Guidance on the use of trastuzumab for the treatment of advanced breast cancer

Evidence-based recommendations on trastuzumab for treating advanced breast cancer in adults.

# Guidance
Trastuzumab in combination with paclitaxel (combination trastuzumab is currently only licensed for use with paclitaxel) is recommended as an option for people with tumours expressing human epidermal growth factor receptor 2 (HER2) scored at levels of 3+ who have not received chemotherapy for metastatic breast cancer and in whom anthracycline treatment is inappropriate.
Trastuzumab monotherapy is recommended as an option for people with tumours expressing HER2 scored at levels of 3+ who have received at least two chemotherapy regimens for metastatic breast cancer. Prior chemotherapy must have included at least an anthracycline and a taxane where these treatments are appropriate. It should also have included hormonal therapy in suitable oestrogen receptor positive patients.
HER2 levels should be scored using validated immunohistochemical techniques and in accordance with published guidelines. Laboratories offering tissue sample immunocytochemical or other predictive tests for therapy response should use validated standardised assay methods and participate in and demonstrate satisfactory performance in a recognised external quality assurance scheme.# Clinical Need and Practice
Approximately 32,000 new cases of breast cancer were reported in England and Wales in 1996. In 1998, breast cancer caused over 11,000 deaths in England and Wales and was the leading cause of death in women aged 35 to 54 years.
Advanced and metastatic breast cancer (MBC) are defined by clinical staging based on the tumour, node and metastasis staging system (stage III denotes locally advanced disease and stage IV indicates metastatic breast cancer).
Between 16% and 20% of women initially presenting with breast cancer have advanced disease with distant metastases and around 50% of those presenting with early or localised breast cancer will eventually develop MBC.
Some breast tumours contain an amplification of the human epidermal growth factor receptor (HER2), which causes overexpression of the HER2 protein and is associated with a poorer prognosis. Approximately 15%-20% of people with MBC overexpress HER2 at the 3+ level, measured by immunohistochemical techniques. The average period of survival after diagnosis of MBC is 18-24 months, but this is reduced by up to 50% for patients overexpressing HER2.
First-line systemic therapy for advanced or metastatic breast cancer is chemotherapy for oestrogen receptor-negative patients (usually an anthracycline-containing regimen or sometimes a combination of cyclophosphamide, methotrexate and fluorouracil), and hormone manipulation therapy for oestrogen receptor-positive patients. However, the choice of therapy is influenced by the rate of progression and distribution of disease and by whether the drugs have already been administered as adjuvant therapies.
Current NICE guidance states that docetaxel and paclitaxel should be available for the treatment of advanced breast cancer where initial cytotoxic chemotherapy (including an anthracycline) has failed or is inappropriate.# The Technology
Trastuzumab is a recombinant humanised monoclonal antibody that specifically targets the HER2 protein. It is licensed for two indications for the treatment of MBC overexpressing HER2 at level 3+. Firstly, it is licensed in combination with paclitaxel for patients with MBC who have not received chemotherapy for metastatic disease and in whom an anthracycline is unsuitable. Secondly, it is licensed as a monotherapy for patients who have received at least two chemotherapy regimens for MBC; prior chemotherapy must have included at least an anthracycline and a taxane, unless these treatments are inappropriate; patients who are oestrogen receptor-positive must also have failed to respond to appropriate hormonal therapy.
Trastuzumab is administered intravenously. Following an initial loading dose of 4 mg per kg body weight, patients receive a weekly dose of 2 mg per kg body weight until disease progression. Side-effects associated with trastuzumab have been noted to include cardiotoxicity and infusion-related reactions.
The basic NHS price according to the British National Formulary (September 2001) for trastuzumab is 407 per 150 mg vial. For a typical patient, a 38-week course of combination therapy costs approximately 15,500 for trastuzumab and 9,600 for paclitaxel. The cost of a 12-week course of treatment with trastuzumab monotherapy is approximately 5,300.
There are costs of testing a woman's suitability for treatment and of monitoring in addition to the cost of administering treatment. HER2 levels must be assessed in patients who are potentially eligible for treatment with trastuzumab, and patients receiving trastuzumab should have left ventricular ejection fraction measured before and during treatment.# Evidence 

