Breast cancer (advanced or metastatic) - lapatinib: appraisal consultation document
Appraisal consultation document
Lapatinib in previously treated women with advanced or metastatic breast cancer
The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of lapatinib (in combination with capecitabine) and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted by the manufacturer and the views put forward by non-manufacturer consultees and commentators, and by the clinical specialist and patient expert representatives nominated for this appraisal by non-manufacturer consultees and commentators. The Committee has developed preliminary recommendations on the use of lapatinib.
This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk). This document should be read in conjunction with the evidence base for this appraisal (the evaluation report) which is available from www.nice.org.uk
Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation .
The process the Institute will follow after the consultation period is summarised below. For further details, see the ‘Guide to the single technology appraisal process' (this document is available on the Institute's website, www.nice.org.uk).
The Appraisal Committee will meet again to consider the original evidence and this appraisal consultation document in the light of the views of the formal consultees.
At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
After considering feedback from the consultation process, the Committee will prepare the final appraisal determination (FAD) and submit it to the Institute.
Subject to any appeal by consultees, the FAD may be used as the basis for the Institute's guidance on the use of the appraised technology in the NHS in England and Wales.
The key dates for this appraisal are:
Closing date for comments: 28 July 2008
Second Appraisal Committee meeting: 18 September 2008
Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.
Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation.
|1||Appraisal Committee's preliminary recommendations|
|1.1||Lapatinib (in combination with capecitabine), within its licensed indication, is not recommended for the routine treatment of women with advanced or metastatic breast cancer whose tumours overexpress HER2 except in the context of clinical trials.|
|2.1||Lapatinib (Tyverb, GlaxoSmithKline) is an inhibitor of the intracellular tyrosine kinase domains of ErbB1 (EGFR) and ErbB2 (HER2) receptors. Lapatinib, in combination with capecitabine, has a marketing authorisation for the treatment of patients with advanced or metastatic breast cancer whose tumours overexpress ErbB2 (HER2). Patients should have progressive disease following prior therapy which must include anthracyclines, taxanes and therapy with trastuzumab in the metastatic setting. The marketing authorisation is granted conditional upon the manufacturer performing and submitting the following: an updated analysis of survival data for study EGF100151; and conducting a phase III randomised, controlled clinical study to evaluate the incidence of brain metastases as the site of relapse with a lapatinib-containing therapy compared with an appropriate, trastuzumab-containing arm. The recommended dosage of lapatinib is 1250 mg/day to be taken continuously. The recommended dosage of capecitabine, when taken with lapatinib, is 2000 mg/m 2 per day taken on days
1–14 of a 21-day cycle.
|2.2||The summary of product characteristics (SPC) states that lapatinib has been associated with decreases in left ventricular ejection fraction (LVEF). Caution should be taken if lapatinib is to be administered to patients with conditions that could impair left ventricular function. LVEF should be evaluated in all patients before initiation of treatment and continue to be evaluated during treatment with lapatinib. The SPC also states that diarrhoea, including severe diarrhoea, has been reported with lapatinib treatment. It therefore recommends proactive management of diarrhoea with anti-diarrhoeal agents. The SPC further recommends that liver function should be monitored before initiation of treatment and monthly thereafter or as clinically indicated. Lapatinib should be discontinued if changes in liver function are severe and patients should not be retreated. For full details of side effects and contraindications, see the SPC.|
|2.3||The acquisition cost for lapatinib is £11.49 per 250-mg tablet and therefore the cost of lapatinib treatment is £57.45 per day. This translates to £20,969 per year. The cost of 60 x 150-mg tablets of capecitabine is £44.47 and 120 x 500-mg tablets is £295.06 (excluding VAT; ‘British national formulary' [BNF] edition 54). The cost of a 21-day cycle of capecitabine treatment, based on a person with a body surface area of 1.77 m 2 , is £244.00 per cycle or £4.238 per year. This gives a combined cost of lapatinib plus capecitabine of approximately £25,207 per year. Costs may vary in different settings because of negotiated procurement discounts.|
|3||The manufacturer's submission|
