Trastuzumab, powder for I.V. infusion, 150 mg, Herceptin®, November 2008
Public Summary Document for Trastuzumab, powder for I.V. infusion, 150 mg, Herceptin®, Nov 2008
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Public Summary Document
Product: Trastuzumab, powder for I.V. infusion,
150 mg, Herceptin®.
Sponsor: Roche Products Pty Ltd
Date of PBAC Consideration: November 2008
1. Purpose of Item
The Department of Health and Ageing requested that the PBAC
re-examine the clinical and cost-effectiveness evidence available
for trastuzumab for metastatic breast cancer (MBC), including the
current use in Australia, and provide advice to Government as to
whether trastuzumab could be recommended for PBS listing for
MBC.
2. Background
At the September 2000 PBAC meeting, the PBAC rejected a major
submission to list trastuzumab for the treatment of patients with
human epidermal growth factor receptor 2 (HER-2) positive
metastatic breast cancer (a) in combination with taxanes for
patients who have not received chemotherapy for metastatic disease;
or (b) as monotherapy for patients who have received one or more
chemotherapeutic regimens for their metastatic disease. The PBAC
rejected the submission for combination therapy due to unacceptably
high cost effectiveness due to the high cost of the drug. The
submission for monotherapy was deferred to allow investigation of
the cost effectiveness of the comparator drugs.
At the December 2000 meeting a minor re-submission, for both
combination therapy and monotherapy was considered. The PBAC again
deferred the submission in order to seek the sponsor’s
preparedness to offer a price reduction as the cost effectiveness
ratios remained unacceptably high. A further re-submission was
presented to the March 2001 PBAC meeting, however in the absence of
an offer of a further price reduction as stipulated in the deferral
of the application to the December 2000 meeting, the application
was rejected.
At the September 2001 meeting the PBAC rejected an application for
a Section 100 listing for the treatment of HER-2 positive patients
with MBC, in combination with taxanes, for patients who have not
received chemotherapy for their metastatic disease and as
monotherapy for the treatment of those patients who have received
one or more chemotherapy regimen(s) for their metastatic disease,
because of unacceptable cost-effectiveness.
The Government established the Herceptin Program in December 2001.
Funding for the Herceptin Program has been reviewed twice by
Government since 2001 prior to this 2008 review request.
In 2004, the review recommended that the Program should continue
but that steps should be taken to minimise wastage. The Department
of Health and Ageing (the Department), following consultations with
the Therapeutic Goods Administration (TGA) and oncologists,
obtained authorisation in August 2005 to allow a three-weekly
rather than weekly dosing regimen to improve convenience for
patients and reduce drug wastage. In addition, Roche Products were
requested to seek TGA registration of an additional vial size to
reduce wastage. Registration has not proceeded to date.
In 2006, the review recommended that the program be funded for a
further two years and that the Department evaluate the
effectiveness and cost-effectiveness of trastuzumab for metastatic
breast cancer, and that the evaluation be considered by the PBAC
and its recommendations made available to Government.
In the period from December 2001 to June 2008 total expenditure on
the Herceptin Program was $212 million and 3193 women were
treated.
Herceptin was listed for early stage breast cancer on the PBS from
1 October 2006. The total PBS expenditure to June 2008 was $100.7
million.
6. Comparator
The comparators were placebo or trastuzumab co-administered with the following regimens:
- taxanes (paclitaxel or docetaxel) ± other chemotherapy
- aromatase inhibitors
- vinorelbine
A clinical comparison of capecitabine with or without trastuzumab,
and use of trastuzumab as monotherapy or beyond disease progression
were presented, however these comparisons did not form the basis of
the economic models.
It was noted that not all the trastuzumab combination therapies
(e.g. combination with vinorelbine or capecitabine) have marketing
approval by the TGA.
7. Clinical Trials
The key, randomised trials are summarised below.
Trastuzumab + taxane versus taxane alone: three randomised, open-label trials for
first-line treatment of HER2 positive patients with advanced or metastatic breast
cancer:
- Slamon 2001: trastuzumab + paclitaxel or paclitaxel only
- Marty 2005: trastuzumab + docetaxel or docetaxel only
- Gasparini 2006: trastuzumab + paclitaxel or paclitaxel only.
Trastuzumab + aromatase inhibitor versus aromatase inhibitor alone: one randomised, open-label trial for first and second-line treatment of post-menopausal women with HER2 positive, hormone receptor positive, MBC:
- TanDEM trial (B016216): trastuzumab + anastrozole vs anastrozole alone.
Trastuzumab + vinorelbine versus trastuzumab + taxanes: one randomised, open-label trial for first-line treatment of HER2 positive MBC:
- Burstein 2007: trastuzumab + vinorelbine vs trastuzumab + paclitaxel/docetaxel.