# Clinical effectiveness

## Combination therapy
One randomised controlled trial (RCT) (n=469) of first-line trastuzumab combination therapy was available. All individuals had HER2 overexpression at least at level 2+. Patients who had not previously received anthracyclines were randomised to an anthracycline in combination with cyclophosphamide with or without trastuzumab. Patients who had previously received an anthracycline as adjuvant therapy (n=188) were randomised to paclitaxel (n=96) or paclitaxel plus trastuzumab (n=92). The primary endpoint was time to progression and the median duration of follow-up was 30 (range 30-51) months. Patients in all arms of the trial were given the option of receiving trastuzumab monotherapy at the time of disease progression, meaning that allocation to this further treatment was non-random.
When only the two relevant treatment arms involving paclitaxel were considered, there was no significant difference in overall survival between the group treated with trastuzumab plus paclitaxel and the group treated with paclitaxel alone (22 vs 18 months, p=0.17). However, the addition of trastuzumab resulted in longer median times to disease progression (7 vs 3 months, p<0.001), duration of response (11 vs 5 months, p<0.01) and time to treatment failure (6 vs 3 months, p<0.001). There was no statistically significant difference between the two treatments in terms of complete response (relative risk  3.65, 95% CI 0.89 to 15.22), but overall tumour response (RR 2.48, 95% CI 1.49 to 4.12), disease progression (RR 0.38, 95% CI 0.27 to 0.53) and treatment failure (RR 0.46, 95% CI 0.33 to 0.63) favoured treatment with trastuzumab. For patients with HER2 3+, trastuzumab and paclitaxel was associated with a longer median survival than paclitaxel alone (25 vs 18 months, no p-value provided).
Quality of life, assessed using the pain and dyspnoea domains and the breast cancer module of the EORTC QLQ-C30 questionnaire, was higher in the group receiving trastuzumab plus chemotherapy than in the group receiving chemotherapy alone.
The most important adverse event seen in the trial was cardiac dysfunction, which occurred in 27% of the group given an anthracycline, cyclophosphamide and trastuzumab, 8% of the group given an anthracycline and cyclophosphamide alone, 13% of the group given paclitaxel and trastuzumab, and 1% of the group given paclitaxel alone. The cardiotoxicity was potentially severe, and in some cases life threatening, but the symptoms were reported generally to improve with standard medical management.
Although not originally observed during clinical trials, serious infusion-related reactions have been reported in 74 from a total of approximately 25,000 patients who received trastuzumab, with the reactions leading to the death of 15 patients. These reactions, which include anaphylaxis and severe dyspnoea, usually occur within 24 hours of the infusion, although delayed reactions have also been reported. Allergic or hypersensitivity reactions, haematological toxicity, hepatic and renal toxicity, diarrhoea and an increased risk of infections have also been noted.