|The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of lapatinib and a review of this submission by the Evidence Review Group (ERG; appendix B).|
|3.1||The manufacturer's analysis included several different comparators including capecitabine monotherapy, capecitabine combination therapy, trastuzumab monotherapy and trastuzumab combination therapy. The manufacturer stated that because of the absence of an alternative HER2-suppressing agent some patients continue to receive trastuzumab beyond progression, either alone, or in combination with cytotoxic chemotherapy. The manufacturer also reported that those patients who are most likely to receive trastuzumab beyond progression are those in whom the drug still appears to be having some effect despite progression and that these patients could receive lapatinib instead. The manufacturer presented the results of some market research (n = 24) that showed 17% of patients currently receive trastuzumab and vinorelbine, 17% receive trastuzumab and capecitabine, and 7% receive trastuzumab monotherapy.|
|3.2||The manufacturer reported details of one randomised controlled trial (RCT). This open-label trial enrolled women with HER2-overexpressing advanced or metastatic breast cancer, who had received prior therapy, which included anthracyclines, taxanes and trastuzumab in the advanced/metastatic setting. Patients were randomised to receive treatment with lapatinib plus capecitabine or capecitabine alone. Enrolment in the trial was halted early after a recommendation from the Independent Data Monitoring Committee (IDMC), because an interim analysis showed an improvement in time to progression (TTP) in the lapatinib plus capecitabine group compared with the capecitabine alone group. Therefore, the trial may have been underpowered to detect a statistical difference in some of the specified outcomes. At the time enrolment was ended, 198 patients were enrolled in the lapatinib plus capecitabine group and 201 in the capecitabine alone group.|
|3.3||The primary outcome measure was TTP, and the secondary outcomes were overall survival, progression-free survival (PFS), overall tumour response rate, clinical benefit rate, and duration of response. The results reported here all relate to the analysis done using data for the April 2006 cut-off date unless otherwise stated. Statistically significant results in favour of the combined treatment group were reported for median TTP, which was 27.1 weeks for lapatinib plus capecitabine compared with 18.6 weeks for capecitabine alone (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.43 to 0.77; p < 0.001). Similarly, a statistically significant difference was reported for median PFS, which was 27.1 weeks for the lapatinib plus capecitabine treatment group compared with 17.6 weeks for the capecitabine control group (HR 0.55; 95% CI 0.41 to 0.74; p < 0.001). There was no statistically significant difference in median overall survival: 67.7 weeks for lapatinib plus capecitabine and 66.6 weeks for capecitabine alone (HR 0.78; 95% CI 0.55 to 1.12; p = 0.177).|
|3.4||Updated median overall survival data (September 2007) showed an increase in the median overall survival in favour of lapatinib plus capecitabine. The median overall survival for lapatinib plus capecitabine was 74.0 weeks compared with 65.9 weeks for the capecitabine control group (HR 0.9; 95% CI 0.71, 1.12; p =0.3). However despite the increase in median overall survival, the results were not significant.|
|3.5||Diarrhoea was reported more commonly in the lapatinib plus capecitabine group compared with the capecitabine alone group: 65% and 40% of women in the two treatment groups, respectively. Palmar-plantar erythrodysaesthesia (PPE), a well-recognised side effect of capecitabine treatment, was also a common adverse event in the RCT, reported by 53% of women in the lapatinib plus capecitabine group and 51% in the capecitabine alone group. In addition, seven (4%) women in the lapatinib plus capecitabine group and two (1%) women in the capecitabine group experienced a decreased LVEF; five of the seven women receiving combination therapy were asymptomatic. For other commonly reported adverse events, rash, vomiting, nausea and fatigue, the incidences were similar in both treatment groups. The European Medicines Agency (EMEA) scientific discussion showed that 24% of patients in the lapatinib plus capecitabine group and 23% in the capecitabine group discontinued treatment owing to adverse events.|
|3.6||The manufacturer's submission included an economic model. The model compared lapatinib plus capecitabine versus capecitabine monotherapy, vinorelbine monotherapy, trastuzumab in combination with vinorelbine or capecitabine, and trastuzumab monotherapy. The effectiveness data of lapatinib and capecitabine used in the model was based on the results of the main trial. A systematic review carried out by the manufacturer did not identify any studies comparing lapatinib plus capecitabine against trastuzumab-containing regimens or other regimens. The manufacturer therefore pooled median TTP data from eight non-RCT studies of trastuzumab-containing regimens, and this was assumed to be equivalent to median PFS for the trastuzumab-containing regimens. Similarly, the manufacturer's systematic review did not identify studies of vinorelbine clinical effectiveness. The manufacturer assumed that the effectiveness of vinorelbine was identical to the clinical effectiveness of capecitabine in the control arm of the main trial.|
