Docetaxel, injection set containing 1 single use vial concentrate for I.V. infusion, 20 mg (anhydrous) in 0.5 mL and 1 single use vial solvent 1.5 mL and 80 mg (anhydrous) in 2 mL and 1 single use vial solvent 6 mL, Taxotere, July 2005
Public Summary Document for Docetaxel, injection set containing 1 single use vial concentrate for I.V. infusion, 20 mg (anhydrous) in 0.5 mL and 1 single use vial solvent 1.5 mL and 80 mg (anhydrous) in 2 mL and 1 single use vial solvent 6 mL, Taxotere, July 2005.
Page last updated: 11 November 2005
Product: Docetaxel, injection set containing 1 single use vial concentrate for I.V. infusion,
20 mg (anhydrous) in 0.5 mL and 1 single use vial solvent 1.5 mL and 80 mg (anhydrous)
in 2 mL and 1 single use vial solvent 6 mL, Taxotere®
Sponsor: Sanofi-Aventis Group
Date of PBAC Consideration: July 2005
1. Purpose of Application
This application sought to extend the current authority required listing for docetaxel on the Pharmaceutical Benefits Scheme (PBS) to include the adjuvant treatment of operable node positive breast cancer.
Docetaxel currently has authority required listings on the PBS for:
- use in advanced breast cancer after failure of prior therapy which includes an anthracycline;
- locally advanced or metastatic non-small cell lung cancer (NSCLC);
- advanced metastatic ovarian cancer after failure of prior therapy which
includes a platinum compound.
3. Registration Status
Docetaxel is registered by the Therapeutic Goods Administration for the following indications:
- Treatment of patients with locally advanced or metastatic breast cancer in whom previous chemotherapy has failed.
- Treatment of patients with locally advanced or metastatic breast cancer after failure of prior anthracycline containing chemotherapy, in combination with capecitabine.
- Adjuvant treatment of patients with operable node-positive breast cancer,in combination with doxorubicin and cyclophosphamide
Non-small cell lung cancer : Treatment of patients with locally advanced or metastatic non-small cell lung cancer, including those who have failed platinum based chemotherapy.
Ovarian cancer : Treatment of metastatic carcinoma of the ovary after failure of first line or subsequent chemotherapy.
Prostate cancer: Treatment of patients with androgen independent (hormone refractory) prostate cancer.
4. Listing Requested and PBAC’s View
The submission sought an authority required for adjuvant treatment of operable node-positive breast cancer in combination with an anthracycline (e.g. doxorubicin) and cyclophosphamide.
The PBAC noted that the key trial was conducted in both oestrogen receptor positive
(ER +ve) and oestrogen receptor negative (ER –ve) patients and that the comparative data in this trial were therefore appropriate to assess the comparative effectiveness of docetaxel for the entire group of women with node-positive breast cancer.
5. Clinical Place for the Proposed Therapy
Docetaxel will be used in combination with an anthracycline (eg. doxorubicin) and cyclophosphamide for the adjuvant treatment of operable node positive breast cancer, including patients who are both oestrogen receptor positive and negative.
The submission nominated the combination therapy of FAC as the anthracycline-based comparator.
F= 5-fluorouracil 500 mg/m 2
A= doxorubicin (Adriamycin) 50 mg/m 2
C= cyclophosphamide 500 mg/m 2 administered every 3 weeks.
The PBAC considered FAC to be an appropriate comparator across both ER +ve and ER -ve patients (see also Recommendation and Reasons).
7. Clinical Trials
The submission presented the results of a head-to-head randomised trial over a mean of 55 months comparing six cycles of TAC (docetaxel + doxorubicin + cyclophosphamide) with six cycles of FAC (5-fluorouracil + doxorubicin + cyclophosphamide) as adjuvant treatment of operable node-positive breast cancer patients. The submission also presented a supportive randomised trial comparing three cycles of FEC (5-fluorouracil + epirubicin + cyclophosphamide) followed by three cycles of docetaxel with six cycles of FEC as adjuvant treatment for operable node-positive breast cancer.
Both of these trials had been published at the time of submission, as follows:
|Martin M et al., on behalf of the TAX316/BCIRG 001 investigators.
|TAC improves disease free survival and overall survival over FAC in node positive early breast cancer patients, BCIRG 001: 55 months follow-up.
|San Antonio Breast Cancer Symposium, Abstract No. 43, December 2003.
|Roche at al.
|Five year analysis of the PACS 01 trial: 6 cycles of FEC100 vs 3 cycles of FEC100 followed by 3 cycles of docetaxel for the adjuvant treatment of node-positive breast cancer.
|Breast Cancer Research Treat 2004; 88 (suppl 1): S16. Abstract 27.
8. Results of Trials
In the key trial (TAX 316/BCIRG001) comparing TAC and FAC there was a statistically significant difference in disease free survival favouring TAC in the primary analysis. There was a 28% reduction in disease relapse for TAC compared to FAC (hazard ratio = 0.72; 95% CI: 0.59 – 0.88) for 5-year disease free survival. There was a statistically significant difference in the secondary outcome of overall survival favouring TAC, with a 30% improvement in survival associated with TAC compared with FAC (hazard ratio 0.70, 95%CI: 0.53, 0.91).
In the key trial TAC was more toxic than FAC with more frequent febrile neutropenia, more Grade 3/4 neutropenia and more infections. TAC was also associated with a higher incidence of long-term amenorrhoea, alopecia,and neurosensory effects.
For PBAC’s comments on these results, see Recommendations and Reasons.