No head to heads trials of trastuzumab + vinorelbine versus vinorelbine alone were
available in the first-line setting. A summary of non-randomised and single arm studies
was presented as evidence for the trastuzumab monotherapy indication.
The studies published at the time of the review for the comparison of trastuzumab
with a taxane versus taxane alone were:
| Trial ID | Protocol/Publication Title | Publication citation |
| Direct randomised trials of trastuzumab+taxane versus taxane alone (first-line treatment) | ||
| Trial H0648g |
Use of chemotherapy plus a monoclonal antibody against HER 2 for metastatic breast cancer that over express HER2. Trastuzumab combined with chemotherapy for the treatment of HER2-positive metastatic breast cancer: Effect of cardiac dysfunction on treatment outcomes in women receiving trastuzumab for HER2-overexpressing metastatic breast cancer. |
Slamon D, Leyland-Jones B, et al. (2001). The New England Journal of Medicine , 344: 783-92. Eiermann W. (2001). Pivotal trial data. Annals of Oncology, 12 (Suppl 1): S57-S62. Tripathy D, Seidman A, et al. (2004). Clinical Breast Cancer 5 (4): 293-8. |
| Trial M77001 |
Randomized Phase II trial of the efficacy and safety of Trastuzumab combine with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first line treatment: Randomised phase II trial (M77001) of trastuzumab (Herceptin) plus docetaxel versus docetaxel alone, as first-line therapy in patients with HER2-positive metastatic breast cancer [abstract]. |
Marty M, Cognetti F, et al. (2001). The M77001 study group. Journal of Clinical Oncology , 23 (13): 4265-74. Extra JM, Cognetti F, et al. (2003). European Journal of Cancer, 1 (5): S202. |
| Trial report not available | Randomized Phase II trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first-line therapy of patients with HER2 positive advanced breast cancer. | Gasparini G, Gion M, et al. (2007). Breast Cancer Res Treat, 101: 355-65. |
| Comparative trial of trastuzumab+taxane versus chemotherapy alone (first-line treatment) | ||
| Trial report not available | Use of the monoclonal antibody anti-HER2 trastuzumab in the treatment of metastatic breast cancer. A cost-effectiveness analysis. | Poncet B, Bachelot T, et al. (2008). American Journal of Clinical Oncology, 31: 363-8. |
| Trastuzumab + Taxane (second-line or subsequent treatment) | ||
| Non comparative studies | ||
| Trial report not available | Efficacy and safety of combined trastuzumab and paclitaxel therapy as a second-line treatment in women with metastatic breast cancer: a single institutional experience. | Furukawa K, Ito Y, et al. (2006). Breast Cancer, 13: 329-33. |
The studies published at the time of the review for the comparison of trastuzumab
+ taxane + chemotherapy versus taxane + chemotherapy were:
| Study | Protocol/Publication Title | Publication citation |
| Trastuzumab + taxane + chemotherapy studies | ||
| Randomised trials | ||
| Robert 2006, 2004, 2001 |
Randomized Phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER2-overexpressing metastatic breast cancer. Randomized phase III trial study of trastuzumab, paclitaxel, and carboplatin versus trastuzumab and paclitaxel in women with HER-2 overexpressing metastatic breast cancer: An update including survival [abstract]. Toxicity profiles: a comparative study of Herceptin (trastuzumab) and Taxol (paclitaxel) versus Herceptin, Taxol, and carboplatin in HER-2 positive patients with advanced breast cancer. |
Robert N, Leyland-Jones B, et al. (2006). Journal of Clinical Oncology, Vol 24, No.18: 2786-92. Robert NJ, Leyland-Jones B, et al. (2004). Annual Proceedings of the American Society of Clinical Oncology. Robert NJ, Slamon D, et al. (2001). Breast Cancer Research and Treatment, 69 (3): 304. |
| BCIRG 007 | Randomised phase III trial of trastuzumab plus docetaxel plus docetaxel with or without carboplatin first line in HER2 positive metastatic breast cancer (MBC). |
Forbes JF, Pienkowski T, et al. (2006). BCIRG 007: Journal of Clinical Oncology , ASCO Annual Meeting Proceedings (Post-Meeting Edition) 24 (18S) (June 20 Supplement) Pegram 2007. Slides that accompanied the abstract from ASCO 2007. BCIRG 007 study. First overall survival analysis of a multimeter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab s first line chemotherapy for patients with metastatic breast cancer containing the Her2/neu alteration. |
| Comparative study | ||