|3.7||The principal determinant of patients' health-related quality of life in the model was assumed to be disease progression. In the main RCT, the pre-progression health-related utility value (0.69) was obtained using the EQ-5D in all patients, regardless of treatment group. The value following disease progression included in the model (0.47) was based on a separate study. Quality-adjusted life years (QALYs) were estimated by applying these values to the mean progression-free and post-progression survival durations for each regimen considered. The manufacturer's model assumed that health utilities did not differ according to treatments received and did not explicitly include the impact of treatment-related adverse events on quality of life.|
|3.8||The cost-effectiveness model distinguished between the costs of care incurred while patients were free from disease progression (and receiving active treatment) and the costs associated with those resources consumed after disease progression. These included drug acquisition costs, hospital resources and chemotherapy administration, pharmacy costs, diagnostic and laboratory costs, and other related costs. The base-case economic analysis was based on a price of £11.00 per tablet. The model also included relative dose adjustment factors to account for differences between planned dose and actual dose prescribed in the main RCT, and to account for differences between independent and investigator-led analyses of PFS. The costs of trastuzumab were based on an assumption that treatment would be administered as a weekly infusion as per the SPC.|
|3.9||The base-case analysis showed that when lapatinib plus capecitabine was compared with capecitabine monotherapy, the QALY gain was 0.171 at an incremental cost of £13,873 giving an incremental cost-effectiveness ratio (ICER) of £81,251 per QALY gained. When compared with vinorelbine monotherapy, the QALY gain was 0.171 at an incremental cost of £11,584 giving an ICER of £67,847 per QALY gained. However, the model suggested that lapatinib plus capecitabine was both more effective and less costly when compared with trastuzumab-containing regimens, so it dominated the latter. The manufacturer presented a range of sensitivity analyses for the comparisons with trastuzumab-containing regimens. When wastage was excluded in the analysis for all medicines, the ICER for lapatinib plus capecitabine increased from being dominant to £1650 per QALY gained in comparison with trastuzumab plus capecitabine, and to £6772 per QALY gained in comparison with trastuzumab monotherapy. In addition, when trastuzumab administration was assumed to be on the basis of a 3 weekly schedule rather than weekly as in the base case, the ICER for lapatinib plus capecitabine increased from being dominant to £20,248 per QALY gained in comparison with trastuzumab plus capecitabine, and to £27,532 per QALY gained in comparison with trastuzumab monotherapy. When the PFS for trastuzumab-containing regimens was assumed to be equal to that of capecitabine, the ICER for lapatinib plus capecitabine increased from being dominant to £1428 in comparison with trastuzumab plus capecitabine, and to £7099 per QALY gained in comparison with trastuzumab monotherapy. A similar trend was seen when the costs of adverse events associated with lapatinib were included in the analysis.|
|3.10||The ERG reported that, although the evidence from the single RCT was of reasonable methodological quality, this was the only evidence on the effectiveness of lapatinib used in the cost-effectiveness analysis. The ERG noted that there was a lack of appropriate randomised data for including evidence on the effectiveness of trastuzumab using an adjusted indirect comparison. The ERG stated that the unadjusted indirect comparison method used resulted in uncertainty surrounding the cost-effectiveness estimates comparing lapatinib plus capecitabine with trastuzumab-containing regimens. It also noted that the effectiveness of vinorelbine was based on an assumption of equivalence with capecitabine rather than empirical data. The ERG highlighted that the manufacturer's market research analysis to determine current service provision for patients with advanced or metastatic breast cancer had limitations. In particular, it was not clear which hospitals the data relate to and whether different regions or specialist hospitals could be over- or under-represented. Furthermore, there were only 24 patients identified by the database who fitted the criteria set out by the manufacturer.|
The ERG conducted an exploratory analysis to ascertain the cumulative impact of the assumptions below on the cost-effectiveness modelling in the manufacturer's submission.
