randomised trials (CA012 &
CA201) comparing nab-paclitaxel 260 mg/m2 every 3 weeks
(q3w) with solvent-based paclitaxel 175 mg/m2 q3w in
patients with metastatic breast cancer, and a supplementary
randomised trial (CA204) comparing nab-paclitaxel in 3 different
dose regimens (300 mg/m2 q3w, 100 mg/m2
weekly and 150 mg/m2 weekly) with docetaxel 100
mg/m2 q3w.
The trials published at the time of submission are listed as below:
| Trial ID/ Author | Protocol title/ Publication title | Publication citation |
| Direct randomised trials (nab-paclitaxel vs. paclitaxel) | ||
| CA012 O’Shaughnessy J et al. Gradishar W et al. | Clinical Study Report Final A controlled randomised Phase III, Multicentre, open label study of AB1-007 (a Cremophor ® -free protein stabilized, nanoparticle paclitaxel) and Taxol ® in patients with metastatic breast cancer. | February 2004 |
| ABI-007 (ABRAXANE™), a nanoparticle albumin-bound ( nab ) paclitaxel demonstrates superior efficacy vs taxol in MBC: a phase III trial. | 26th Annual San Antonio Breast Cancer Symposium December 2003. | |
| Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. | J Clin Oncol 2005; 23: 7794-803. | |
| CA201 Guan Z et al. | CA201 Clinical Study Report A controlled, randomized, open label study to evaluate the efficacy and safety of capxol (a Cremophor-free, nanoparticle paclitaxel) and Cremophor-formulated paclitaxel injection in patients with metastatic breast cancer. | January 2007 |
| Randomized study comparing nab -paclitaxel with solvent-based paclitaxel in Chinese patients with metastatic breast cancer [poster]. | American Society of Clinical Oncology Meeting; June 1-5, 2007; Chicago, IL. Abs 1038 | |
| Supplementary randomised trial (nab-paclitaxel vs. docetaxel) | ||
| CA024 Ranganathan A et al. Gradishar W et al. | Protocol CA024 Amendment 4 A randomized Phase II study of weekly or every 3 weeks ABI-007 versus every 3 weeks Taxotere as first line therapy of Stage IV (metastatic) breast cancer | 6 April 2007 |
| Randomized phase II trial of weekly or every-3-week albumin-bound paclitaxel versus every-3-week docetaxel as first-line therapy in patients with metastatic breast cancer. | Clin Breast Cancer. 2007; 7: 445-6 | |
| A randomised Phase 2 study of weekly or every-3-week nab -Paclitaxel versus every-3-week docetaxel as first-line therapy in patients with metastatic breast cancer. | San Antonio Breast Cancer Conference Plenary Session, December 2006 | |
8. Results of Trials
Nab-paclitaxel vs. paclitaxel
Results of overall response rates derived from fixed effect meta-analyses using the
ITT population and a range of subgroups are summarised in the table below. Response
rates were statistically significantly higher for nab-paclitaxel compared with paclitaxel.
Data on overall response rates are shown in the table below.