| Tauer 2006 | Randomized phase II trial of two different schedules of carboplatin (C) and paclitaxel (P) + trastuzumab (T) as first line treatment for metastatic breast cancer (MBC) [abstract]. | Tauer K, Schwartzberg LS, et al. (2006). Journal of Clinical Oncology¸ ASCO Annual Meeting Proceedings (Post-Meeting Edition) 24 (18S) (June 20 Supplement). |
| Non comparative studies | ||
| Pegram 2004 | Results of two open-label, multicenter phase II studies of docetaxel, platinum salts and trastuzumab in HER2-positive advanced breast cancer | Pegram M, Pienkowski T, et al. (2004), Journal of the National Cancer Institute, 96 (10): 759-69. |
| Burris 2004 | Phase II trial of trastuzumab followed by weekly paclitaxel/carboplatin as first-line treatment for patients with metastatic breast cancer. | Burris III H, Yardley D, et al. (2004). Journal of Clinical Oncology, 22 (9): 1621-9. |
| Perez 2005a | Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983552. | Perez E, Suman V. (2005). Clinical Breast Cancer, 6 (5): 425-32. |
| Taxane + carboplatin studies | ||
| Single arm of randomised trials | ||
| Fountzilas 2004 | Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy in patients with advanced breast cancer: a phase III study conducted by the Hellenic Cooperative Oncology Group. | Fountzilas G, Kalofonos H, et al. (2004), Annals of Oncology 15: 1517-26. |
| Non comparative studies | ||
| Perez 2005b | A phase II trial of docetaxel and carboplatin as first-line chemotherapy for metastatic breast cancer: NCCTG study N9932. | Perez A, Suman V, et al. (2005)., Oncology, 69: 117-21. |
| Perez 2000 | A phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast carcinoma. | Perez A, Hillman D, et al. (2000)., Cancer, 88: 124-31. |
| Ford 1997 | A phase II study of repetitive cycles of dose-intense carboplatin plus paclitaxel chemotherapy and peripheral blood stem cells in metastatic breast cancer. | Ford C, Spitzer G, et al. (1997). Seminars in Oncology, 5 (Suppl 17): S-17-81-6. |
Trast=trastuzumab, Pac=paclitaxel, TPC=trastuzumab + paclitaxel + carboplatin, TP=trastuzumab
+ paclitaxel, TDC=trastuzumab + docetaxel + carboplatin, TD=trastuzumab + paclitaxel,
MBC=metastatic breast cancer, TTP=time to progression, OS=overall survival, +ve=positive
The studies published at the time of the review for the comparative effectiveness
of trastuzumab + aromatase inhibitors and aromatase inhibitors alone were:
| Trial ID | Protocol/ publication title | Publication citation |
| Non-comparative study | ||
| Trastuzumab + letrozole | ||
| Marcom 2007 | The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers. | Marcom P, Isaacs C, et al. (2007). Breast Cancer Res Treat, 102: 43-49. |
ER=oestrogen receptor
The TaNDEM study was not published at the time of the review.
The studies published at the time of the review for trastuzumab + vinorelbine and
vinorelbine alone in first-line treatment of metastatic breast cancer were:
| Trial ID | Protocol/ publication title | Publication citation |
| Trastuzumab +Vinorelbine Studies | ||
| Randomised trials | ||
| Burstein 2007 | Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexperessing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. | Burstein H, Keshaviah A, et al. (2007). Cancer, 110(5): 965-72. |
| Non randomised studies | ||
| Burstein 2003 | Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicentre phase II trial with clinical outcomes, analysis of serum markers as predictive factors, and cardiac surveillance algorithm. | Burstein H, Harris L, et al. (2003). Journal of Clinical Oncology , 21 (15): 2889-95. |
| Chan 2006 | Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international phase II trial. | Chan A, Martin M, et al. (2006). British Journal of Cancer; 95: 788-93. |
| Jahanzeb 2002 | Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2+ metastatic breast cancer. | Jahanzeb M, Mortimer J, et al. (2002). The Oncologist 7:410-7. |
| Bernardo 2004 | Final results of phase II study of weekly trastuzumab and vinorelbine in chemonaive patients with HER2-overexpressing metastatic breast cancer [abstract]. | Bernardo G, Palumbo R, et al. (2004). Journal of Clinical Oncology, 23: 59 (abstr 731). |
| De Wit 2004 | Vinorelbine and trastuzumab as first line therapy in patients with HER2-positive metastatic breast cancer-interim analysis of a prospective, open-label, multicentre phase II trial [abstract]. | DeWit M, Becker K, et al. (2004). Ann Oncol, 15 (suppl 3): 37 (abstr 138p). |
| Vinorelbine Alone | ||