## Monotherapy
No comparative RCTs of trastuzumab monotherapy (i.e. versus systemic therapy without trastuzumab) were available. Of the studies that were identified, two were case-series of trastuzumab (H0551g, n=46; H0649g, n=222) and one was a RCT of trastuzumab monotherapy, which was concerned with an unlicensed indication and was essentially a dose ranging study (H0650g, n=113). Women in H0650g received first-line monotherapy with trastuzumab, which is an unlicensed indication.
In H0649g, 4% of women experienced a complete response to treatment and 12% experienced a partial response. The overall response rate was 15%. Smaller proportions of women responded to treatment in study H0551g.
The median duration of survival in H0649g was 13 months for all women and 16 months in a sub-group analysis of women overexpressing HER2 at 3+ levels. In the manufacturer's submission, survival reported in H0649g was indirectly compared with survival reported in two RCTs of vinorelbine monotherapy. Both RCTs contained a treatment arm consisting of vinorelbine monotherapy as second-line or salvage therapy for MBC. In one of these RCTs, 91% of participants had received prior treatment with anthracyclines for advanced breast cancer. The median duration of survival for people receiving vinorelbine monotherapy was 8 months. The reported median duration of survival in the other study was 10 months. Participants in these two RCTs were not selected on the basis of their HER2 status, which may suggest that their prognosis was better than those in H0649g.
The manufacturer also submitted evidence from the Imperial Cancer Research Fund database at Guy's and St Thomas' Hospital NHS Trust on patients who had received third-line chemotherapy for MBC and who were not treated on the basis of their HER2 expression status. Analysis of these data showed that the median survival for these patients was 6.3 months.
Trastuzumab monotherapy appeared to have a relatively low toxicity level. For study H0649g, the common adverse events (occurring in approximately 40% of people) were infusion-related fever and/or chills that usually occurred only during the first infusion. The most clinically significant adverse event was cardiac dysfunction, which occurred in 10 people (5%). However, only 1% of participants in this study discontinued treatment because of treatment-related adverse events. In study H0551g toxicity was reported as minimal, although two patients died as a result of cardiac dysfunction. In study H0650g the adverse events recorded were mainly mild to moderate in nature and were mostly associated with the higher dose regimen; only one person experienced cardiac dysfunction.

# Cost-effectiveness

## Combination therapy
The manufacturer evaluated the cost-effectiveness of trastuzumab in combination with paclitaxel versus paclitaxel alone for patients with HER2 3+, based on results from the RCT. Estimates of direct medical and social care costs were included in the evaluation, including the costs of HER2 testing (21 for a single test) and cardiac testing (520-640 for four tests).
The manufacturer estimated the incremental cost-effectiveness ratio to be 37,500 per Quality-Adjusted Life-Year (QALY) gained (and substantially less per life-year gained). This survival benefit used to estimate the QALY gain was based on a weighting of case-mix reflecting the selection of patients in the pivotal trial who, after the trial, crossed over to trastuzumab monotherapy. After extrapolating the trial results for this selection of patients, approximately 10 months mean survival advantage was imputed into the economic evaluation. A number of other sources, in particular two non-controlled studies that examined the use of taxane monotherapy as first-line treatment for metastatic breast cancer, suggest a survival advantage of combination therapy compatible, or even better, than this.

## Monotherapy
One economic evaluation of monotherapy comparing trastuzumab with vinorelbine monotherapy was available to the Committee. Direct information relating to clinical effectiveness was unavailable (as there were no RCTs of trastuzumab other than a dose ranging study). Health outcomes were expressed in terms of life years and QALY by extrapolating survival from non-controlled studies. Direct medical and social care costs were included in the evaluation. Information on clinical effectiveness was imputed from H0649g and an RCT of vinorelbine versus melphalan that contained patients who were at an earlier stage of the disease and who were not selected on the basis of HER2 expression status. Patients who received vinorelbine in the RCT survived for approximately a median of 8 months. The manufacturer referenced two other non-controlled studies in an attempt to validate this period of survival for patients receiving vinorelbine. One of these studies examined median survival in patients at a similar disease stage who received vinorelbine monotherapy; in this study, median survival was approximately 6 months.
The estimated incremental cost-effectiveness ratio was approximately 7,500 per life-year gained if trastuzumab was used instead of vinorelbine, when it was assumed that the additional survival attributable to trastuzumab monotherapy was 8 months. The manufacturers also provided a cost per QALY of approximately 19,000 by assuming that the 8 months of additional survival was equivalent to 2.6 quality-adjusted months.

# Considerations

## Combination therapy
Appraisal Committee considered that a survival gain of approximately 10 months used in the economic evaluation was likely to be an underestimate of the true survival gain attributable to combination therapy given that patients in the non-controlled studies of taxane monotherapy were not HER2 selected. The Appraisal Committee also concluded that the utility weights used to adjust survival for changes in quality of life were low.
Based on these factors, the Appraisal Committee believed that trastuzumab combination therapy was likely to be lower than the estimate of 37,500 per QALY gained provided by the manufacturer.
The Appraisal Committee also noted that improvements in survival of this magnitude due to therapeutic intervention have rarely been recorded in women with metastatic breast cancer.