Patients with overall response (invORR*, investigator assessment of overall response rate)
| Study | nab -paclitaxel n/N (%) | Paclitaxel n/N (%) | OR (95% CI) | RR (95% CI) | p value |
| All patients (ITT) | |||||
| CA012 | 76/229 (33.2) | 42/225 (18.7) | 2.16 (1.40, 3.34) | 1.78 (1.28, 2.47) | 0.001 |
| CA201 | 54/104 (53.8) | 29/106 (29.2) | 2.87 (1.61, 5.09) | 1.90 (1.32, 2.72) | <0.001 |
| Total | 2.39 (1.69, 3.39) | 1.83 (1.43, 2.33) | <0.0001 | ||
| Patients receiving 1st line therapy | |||||
| CA012 | 41/97 (42.3) | 24/89 (27.0) | 1.98 (1.07, 3.68) | 1.57 (1.04, 2,37) | 0.029 |
| CA201 | 33/61 (54.1) | 17/64 (26.6) | 3.26 (1.54, 6.89) | 2.04 (1.27, 3.25) | 0.001 |
| Total | 2.42 (1.51, 3.90) | 1.75 (1.29, 2.39) | 0.0004 | ||
| Patients receiving > 1st line therapy | |||||
| CA012 | 35/132 (26.5) | 18/136 (13.2) | 2.37 (1.26, 4.44) | 2.00 (1.20, 3.35) | 0.006 |
| CA201 | 21/43 (48.8) | 12/42 (28.6) | 2.39 (0.97, 5.86) | 1.71 (0.97, 3.02) | 0.122 |
| Total | 2.37 (1.42, 3.97) | 1.88 (1.28, 2.77) | 0.001 | ||
| Patients with prior anthracycline therapy (adjuvant or metastatic) | |||||
| CA012 | 60/176 (34.1) | 32/175 (18.3) | 2.31 (1.41, 3.79) | 1.86 (1.28, 2,71) | 0.002 |
| CA201 | 28/60 (46.7) | 22/72 (30.6) | 1.99 (0.97, 4.06) | 1.53 (0.98, 2.37) | 0.097 |
| Total | 2.20 (1.47, 3.31) | 1.73 (1.30, 2.31) | 0.002 | ||
| Patients with prior metastatic anthracycline therapy | |||||
| CA012 | 31/115 (27.0) | 18/130 (13.8) | 2.30 (1.20, 4.38) | 1.95 (1.15, 3.29) | 0.010 |
Abbreviations: invORR: overall response rate based on Investigator Response Assessment
Dataset i.e. the proportion of patients who achieved complete or partial overall response;
OR: odds ratio; RR: relative risk.
Patient survival and median time to death in Trials CA012 and CA201 are shown below.
Patient survival
| Trial | Nab -paclitaxel n/N (%) | paclitaxel n/N (%) | OR (95% CI) | RR (95% CI) | P Value | |
| Proportion of patients who died | ||||||
| All patients (ITT) | ||||||
| CA012 | 172/229 (75) | 175/225 (78) | 0.86 (0.56, 1.33) | 0.97 (0.87, 1.07) | ||
| CA201 | 20/104 (19) | 13/106 (12) | 1.70 (0.80, 3.63) | 1.57 (0.82, 2.98) | ||
| Total | 1.13 (0.59, 2.16) | 1.12 (0.70, 1.79) | 0.90 | |||
| Patients receiving 1 st line therapy | ||||||
| CA012 | 73/98 (74) | 60/89 (67) | 1.41 (0.75, 2.66) | 1.10 (0.92, 1.33) | 0.29 | |
| Patients receiving > 1 st line therapy | ||||||
| CA012 | 99/131 (76) | 115/136 (85) | 0.56 (0.31, 1.04) | 0.89 (0.79, 1.01) | 0.07 | |
| Patients who failed anthracyclines | ||||||
| CA012 | 98/127 (77) | 119/142 (84) | 0.65 (0.36, 1.20) | 0.92 (0.82, 1.04) | 0.23 | |
| Median time to death – weeks | ||||||
| N | nab -paclitaxel median (95% CI) | N | paclitaxel median (95% CI) | Hazard Ratio (95% CI) | P Value | |
| All patients (ITT) | ||||||
| CA012 | 229 | 65.0 (53.4, 76.9) | 225 | 55.3 (48.0, 66.4) | 0.899 (0.728, 1.110) | 0.322 |
| CA201 a | 104 | >58.9 (47.3, >58.9) | 106 | >80.0 | 1.512 (0.752, 3.040) | 0.242 |
| Patients receiving 1 st line therapy | ||||||
| CA012 | 98 | 71.0 (59.4, 87.7)) | 89 | 77.9 (58.1, 98.0) | 1.215 (0.863, 1.709) | 0.264 |
| Patients receiving > 1 st line therapy | ||||||
| CA012 | 131 | 56.4 (45.1, 76.9) | 136 | 46.7 (39.0, 55.3) | 0.726 (0.553, 0.952) | 0.020 |
| Patients who failed anthracyclines | ||||||
| CA012 | 127 | 57.0 (45.1, 76.6) | 142 | 46.7 (38.3, 55.3) | 0.762 (0.582, 0.997) | 0.047 |
Abbreviations: OR: odds ratio; RR: relative risk.
Only a subgroup of patients recruited in CA012 (prior anthracycline failure subgroup)
was representative of the target population for whom the listing was sought. Survival
data relevant to this subgroup showed no statistically significant difference in overall
survival (77% vs. 84%, p=0.23). The proportions of patients who had died were substantially
different in trials CA012 and CA201 (this may reflect the immature data in CA201).