| Bruno 1995 | Phase II trial of weekly i.v. vinorelbine as a single agent in first-line advanced breast cancer chemotherapy. The Latin-American experience. | Bruno S, Puerto VL, et al. (1995). American Journal of Clinical Oncology 18(5): 392-6. |
| Freyer 2003 | Phase II study of oral vinorelbine in first-line advanced breast cancer chemotherapy. | Freyer, G, Delozier T, et al. (2003). Journal of Clinical Oncology, 21(1): 35-40. |
| Fumoleau 1993 | Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy. | Fumoleau P, Delgado F, et al. (1993). Journal of Clinical Oncology, 11(7): 1245-52. |
| Garcia-Conde 1994 | Phase II trial of weekly IV vinorelbine in first-line advanced breast cancer chemotherapy. | Garcia-Conde J, Lluch A, et al. (1994). Annals of Oncology 5 (9): 854-7. |
| Romero 1994 | Vinorelbine as first-line chemotherapy for metastatic breast carcinoma. | Romero A, Rabinovich M, et al. (1994). Journal of Clinical Oncology, 12(2): 336-41. |
| Vogel 1999 | Vinorelbine as first-line chemotherapy for advanced breast cancer in women 60 years of age or older. | Vogel C, O'Rourke M, et al. (1999). Annals of Oncology 10(4): 397-402. |
The studies published at the time of the review for the comparison of trastuzumab
+ vinorelbine versus vinorelbine alone in the second-line or subsequent setting were:
| Trial ID | Protocol/ publication title | Publication citation |
| Trastuzumab + vinorelbine versus vinorelbine alone studies | ||
| Comparative study | ||
| Papaldo 2006 | A phase II study on metastatic breast cancer patients treated with weekly vinorelbine with or without trastuzumab according to HER2 expression: changing the natural history of HER2-positive disease. | Papaldo P, Fabi A, et al. (2006). Annals of Oncology , 17: 630-6. |
| Trastuzumab + vinorelbine studies | ||
| Non-comparative studies | ||
| Bayo-Calero 2004 | A multicenter study with trastuzumab and vinorelbine as first and 2nd line treatment in patients (pats) with Her2 positive metastatic breast cancer (MBC). | Bayo-Calero JL, Mayordomo-Ca´mara JI, et al. (2004). Breast Cancer Res Treat, 82 (Suppl 1) (Abstr 5069). |
| Burstein 2001 | Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. | Burstein, H. J., I. Kuter, et al. (2001). Journal of Clinical Oncology 19 (10): 2722-30. |
| Catania 2007 | Optimizing clinical care of patients with metastatic breast cancer: a new oral vinorelbine plus trastuzumab combination. | Catania C, Medici M, et al. (2007). Annals of Oncology 18 (12): 1969-75. |
| De Maio 2007 | Vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer: a single-centre phase 2 trial. | De Maio E, Pacilio C, et al. (2007). BMC Cancer 7: 50. |
| Suzuki 2003 | Combination of trastuzumab and vinorelbine in metastatic breast cancer. | Suzuki Y, Tokuda Y, et al. (2003). Japanese Journal of Clinical Oncology 33(10): 514-7. |
| Vinorelbine studies | ||
| Barni 1994 | Vinorelbine as single agent in pretreated patients with advanced breast cancer. | Barni S, Ardizzoia A, et al. (1994). Tumori 80(4): 280-2. |
| Degardin 1994 | Vinorelbine (navelbine) as a salvage treatment for advanced breast cancer. | Degardin M, Bonneterre J, et al. (1994). Annals of Oncology 5(5): 423-6. |
| Gasparini 1994 | Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. | Gasparini G, Caffo O, et al. (1994). Journal of Clinical Oncology 12 (10): 2094-101. |
| Ibrahim 1999 | Phase II study of vinorelbine administered by 96-hour infusion in patients with advanced breast carcinoma. | Ibrahim N K, Rahman Z, et al. (1999). Cancer 86 (7): 1251-7. |
| Jara-Sanchez 2003 | Vinorelbine as a 96-hour continuous infusion in heavily pretreated patients with metastatic breast cancer: a cooperative study by the GEICAM group. | Jara-Sanchez C, Martin M, et al. (2003). Clinical Breast Cancer 3 (6): 399-404. |
| Martin 2007 | Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. [see comment]. | Martin M, Ruiz A, et al. (2007). Lancet Oncology 8 (3): 219-25. |
| Nistico 2000 | Weekly schedule of vinorelbine in pretreated breast cancer patients. | Nistico C, Garufi C, et al. (2000). Breast Cancer Research & Treatment 59 (3): 223-9. |
| Terenziani 1996 | Vinorelbine: an active, non cross-resistant drug in advanced breast cancer. Results from a phase II study. | Tereziani M, Demicheli R, et al. (1996). Breast Cancer Research and Treatment, 39: 285-90. |
| Toussaint 1994 | Phase I/II trial of continuous infusion vinorelbine for advanced breast cancer. | Toussaint C, Izzo M, et al. (1994). Journal of Clinical Oncology, 12 (10): 2102-12. |