## Monotherapy
The evidence for the effectiveness of trastuzumab monotherapy was limited to two case-series and one RCT, which was concerned with an unlicensed indication and was essentially a dose ranging study. The report for the first case-series (H0551g) did not state the line of therapy being assessed or the length of follow-up. The second case-series (H0649g), which was relatively well reported, suggested that in terms of response rate trastuzumab monotherapy was an effective treatment in patients with MBC and HER2 overexpression at levels 3+.
Although the Appraisal Committee had some reservations about the quality and robustness of the economic evaluation for trastuzumab monotherapy, as survival was not based on results from controlled studies, it was believed that these misgivings would not increase the ratio sufficiently to suggest that it is not cost-effective.# Implications for the NHS
Patients who receive treatment with trastuzumab should be monitored for the possibility of cardiotoxicity.
The manufacturer estimated the gross impact of providing trastuzumab plus paclitaxel instead of paclitaxel alone and trastuzumab monotherapy to be approximately 17 million per annum. This estimate is based on the following assumptions: HER2 status is assessed in 20,000 patients with metastatic disease at a cost of 21 per test; 1600 patients receive monotherapy at a cost of 5,300 per person; 450 patients receive combination therapy costing an additional 15,500 to provide trastuzumab and paclitaxel instead of paclitaxel alone; each person receives four cardiac tests at a cost of 580 for each set of four tests. (Overall calculation:  +  +  + ).# Further Research
Information linking side-effects associated with treatments with quality of life would enhance the comprehensiveness of future economic evaluations of treatments for advanced breast cancer.# Related Guidance
The Institute issued guidance in September 2001 on the use of taxanes for the treatment of breast cancer:
National Institute for Clinical Excellence (2001) Guidance on the use of taxanes for the treatment of breast cancer: NICE Technology Appraisal Guidance No. 30. London: National Institute for Clinical Excellence. # Review of Guidance
Information on the review of the guidance on this technology is available on the NICE website.
Andrew DillonChief ExecutiveMarch 2002# Appendix B. Sources of Evidence 
The following documentation and opinion was made available to the Appraisals Committee:
a. Assessment Report:
Prepared by The NHS Centre for Reviews and Dissemination (A rapid and systematic review of the clinical effectiveness and cost-effectiveness of trastuzumab and vinorelbine for breast cancer, February 2001)
Prepared by The NHS Centre for Reviews and Dissemination (A rapid and systematic review of the clinical effectiveness and cost-effectiveness of trastuzumab for breast cancer, October 2001)
b. Manufacturer/sponsor submissions:
Roche
c. Professional/specialist group submissions from:
British Psychosocial Oncology Society
Imperial Cancer Research Fund
MRC Clinical Trials Unit
National Cancer Research Institute
Royal College of General Practitioners
Royal College of Pathologists
Royal College of Physicians
d. Patient group submissions from:
Breakthrough Breast Cancer, CancerBACUP and the UK Breast Cancer Coalition joint submission
Breast Cancer Care
Macmillan Cancer Relief
e. Other group submissions from:
Department of Health
National Assembly for Wales
f. External expert and patient advocate submissions from:
Professor Robert Coleman, Professor of Medical Oncology, Cancer Research Centre,Weston Park Hospital, University of Sheffield
Bernie Gardiner, Information Nurse Specialist, Breast Cancer Care
Margaret King, Vice Chair, UK Breast Cancer Coalition# Appendix C. Guidance on the use of trastuzumab for the treatment of advanced breast cancer. Patient information
'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.# Changes after publication
March 2014: implementation section updated to clarify that trastuzumab is recommended as an option for treating advanced breast cancer. Additional minor maintenance update also carried out.
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
The recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
 National Institute for Health and Clinical Excellence 2002. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.