Median time to death was significantly prolonged in the nab-paclitaxel arm for the
subgroup who failed anthracycline therapy. However, the upper limit of the confidence
interval was very close to 1.0 (HR: 0.762, 95% CI: 0.582, 0.997). Given that no adjustment
for multiplicity in the multiple subgroup analyses had been conducted, the US Food
and Drug Administration (FDA) had expressed the view that the p value presented for
overall survival was not interpretable.
Nab-paclitaxel vs. docetaxel
Data on overall response, progression free survival and overall survival in Trial
C204 are presented below.
Patients with overall response (invORR)
| nab-paclitaxel | docetaxel | OR | p b | p c | |||
| 300mg/m 2 q3w n/N (%) | 100mg/m 2 wkly n/N (%) | 150mg/m 2 wkly n/N (%) | 100mg/m 2 q3w n/N (%) | (95% CI) | value | Value | |
| Responders a | 35/76 (46) | 48/76 (63) | 55/74 (74) | 29/74 (39) | 2.43 (1.42, 4.16) | <0.001 | <0.001 |
| CR | 1/76 (1) | 2/76 (3) | 2/74 (3) | 2/74 (3) | 0.029 | 0.9197 | |
| PR | 34/76 (45) | 46/76 (61) | 53/74 (72) | 27/74 (36) | 0.010 | <0.0001 |
Abbreviations: OR: odds ratio; CR: complete response; PR: partial response
aPatients with confirmed complete or partial overall response
bp values are based on a Cochran-Mantel-Haenszel (CMH) test stratified by study site
cp values are based on a Fisher exact test undertaken in the evaluation
Progression-free survival and median survival
| nab-paclitaxel | docetaxel 100mg/m2 q3w | p a value | p b Value | |||
| 300mg/m 2 q3w | 100mg/m 2 wkly | 150mg/m 2 wkly | ||||
| Investigator Assessed Progression-Free Survival | ||||||
| Pts who progressed or died n/N (%) | 44/76 (58) | 59/76 (78) | 36/74 (49) | 44/74 (59) | 0.0024 | |
| Median (95% CI) PFS (months) | 10.9 (8.9, 14.6) | 7.5 (7.2, 9.3) | 14.6 (10.0, 18.9) | 7.8 (6.3, 11.0) | 0.008 | |
| Patient Survival | ||||||
| Patients who died n/N (%) | 24/76 (32) | 32/76 (42) | 19/74 (26) | 26/74 (35) | 0.1933 | |
| Median (95% CI) survival (months) | 21.7 (21.7, >23.7) | >23.0 (16.6, >23.0) | >22.7 | 19.7 (18.0, >21.2) | 0.111 | |
Abbreviations: PFS, progression free survival.
a p values are based on a log rank test and refer to the overall p values
bp values are based on a Fisher exact test undertaken in the evaluation
It was difficult to interpret the results given the different dose regimens of nab-paclitaxel
used and combination across three weekly and weekly dosage administration schedules.
Overall response rates were similar between nab-paclitaxel 300mg/m2 three weekly and docetaxel 100mg/m2 three weekly. A more relevant comparison may be nab-paclitaxel 100mg/m2 weekly and docetaxel administered weekly. However, there was no significant difference
in patient survival among the four treatment arms. No results related to the target
population for whom the listing was sought were presented in the submission.
The PBAC noted nab-paclitaxel had a different safety profile compared to paclitaxel,
with statistically significantly higher incidence of sensory neuropathy, fatigue and
gastrointestinal toxicities reported.
9. Clinical Claim
The submission claimed nab-paclitaxel was superior in terms of
comparative effectiveness over paclitaxel. The PBAC considered that
this may not be reasonable. The PBAC concluded that, based on the
clinical evidence presented, the claim of a clinically significant
benefit for treatment with nab-paclitaxel over paclitaxel and
docetaxel had not been substantiated, and therefore that the
presented cost-effectiveness analysis (CEA) lacked an adequate
basis.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
A trial based economic evaluation was presented. A
cost-effectiveness analysis was performed to obtain costs per
life-year gained based on overall survival (OS) in CA012.