| Udom 2000 | Two weekly vinorelbine: administration in patients who have received at least two prior chemotherapy regimes for advanced breast cancer. | Udom DI, Vigushin DM, et al. (2000). European Journal of Cancer, 36: 177-82. |
| Verma 2007 | Survival differences observed in metastatic breast cancer patients treated with capecitabine when compared with vinorelbine after pre-treatment with anthracycline and taxane. | Verma S, Wong SN, et al. (2007). American Journal of Clinical Oncology , 30 (3): 297-302. |
| Zelek 2001 | Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. | Cancer, 92 (9): 2267-72. |
The studies published at the time of the review for the assessment of the use of trastuzumab as monotherapy were:
| Trial ID | Protocol/ publication title | Publication citation |
| Comparative study (retrospective) – first, second and subsequent | ||
| Trastuzumab versus trastuzumab + chemotherapy | ||
| Kostler 2005 | Single-agent trastuzumab versus trastuzumab plus cytotoxic chemotherapy in metastatic breast cancer: a single-institution experience. | Kostler WJ, Steger GG, et al. (2005). Anti-Cancer Drugs , 16 (2): 185-90. |
| Non-comparative studies – first-line treatment | ||
| Vogel 2002 | Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer. | Vogel CL, Cobleigh MA, et al (2002). Journal of Clinical Oncology , 20 (3): 719-26. |
| Baselga 2005 | Phase III Study of Efficacy, Safety and Pharmacokinetics of Trastuzumab Monotherapy Administered on a 3-weekly Schedule. | Baselga J, Carbonell X, et al. (2005). Journal of Clinical Oncology, 23 (10): 2162-70. |
| Non-comparative studies – second-/subsequent line treatment | ||
| Cobleigh 1999 | Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer that has Progressed after Chemotherapy for Metastatic Disease. | Cobleigh MA, Vogel MA, et al. (1999). Journal of Clinical Oncology, 117 (9): 2639-48. |
| Sawaki 2004 | Efficacy and Safety of Trastuzumab as a Single Agent In Heavily Pre-treated Patients with Her2/NEU-Overexpressing Metastatic Breast Cancer. | Sawaki M, Ito Y, et al (2004). Tumori, 90: 40-3. |
The studies published at the time of the review for the comparison of trastuzumab + capecitabine and capecitabine alone in the first-line setting were:
| Trial ID | Protocol/ publication title | Publication citation |
| Trastuzumab + capecitabine studies | ||
| Non comparative studies | ||
| Yamamoto 2008 | A phase II study of trastuzumab and capecitabine for patients with HER2-overexpressing metastatic breast cancer: Japan Breast Cancer Research Network (JBCRN) 00 Trial. | Yamamoto D, Iwase S, et al (2008). Cancer Chemotherapy Pharmacology, 61: 509-514. |
| Capecitabine studies | ||
| Single arm of a randomised trial | ||
| O’Shaughnessy 2001 | Randomized, open-label, phase II trial of oral capecitabine (Xeloda®) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluoroucacil) as first-line therapy for advanced/metastatic breast cancer. | O’Shaughnessy J, Blum J, et al. (2001). Annals of Oncology, 12: 1247-1254. |
| Non comparative studies – first line | ||
| Bajetta 2005 | Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. | Bajetta E, Procopio G, et al. (2005). Journal of Clinical Oncology, 23 (10): 2155-2161. |
| Minea 2004 (abstract only) | Capecitabine monotherapy for elderly patients with metastatic breast cancer. | Minea L, Stanculeanu D, et al (2004). Journal of Clinical Oncology, 22 (suppl 14): 76s |
| Yap 2007 | Clinical efficacy of capecitabine as first-line chemotherapy in metastatic breast cancer – How low can you go? | Yap Y, Kendall A,, et al. (2007). The Breast; 16: 420-424. |
The studies published at the time of the review for the comparison of trastuzumab + capecitabine and capecitabine alone in the second-line or subsequent settings were:
| Trial ID | Protocol/ publication title | Publication citation |
| Trastuzumab + capecitabine versus capecitabine alone (beyond disease progression) | ||
| Randomised trials | ||
| von Minckwitz 2008 | Capecitabine vs. capecitabine + trastuzumab in patients with HER-2 positive metastatic breast cancer progressing during trastuzumab treatment – the TBP phase III study (GBG 26 / BIG 3-05). | Von Minckwitz G, Zielinski C, et al. (2008). 44 th ASCO Annual Meeting, May 30-June 3, Chicago, Illinois, USA. |
8. Results of Trials
Trastuzumab + taxane versus taxane alone:
The time to progression, progression free survival and overall survival across the
direct randomised trials are presented in the table below.