9. Clinical Claim
The submission described TAC as significantly more effective than other anthracycline based therapies, but more toxic.
The PBAC accepted this claim concluding that adjuvant TAC chemotherapy offers a statistically significant and clinically important improvement in disease free survival and overall survival compared with FAC as adjuvant treatment for node positive breast cancer.
10. Economic Analysis
A preliminary (trial based) economic evaluation was presented. The PBAC agreed that the choice of a cost-effectiveness approach was valid. The resources included drug costs, drug administration costs, the cost of managing adverse events, the cost of monitoring patients in remission, and the cost for relapsing patients.
A modelled economic evaluation usinga cost-utility approach was presented. The PBAC agreed that the choice of the cost-utility approach was valid. The model was a decision analysis with a Markov process.
The base case modelled incremental discounted cost per extra discounted quality adjusted life year (QALY) gained fell in the range $15,000 to $45,000for TAC over FAC; while thebase case modelled incremental discounted cost per extra discounted life-year gained fell in the range $15,000 - $45,000 forTAC over FAC.
The PBAC noted that there were a number of uncertainties associated with the modelled economic evaluation.
11. Estimated PBS Usage and Financial Implications
The submission estimatedan incremental cost to the PBS in the range $10 - $30 million in year 4 of listing of docetaxel for this indication.
12. Recommendation and Reasons
The PBAC considered the submission’s comparator of anthracycline-based therapy, based on a comparison of 5-fluorouracil, doxorubicin and cyclophosphamide (FAC), with docetaxel with anthracycline (doxorubicin) and cyclophosphamide (TAC) to be an appropriate basis for considering whether to recommend adding the requested restriction and across both oestrogen receptor positive and oestrogen receptor negative patients. Although doxorubicin, because of its cumulative cardiotoxicity, is used less in Australia than epirubicin, epirubicin and doxorubicin are considered to be interchangeable, in terms of efficacy. Given that the current paclitaxel PBS listing restricts use to the fewer eligible adjuvant breast cancer patients with oestrogen receptor negative disease, an informative secondary comparison would be against appropriately specified paclitaxel-based regimens in these patients, however there is uncertainty in the data available to date.
The PBAC noted that the key trial was conducted in both oestrogen receptor positive and oestrogen receptor negative patients and that the comparative data in this trial were therefore appropriate to assess the comparative effectiveness of docetaxel for the entire group of women with node-positive breast cancer. The appropriate intent-to-treat analysis confirmed statistically significant advantages for TAC over FAC in both disease free survival and overall survival. There was no statistically significant difference between TAC and FAC in disease free survival in the sub-group of patients with four involved nodes or greater. However, there was a trend favouring docetaxel in this sub-group and in the primary outcome of disease-free survival, and there was no significant treatment effect modification for this outcome by nodal status (although in the secondary outcome of overall survival there was a significant treatment effect modification by nodal status). The PBAC thus agreed that any restriction should not limit use of docetaxel to patients with only 1-3 involved nodes.
The PBAC therefore accepted the submission’s therapeutic claim that TAC is significantly more effective than anthracycline-based chemotherapy, but also considered that it is associated with greater toxicity. The PBAC noted the Brain et al trial (2005), comparing docetaxel plus doxorubicin with doxorubicin plus cyclophosphamide, conducted in France, had been terminated because of two deaths and one case of perforative peritonitis in the docetaxel arm. However, the PBAC accepted the advice given during the sponsor’s hearing that deaths in the key trial did not reflect those in the Brain et al trial. Further, the sponsor’s argument that usage of G-CSF is different in Australia from the usage that occurred in this trial and noted that incidences of febrile neutropenia in the key trial were fewer than those reported in the Brain et al trial, was also accepted. The PBAC also noted that the key trial’s protocol for the preventative use of G-CSF is consistent with the current secondary prevention PBS restrictions for filgrastim and lenograstim in breast cancer. The introduction of TAC into clinical practice may necessitate the primary use of G-CSF given the high rates of febrile neutropenia and G-CSF is not currently PBS-listed for such use.
The PBAC noted that there were a number of uncertainties associated with the modelled economic evaluation. A number of specific matters about the model were raised for the sponsor to address in a resubmission.
The PBAC concluded that adjuvant TAC chemotherapy offers a statistically significant and clinically important improvement in disease free survival and overall survival compared with FAC as adjuvant treatment for node positive breast cancer. However there is considerable uncertainty about the incremental cost-effectiveness of TAC over FAC because of problems with the model and the PBAC therefore deferred the submission to seek clarification of this uncertainty with the economic model.
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
Sanofi-aventis acknowledges the PBAC’s view that TAC offers a significant efficacy advantage over FAC in the adjuvant treatment of node-positive breast cancer in terms of disease free survival and overall survival. The toxic effects associated with TAC are consistent with those reported for TAC in the metastatic setting and were manageable with standard supportive measures (Martin et al., 2005). However, less patients in the TAC regimen required a delay or adjustment in their treatment compared to FAC (33.6% vs. 39.8%, respectively), suggesting that patients treated with TAC were able to tolerate the regimen. This is supported by quality of life (QoL) data which showed that, although both chemotherapy regimens were associated with transient, statistically significant reductions in QoL scores, these scores returned to baseline levels after the first follow up visit after treatment and were similar between the treatment groups (Martin et al., 2005).
The PBAC has provided three specific issues regarding the economic model that sanofi-aventis will be addressing in a resubmission to confirm the cost effectiveness of docetaxel in the adjuvant treatment of node positive operable breast cancer.