The submission compared costs and outcomes for all patients dosed
in CA012, and for patients with prior anthracycline exposure and
patients who were on >1st line therapy. However, none
of the three groups presented in the economic evaluation fully
represented the population for whom the listing was sought.
Total costs were calculated per cycle to 18 cycles (52 weeks) from
the perspective of the health care system as no patients continued
treatment after 18 cycles of therapy. Overall survival estimates
were based on CA012 for both treatment arms until 150 weeks with no
further extrapolation beyond the trial horizon.
The incremental cost per life year saved for the ITT population was
between $45,000 and $75,000. The sensitivity analysis presented
indicated that the ICER was highly sensitive to the estimate of
survival.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated a financial cost to the PBS of less than
$10 million per year. The PBAC considered the submission’s
estimates were uncertain with potential for usage beyond the
requested restriction.
12. Recommendation and Reasons
The PBAC noted that nab-paclitaxel was an albumin bound form of
paclitaxel and was likely to have a higher uptake by cancer cells
due to increased transendothelial transport on albumin. The PBAC
also noted that nab-paclitaxel has a different safety profile and a
different dosage to paclitaxel. The new formulation was noted to
have potential advantages which included: no cremophor EL or
ethanol in the formulation which reduced hypersensitivity
reactions, no requirement for premedications, a shorter infusion
time, and the possibility of using standard drip sets.
The PBAC also noted that the requested listing for nab-paclitaxel
was for advanced breast cancer which is consistent with the current
listing of the comparator, paclitaxel. However,
nab-paclitaxel’s TGA registration is for
“metastatic breast cancer” and in its pre-subcommittee
response the sponsor acknowledged this discrepancy and had no
objection to limiting the PBS indication to patients with
metastatic breast cancer if recommended for listing.
The PBAC agreed that paclitaxel was the appropriate main comparator
and that docetaxel was an appropriate secondary comparator, with
data from three studies presented: one randomised comparative study
of nab-paclitaxel and paclitaxel in patients with metastatic breast
cancer (CA021) with mature survival data, and two other ongoing,
randomised trials comparing nab-paclitaxel with paclitaxel
(CA201) and docetaxel (CA204), respectively, in which the survival
data are immature.
The primary outcome of the clinical trials of
nab-paclitaxel with paclitaxel (CA012 and CA201) was
response rate and the PBAC agreed that in the meta-analysis,
response rates were statistically significantly higher for
nab-paclitaxel compared with paclitaxel in the ITT
population and for the subgroup of patients from trial CA012 with
prior anthracycline failure who were representative of the target
population for whom the listing is sought.
However this subgroup showed no statistically significant
difference in the more patient relevant endpoint of overall
survival (77% vs. 84%, p=0.23), nor was a statistically significant
difference in overall survival seen in the ITT populations from
either trial CA012 or CA201. Although the PBAC noted that the
median time to death in trial CA012 was significantly greater in
the nab-paclitaxel treatment arm for patients receiving
second or greater line therapy (p = 0.020) and in patients who had
received prior anthracycline therapy (p = 0.047), the later result
was of marginal statistical significance and in addition, the p
value presented was not interpretable given that there was no
adjustment for multiplicity in the multiple subgroup analyses
conducted (the Pre-Sub-Committee response argument that multiple
testing adjustments were not necessary as the multiple nested
testing analysis in Study CA012 reduced the false discovery rate
was not accepted by the Committee).
In addition, the PBAC noted that there was no significant difference in patient survival in study CA204 among the four treatment arms (nab-paclitaxel 300 mg/ m2 q3w, 100 mg/ m2 wkly, 150 mg/ m2 wkly and docetaxel 100 mg/m2 q3w), although it was accepted that the survival data from this trial were immature. Furthermore, no results related to the target population for whom the listing was sought were presented in the submission.
The PBAC also noted that nab-paclitaxel had a different safety profile to paclitaxel with more GIT toxicity, fatigue and sensory neuropathy reported but that no comparative safety claim was provided in the submission.
Thus the Committee concluded that, based on the clinical
evidence presented, the claim of a clinically significant benefit
for treatment with nab-paclitaxel over paclitaxel and
docetaxel had not been substantiated, and therefore that the
presented cost-effectiveness analysis (CEA) lacked an adequate
basis. In addition, the presented sensitivity analysis indicated
that the ICER was highly sensitive to the estimate of survival,
with a difference of 3.65 days increasing or decreasing the ICER by
$10,000, increasing the uncertainty further.