| Median time in Months (95% CI) | Absolute difference | HR (95% CI) | P-value (log-rank) | ||
| Trial | Trast + Taxane^ | Taxane^ | |||
| Time to disease progression a | |||||
| Slamon 2001* | N=92 6.9 (5.3, 9.9) | N=96 3.0 (2.1, 4.3) | 3.9 | NR | <0.001 |
| Marty 2005 | N=92 11.7 (9.2, 13.5) | N=94 6.1 (5.4, 7.2) | 5.6 | NR | 0.0001 |
| Gasparini 2006 a | N=63 10.0 | N=60 6.8 | 3.2 | NR | 0.076 |
| Progression free survival | |||||
| Marty 2005 | N=92 12.0 (9.9, 15.8) | N=94 6.8 (5.8, 8.3) | 5.2 | NR | 0.1206 |
| Overall survival | |||||
| Slamon 2001 | N=92 22.1 (16.9, 30.7) | N=96 18.4 (12.7, 24.4) | 3.7 | NR | 0.17 |
| Marty 2005 | N=92 31.3 (27.3, 42.0) | N=94 22.7 (19.1, 30.9) | 8.6 | NR | 0.1449 |
Abbreviations: Trast=trastuzumab, HR=hazard ratio, NR=not reported
* primary outcome of the trial
^ paclitaxel in Slamon 2001 and Gasparini 2006, docetaxel in Marty 2005.
a reported as number of days in Gasparini, converted to months in this review: x days/30
= y months
Source: published reports of Slamon, Marty and Gasparini.
Note: Progression free survival was only reported for Marty 2005. Overall survival
was not reported by Gasparini 2006.
There was a statistically significant increase in median time to disease progression
in patients taking trastuzumab plus a taxane compared to taxane alone in the studies
by Slamon and Marty, but not in the Gasparini trial.
The publication by Gasparini et. al. (2007) presented the results of an unplanned
interim analysis of 123 patients after a median follow-up of 16.6 months. The planned
sample size of the study was 160 patients, 80 in each treatment arm. In this study,
HER2 positivity was only assessed using immunohistochemistry (IHC). There was no fluorescence
in situ hybridisation (FISH) confirmation of HER2 positivity in IHC 2+ patients, which
is standard practice. The primary endpoint of the study was overall response rate
(ORR). The study was not powered to measure a statistically significant difference
in time to progression, as this was a secondary endpoint. Overall survival results
were not reported as median overall survival had not been reached. Although the difference
in median time to progression between treatment arms did not reach statistical significance
for the combined IHC 2+ and IHC 3+ population (p=0.076), there was a statistical difference
in the IHC 3+ alone population and patients with visceral involvement (p=0.030).
The PBAC was concerned that the results for progression free survival in the Marty
et al trial did not reach statistical significance, although it was the main trial
used in the economic evaluation. The primary endpoint in Marty et al 2005 was overall
response rate (best response). The study was not powered to measure a statistical
difference between treatment arms for the secondary endpoints of time to progression
(TTP), progression-free survival (PFS) and overall survival (OS). TTP was defined
as the number of days from randomisation to date of documented progressive disease.
PFS was defined as the number of days from randomisation to date of death or progressive
disease.
The 24-month PFS results were not reported in the publication for Study M77001 but
were provided in the accompanying 24-month Addendum on which the publication was based.
At the 24-month data cut-off, all three endpoints (time to disease progression, progression-free
survival and overall survival) were statistically significant different between the
treatment arms of trastuzumab with a taxane versus a taxane alone.
Trastuzumab + aromatase inhibitor versus aromatase inhibitor alone:
Results from the TaNDEM trial indicated that a statistically significantly greater
proportion of patients treated with combination trastuzumab and aromatase inhibitors
achieved a partial and overall response, and also experienced increased time to progression
and progression free survival, but not overall survival compared with those treated
with aromatase inhibitors alone. There was no significant difference in overall survival,
however more than half of the patients in the anastrozole-alone arm crossed over to
a trastuzumab-containing regimen after progression of disease.