|3.12||Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/TAxxx|
|4||Consideration of the evidence|
|4.1||The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of lapatinib, in combination with capecitabine, having considered evidence on the nature of the condition and the value placed on the benefits of lapatinib plus capecitabine by women with advanced/metastatic breast cancer, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.|
|4.2||The Committee considered current clinical practice in the treatment of advanced or metastatic breast cancer following progression after treatment with anthracycline-based regimens, taxanes and trastuzumab. The Committee heard from clinical experts that the effect of continuation with trastuzumab treatment beyond disease progression was unknown and this practice varied considerably in England and Wales. The Committee also noted from the ERG that there was uncertainty in the market research that was used as a basis for using trastuzumab in the advanced or metastatic setting as set out in section 3.9. The Committee further noted that the evidence on the efficacy of trastuzumab-containing regimens beyond progression in the advanced or metastatic settings was limited and that other chemotherapy agents including capecitabine were also prescribed in this setting. The Committee noted additionally the statement in the manufacturer's submission that the most commonly used treatment for women with advanced or metastatic breast cancer beyond progression was capecitabine-containing regimens. The Committee therefore concluded that there is no agreed standard treatment for patients whose disease progresses after treatment with trastuzumab. The Committee was also persuaded that the clinical effectiveness of continuing trastuzumab treatment beyond disease progression has not been demonstrated.|
|4.3||The Committee discussed the clinical effectiveness of lapatinib plus capecitabine presented in the main trial. It noted that lapatinib plus capecitabine was associated with an improved TTP, PFS and other secondary outcomes compared with capecitabine alone. The Committee considered the manufacturer's assertion that lapatinib has the potential to be beneficial to patients with brain metastases because of its smaller molecular size, allowing it to cross the blood–brain barrier and penetrate the central nervous system (unlike trastuzumab). The Committee noted that the evidence to support this in terms of clinical effectiveness was still limited. In addition, the Committee noted that the manufacturer was specifically requested by the EMEA to investigate further this potentially important effect of lapatinib. This is to be done by conducting a phase III randomised, controlled clinical study to evaluate the incidence of brain metastases as the site of relapse with a lapatinib-containing therapy compared with an appropriate, trastuzumab-containing arm as part of the conditional approval of marketing authorisation. The Committee concluded that the data currently available were insufficient for it to consider patients with brain metastases as a separate subgroup.|
|4.4||The Committee noted that adverse events reported in the main RCT by patients in the lapatinib plus capecitabine group included diarrhoea and PPE, and these were marginally higher than those reported with capecitabine alone. Experts commented that people at this stage of disease are often willing to accept side effects in order to have the benefits of lapatinib plus capecitabine treatment. The Committee also noted that, although the side effects were significant, they could be relatively easily controlled.|
|4.5||The Committee agreed that the evidence to show that lapatinib plus capecitabine had fewer side effects than trastuzumab was limited. The Committee also discussed the potential for cardiotoxicity associated with lapatinib treatment and noted the results in the main RCT. The Committee considered the manufacturer's assertion that lapatinib was less cardiotoxic compared with trastuzumab. The Committee agreed that the currently available evidence suggests that cardiotoxicity was less of a problem with lapatinib treatment. However, the Committee was not persuaded that, in the situation of limited life expectancy associated with advanced or metastatic breast cancer, this would necessarily influence the choice of treatments. This was supported by the testimony of the professional and patient experts.|
|4.6||The Committee considered the evidence on the cost effectiveness of lapatinib plus capecitabine presented in the manufacturer's submission. The Committee discussed the comparisons presented in the submission, in which lapatinib plus capecitabine was compared with capecitabine monotherapy, vinorelbine monotherapy and trastuzumab-containing regimens. The Committee understood that the efficacy data used for the comparison with capecitabine monotherapy was based on the clinical trial and noted that the ICER presented by the manufacturer for this comparison was over £80,000. The Committee concluded that this did not represent a cost-effective use of NHS resources.|
|4.7||The Committee noted that the other comparisons presented in the modelling were not based on data from RCTs and that the efficacy of vinorelbine was assumed to be the same as that of capecitabine. This was because there was no evidence on the efficacy of vinorelbine monotherapy or combination therapy in this group of patients. The Committee considered that the data supporting this comparison were subject to considerable uncertainty. It noted additionally that the results of lapatinib plus capecitabine compared with vinorelbine monotherapy gave an ICER of about £68,000 per QALY gained and concluded this did not represent a cost-effective use of NHS resources.|