The PBAC also noted that ESC had raised a number of other areas of
clinical and economic uncertainty and agreed these would need to be
addressed by any future submissions.
Therefore, the PBAC rejected the submission on the basis of
uncertainty in clinical benefits and uncertain cost-effectiveness.
However, the Committee indicated it would be prepared to consider a
submission presenting a cost-minimisation analysis of
nab-paclitaxel versus paclitaxel at its 11 December Special
meeting.
Recommendation
Reject
Further Information
Further to the PBAC’s consideration of this product at the
5-7 November 2008 meeting (at which the committee rejected the
submission, but indicated its willingness to consider a submission
presenting a cost minimisation analysis), the sponsor presented a
re-submission to the PBAC Special Meeting held in December 2008.
The re-submission presented a cost minimisation of nab-paclitaxel
versus paclitaxel. The equi-effective doses used were 260
mg/m2 of nab-paclitaxel and 175 mg/m2 of
paclitaxel with additional cost offsets claimed for drug
administration, premedications and adverse events.
No new clinical data were presented.
Differences from the previous submission in the assumptions and
inputs in the pricing calculations compared with the economic model
related to body surface area, incidence of adverse events and
paclitaxel price.
The re-submission estimated the number of patient treatment cycles
to be less than 10,000 by Year 5 of listing. It estimated there
would be a net cost saving to the PBS of less than $500,000 per
year by Year 5 achieved through a reduction in the use of other
taxanes and concomitant medications.
The PBAC recommended the listing of nab-paclitaxel on the PBS for
metastatic breast cancer after failure of prior therapy which
includes an anthracycline on a cost-minimisation basis with
paclitaxel using the price per mg methodology and the
equi-effective doses being 260 mg/m2 of nab-paclitaxel
and 175 mg/m2 of paclitaxel.
The PBAC considered that a maximum quantity of 1 is more
appropriate as the dose will vary according to the body surface
area of the patient and that a prescriber can request the
appropriate number of vials at the time of the authority
application. The PBAC also noted that submission sought listing in
patients with metastatic breast cancer as opposed to advanced
breast cancer as requested in November 2008. The PBAC considered
that metastatic breast cancer was the more appropriate of the two
as this is consistent with the TGA registration.
The PBAC noted that the clinical data presented in the submission
was the same as that considered in the November 2008 major
submission. Consequently, the PBAC’s conclusion from November
2008 that there is no clinically significant benefit in treatment
with nab-paclitaxel over paclitaxel, remained. Although the claim
of a clinically significant benefit for treatment with
nab-paclitaxel over paclitaxel was maintained in the submission, in
the context of a cost-minimisation analysis, the PBAC did not
consider this to be directly relevant to its deliberations and the
sponsor indicated a willingness to accept listing on this basis. As
a result of this, the PBAC was interested in whether nab-paclitaxel
outcomes are no worse than paclitaxel outcomes and from the trial
results presented, the PBAC concluded that this was the case.
However, the PBAC did consider the possibility that nab-paclitaxel
may produce better outcomes than paclitaxel but as outlined
previously in the November 2008 PBAC meeting minutes, uncertainty
existed over the validity of this claim.
The PBAC also recalled that the ESC had raised a number of other
areas of clinical and economic uncertainty in the November 2008
submission needing addressing, but again, in the context of a
cost-minimisation analysis, the PBAC did not consider these issues
relevant.
The PBAC noted that the adverse events experienced in the first
treatment cycle were used to estimate the incidence of toxicities
per treatment cycle as opposed to the total trial period as used in
the November 2008 submission. By using adverse events experienced
in the first treatment cycle only, the adverse events costs
associated with nab-paclitaxel changed from a cost to a saving.
However, the PBAC considered that this had little impact on the
analysis.
Recommendation
NAB-PACLITAXEL, powder for I.V. infusion (suspension), 100 mg
Restriction:
Authority Required
Metastatic breast cancer after failure of prior therapy which
includes an anthracycline
Maximum quantity: 1
Number of repeats: Nil
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
Specialised Therapeutics is pleased to have been able to work with
the PBAC to make Abraxane available to Australian women with
metastatic breast cancer.