Trastuzumab + vinorelbine versus trastuzumab + taxane:
The time to progression and time to treatment failure for the randomised trial reported
by Burstein 2007 are presented in the table below.
| Outcome | Trast+vino N=41 | Trast+taxane N=40 | log rank p value |
| Time to progression | 8.5 months | 6.0 months | 0.09 |
| Time to treatment failure | 5.8 months | 4.7 months | 0.15 |
Abbreviations: Trast-trastuzumab, Vino-vinorelbine
Data from Burstein (2007) indicated that the effectiveness of trastuzumab in combination
with vinorelbine appeared to be similar as when it was combined with a taxane, as
no significant differences in the outcomes reported were observed. In terms of safety,
the toxicity profiles of vinorelbine and taxanes differed. Vinorelbine appeared to
be associated with more neutropenia (although treatment with filgrastim was not reported),
whereas taxanes ware associated with alopecia (both taxanes) and fluid retention (docetaxel).
Trastuzumab monotherapy:
No information was presented in the review to inform the comparative effectiveness
of trastuzumab monotherapy compared with trastuzumab + chemotherapy in either the
first- or second-line setting. There was also no information presented in the review
to inform the comparative safety of trastuzumab monotherapy compared with trastuzumab
+ chemotherapy in either the first- or second-line setting, however it would be anticipated
that any adverse events that are attributable to the chemotherapy would not be experienced
by patients being treated with trastuzumab monotherapy.
Data from Kostler (2005) indicated that trastuzumab monotherapy may have similar effectiveness
to trastuzumab + chemotherapy, however these data needed to be considered carefully
as the study was retrospective and very few patients treated with monotherapy were
included in the analysis (n=14).
A greater proportion of patients treated with trastuzumab experienced cardiac dysfunction
compared to patients treated with chemotherapy alone. Current practice was aimed at
avoiding cardiovascular events by application of cardiovascular eligibility criteria
and prospective cardiac monitoring. The costs for this monitoring were included in
the economic evaluation.
For PBAC’s views see Recommendation and reasons.
9. Clinical Claim
For PBAC’s views see Recommendation and
reasons.
10. Economic Analysis
Premodelling studies:
The following premodelling studies were undertaken:
- Estimation of the administration schedules of the therapies of interest used in Australian clinical practice;
- Use of premedications for the various therapies;
- Monitoring associated with the treatment of metastatic breast cancer;
- Extrapolation of trial data to a 10-year time horizon:
- Exponential extrapolation of trial data used in the AUC model, with a hazard ratio = 1 beyond truncation;
- Weibull function(s) for the extrapolation of trial data used in the Markov model. Time-dependent transition probabilities were estimated from the extrapolation.
Two economic evaluations, an Area Under the Curve (AUC) and a
Markov model, comparing the costs and outcomes if trastuzumab was
available on the PBS for patients with HER2 positive metastatic
breast cancer with the costs and outcomes if trastuzumab was not
available were presented. Both models had a time horizon of 10
years and both estimated an incremental cost per life year gained
and a cost per Quality Adjusted Life Year (QALY). The AUC model was
constructed for consistency purposes with the previous model
considered by the PBAC in the earlier submissions.
Results from two trials were used to derive outcomes for both
models: the M77001 trial (reported by Marty 2005) and the TaNDEM
trial. The M77001 trial compared trastuzumab + docetaxel with
docetaxel alone in patients with metastatic breast cancer. The
TaNDEM trial compared trastuzumab + anastrozole with anastrozole
alone.
The incremental cost/ extra life-year gained over 10 years using
the AUC model was between $75,000 and $105,000, and the incremental
cost/ extra QALY gained over 10 years was between $105,000 and
$200,000.
For the Markov model, the incremental discounted cost/extra
discounted life-year gained over 10 years was between $75,000 and
$105,000. The incremental discounted cost/extra discounted QALY
gained over 10 years was between $105,000 and $200,000.
Sensitivity analysis showed that the models were most sensitive to
the estimate of treatment effect for trastuzumab (AUC), utility
weights applied to patients in the “progressing”
disease state in both models and the cost of trastuzumab
(demonstrated by increasing the assumed weight of patients in both
models). Sensitivity analyses for the AUC model were conducted
during the review.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year were estimated to be less
than 10,000, and was based on the number currently receiving
trastuzumab through the Herceptin Program. The annual expenditure
on the Herceptin Program was currently between $30 million and $60
million (excluding GST).
12. Recommendation and Reasons
The Government had requested the PBAC to review the clinical and
cost-effectiveness of trastuzumab when used in the treatment of
HER-2 positive metastatic breast cancer (MBC). Since 2002
trastuzumab has been publicly funded for use in metastatic breast
cancer in a program that operates independent of the Pharmaceutical
Benefits Scheme.