|4.8||The Committee next considered the cost effectiveness of lapatinib plus capecitabine compared with trastuzumab-containing regimens presented in the manufacturer's submission. The Committee understood that the analysis was based on an unadjusted indirect comparison to derive the efficacy estimates of trastuzumab-containing regimens used in the model. The Committee expressed concerns about the pooling of estimates from non-RCT and observational studies. The Committee noted that the patient characteristics in the pooled studies were not reported. It concluded that, in the absence of data from randomised studies in this patient group, the unadjusted indirect comparison was associated with considerable uncertainty around the relative effectiveness of lapatinib plus capecitabine compared with trastuzumab-containing regimens.|
|4.9||The Committee also discussed the relevance of trastuzumab-containing regimens as comparators in the economic analysis. The Committee heard from clinical specialists that trastuzumab treatment beyond progression was not standard clinical practice, and the clinical effectiveness of trastuzumab in patients who have disease progression on treatment was unproven. The Committee therefore concluded that, although the analysis presented by the manufacturer suggested that lapatinib plus capecitabine compared with trastuzumab-containing regimens was cost effective in the base case, it was derived from highly uncertain clinical-effectiveness data, and there was a lack of appropriate evidence to support the justification of this therapy as a comparator in this setting. Thus, the Committee concluded that the results of the manufacturer's cost-effectiveness analysis in this situation were unsupportable, and the Committee could not recommend that the use of lapatinib plus capecitabine was a cost-effective use of NHS resources.|
|4.10||The Committee considered whether there were any subgroups of patients for whom treatment with lapatinib would be cost effective, such as patients with brain metastases. It considered that there was insufficient evidence to recommend treatment with lapatinib for any patient subgroup but concluded that further research would be beneficial to identify such subgroups. The Committee was aware that the EMEA had recommended a trial be undertaken to evaluate the incidence of brain metastases as a site of relapse with lapatinib-containing therapy compared with an appropriate trastuzumab-containing control arm. The Committee concluded that trials to establish the effectiveness of lapatinib in subgroups of patients, that included all appropriate treatment comparisons, should be considered.|
|5.1||The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in ‘Standards for better health' issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.|
|5.2||'Healthcare standards for Wales' was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 that requires local health boards and NHS trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months.|
NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]
|6||Proposed recommendations for further research|
|6.1||The Committee proposed the following research: a trial of lapatinib plus capecitabine compared with trastuzumab-containing regimens and other chemotherapy regimens used in the advanced or metastatic setting after progression with trastuzumab. In this research, emphasis should be placed on identifying potential subgroups who may particularly benefit from this treatment.|
NICE has issued the following related guidance.
NICE is developing the following guidance (details available from www.nice.org.uk):
|8||Proposed date for review of guidance|
|8.1||The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.|
|8.2||The review date for this guidance is anticipated to be in May 2013 and will coincide with the publication of the anticipated extra work requested by the EMEA.|
Chair, Appraisal Committee
|Appendix A. Appraisal Committee members and NICE project team|
|A. Appraisal Committee members|
The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches.
Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.
The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.
Dr Jane Adam
Professor A E Ades
Dr Amanda Adler
Dr Tom Aslan
Professor David Barnett (Chair)
Mrs Elizabeth Brain
Professor Karl Claxton
Mrs Fiona Duncan
Dr Paul Ewings
Professor John Geddes
Mr John Goulston
Mr Adrian Griffin
Dr Rowan Hillson
Professor Philip Home (Vice Chair)
Dr Simon Maxwell
Dr Alec Miners
Dr Ann Richardson
Mr Mike Spencer
Mr David Thomson
Dr Norman Vetter
Dr Paul Watson
|B. Guideline representatives|
The following individuals, representing the Guideline Development Group responsible for developing the Institute's clinical guideline related to this topic, were invited to attend the ACD meeting to observe and to contribute as advisers to the Committee.
|B. NICE Project Team|
Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.
Dr Louise Longworth
|Appendix B. Sources of evidence considered by the Committee|
The Evidence Review Group (ERG) report for this appraisal was prepared by the Southampton Health Technology Assessments Centre and Wessex Institute for Health Research and Development:
The following organisations accepted the invitation to participate in this appraisal. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.
II Professional/specialist and patient/carer groups:
III Other consultees
IV Commentator organisations (did not provide written evidence and without the right of appeal):
The following individuals were selected from clinical specialist and patient advocate nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on lapatinib by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.
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