The Committee considered that, in terms of clinical effectiveness:
- Combined therapy with trastuzumab plus taxanes (docetaxel or paclitaxel) was more effective, but associated with greater toxicity, than taxanes alone as a first line treatment for MBC. This had previously been accepted by the PBAC;
- Dual therapy involving trastuzumab plus aromatase inhibitors in oestrogen receptor positive patients was more effective, but associated with greater toxicity, than aromatase inhibitors alone in first and second line MBC;
- There appeared to be a trend of increased efficacy of trastuzumab plus vinorelbine over vinorelbine alone for first-line treatment of MBC, but this was based on a comparison of single arm studies with confounding;
- Treatment with trastuzumab plus vinorelbine was equi-effective with trastuzumab plus taxanes for first-line treatment of MBC. The toxicity profiles of vinorelbine and taxanes differed. Vinorelbine appeared to be associated with more neutropenia (although treatment with filgrastim was not reported), whereas taxanes were associated with hair loss and fluid retention;
- The additional benefit of ‘triple therapy’ involving trastuzumab plus taxane plus another cytotoxic agent (e.g. carboplatin or capecitabine) was uncertain and was more toxic; and
- The effectiveness of trastuzumab used beyond disease progression was uncertain with some studies reporting decreasing time to progression and response rates with subsequent treatment, whereas others reported comparable time to progression and response rates over time.
The Committee further agreed that:
- The evidence of clinical benefit for trastuzumab when used as monotherapy was uncertain;
- The evidence of clinical benefit for trastuzumab when it was used for the first time as part of second or third line treatment in patients who have been pre-treated with one or more lines of chemotherapy is inconclusive; and
- There was no information on the efficacy of trastuzumab in patients with MBC who also received trastuzumab as part of their adjuvant treatment.
The Committee considered that the Markov model used to assess the
cost-effectiveness of trastuzumab in MBC was robust. Any
assumptions that might favour trastuzumab and underestimate the
incremental cost-effectiveness ratio (ICER), for example: that
there was no use of drug beyond progression and that there were no
costs associated with progression; were likely to be balanced by
assumptions that bias the ICER against trastuzumab, for example the
likelihood that the survival advantage in first line setting was
underestimated because of cross over and the poor patient selection
resulting from inaccurate testing for HER-2 when some of the
studies were designed.
However, at the current price of trastuzumab the base case
incremental cost effectiveness ratio was above the range usually
considered by the PBAC as being acceptable for PBS-subsidy lying
between $105,000 and $200,000 (assuming a section 100 listing,
including wastage and assigning a utility of 0.65 for the
progressing disease health state). Even if, as considered not
unreasonable by PBAC, the utility for progressing disease was set
at 0.7, the ICER remained unacceptably high lying between $75,000
and $105,000. (The Committee also noted that the use of trastuzumab
in combination with vinorelbine was not supported by the TGA
registration for trastuzumab and therefore that the above
cost-effectiveness analysis which assumed 40 % use of this regimen
may not represent the most appropriate base case. The incremental
cost-effectiveness ratio in a “TGA approved indication”
analysis was between $105,000 and $200,000).
The PBAC noted the high base case ICER (lying between $105,000 and
$200,000) for trastuzumab for HER-2 positive MBC and considered
that a significant price reduction would be required in order for
the ICER to fall into a range which would make it acceptable for
PBS-subsidy, and asked that the Minister be so advised. The
Committee further requested the Minister be advised that the PBAC
in this instance may be prepared to consider a full economic
evaluation of trastuzumab capturing all stages of the
disease.
Lastly the Committee asked that the Minister be advised that,
although the measures listed below would not by themselves make
trastuzumab acceptably cost-effective in terms of PBS-subsidy, they
would nonetheless substantially improve the cost-effectiveness of
trastuzumab when supplied via the non-PBS Herceptin program (and
these same measures would be stipulated by PBAC in the event of a
PBS-subsidy of trastuzumab in MBC):
- confine trastuzumab use to first line treatment of MBC in combination with a taxane (docetaxel or paclitaxel). The use of trastuzumab as first line treatment of MBC in combination with vinorelbine was supported by the clinical trial evidence, but this combination was not registered with the TGA;
- confine use of trastuzumab to patients who have their HER-2 positive status confirmed by ISH testing;
- allow trastuzumab to be used once only for MBC. Changing the partner chemotherapy should only be permitted if patients develop an intolerance to the chemotherapy agent and not as a means of continuing treatment with trastuzumab beyond disease progression;
- not allow trastuzumab to be used as monotherapy in patients newly diagnosed with HER-2 positive MBC (noting that around one-third of the current usage of Herceptin on the non-PBS MBC program is as monotherapy); unless there was an absolute contraindication to chemotherapy.
- not allow trastuzumab to be used as part of triple combination therapy;
- not allow trastuzumab to be used beyond progression (of MBC);
- not allow use in combination with aromatase inhibitors;
The PBAC indicated its willingness to continue to work with the
Government and the sponsor on any of the matters raised in this
review.
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 sponsor has no further comment.
