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 met 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.

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: 04 November 2008

Third Appraisal Committee meeting: 19 November 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 The technology
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 was granted conditional on the manufacturer performing and submitting an updated analysis of survival data for study EGF100151 (now completed); 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/m2 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 warns of toxicity to the liver and 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 re-treated. 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 56). The cost of a 21-day cycle of capecitabine treatment, based on a person with a body surface area of 1.77 m2 , is £244.00 per cycle or £4238 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, vinorelbine monotherapy, 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 market research (n = 24 patients) 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 monotherapy group. Therefore, the trial may have been underpowered to detect a statistical difference in some of the specified secondary outcomes. At the time enrolment was ended, 198 patients were enrolled in the lapatinib plus capecitabine group and 201 in the capecitabine monotherapy 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 monotherapy (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 group compared with 17.6 weeks for the capecitabine monotherapy 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 monotherapy (HR 0.78; 95% CI 0.55 to 1.12, p = 0.177).
3.4 Diarrhoea was reported more commonly in the lapatinib plus capecitabine group compared with the capecitabine monotherapy 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 monotherapy 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 monotherapy group discontinued treatment because of adverse events.
3.5 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 clinical-effectiveness data for lapatinib and capecitabine used in the model were 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 clinical effectiveness of vinorelbine was identical to that of capecitabine in the control arm of the main trial.
3.6 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.
3.7 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.
3.8 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.
3.9 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 per QALY gained 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 terms of details of data collection and characteristics of respondents and non-respondents.
3.11

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.

  • Trastuzumab administration every 3 weeks, rather than weekly.
  • The cost for administering chemotherapy infusion for trastuzumab changed from £207 per infusion used in the manufacturer's submission to £117 per infusion based on a published assessment report for a previous appraisal.
  • Mean hazard ratio for PFS with trastuzumab-containing regimens based on the minimum estimate of median TTP from the pooled studies.
  • Including the distributions of body surface area and weight used to estimate drug use from the main clinical trial.

The ERG results showed that, when these assumptions were considered cumulatively, the ICER for lapatinib plus capecitabine increased from being dominant to up to £37,336 per QALY gained when compared with trastuzumab-containing regimens.

  Additional data provided by the manufacturer
3.12 The manufacturer provided updated overall survival data for a September 2007 cut-off from the lapatinib RCT. The data showed an increase in the median overall survival compared with the April 2006 cut-off data (see section 3.3). Median overall survival for the lapatinib plus capecitabine group for the September 2007 data was 74.0 weeks compared with 65.9 weeks for the capecitabine monotherapy group (HR 0.90; 95% CI 0.71 to 1.12, p = 0.3). These data may be subject to confounding because of crossover in the trial.
3.13 The manufacturer also provided updated clinical-effectiveness data for trastuzumab. The original pooled estimate of TTP data from eight studies (described in section 3.5) was updated with a further four newly available studies, including one RCT of trastuzumab plus capecitabine compared with capecitabine monotherapy. The updated pooled estimate of median TTP was 27 weeks (95% CI 23.3 to 31.1) with a hazard ratio of 0.70 (95% CI 0.61 to 0.81). In addition to the pooled estimate, the manufacturer also provided data separately for the RCT of trastuzumab plus capecitabine compared with capecitabine monotherapy. The median TTP for trastuzumab plus capecitabine was 8.2 months (95% CI 7.3 to 11.2) compared with 5.6 months (95% CI 4.2 to 6.3) for capecitabine monotherapy (HR 0.69; p = 0.034). The median overall survival for trastuzumab plus capecitabine was 25.5 months (95% CI 19.0 to 30.7) compared with 20.4 months (95% CI 17.8 to 24.7) for capecitabine monotherapy (HR 0.76; p  = not significant). In addition, the manufacturer also presented updated results of the market research data (n = 98 patients), which reported that 21% of patients had received trastuzumab plus capecitabine, 20% trastuzumab plus vinorelbine, 2% trastuzumab monotherapy and 11% had received other trastuzumab-containing regimens. Data showed that 46% of people had non-trastuzumab-containing regimens, most frequently capecitabine (32%).
3.14 The manufacturer also provided a revised base-case economic analysis using updated median overall survival data for lapatinib plus capecitabine and updated PFS and overall survival for trastuzumab plus capecitabine from the trastuzumab RCT. The economic analysis also included updated assumptions about trastuzumab administration and lapatinib price. In the revised analyses, it was assumed that 15% of trastuzumab was wasted and that trastuzumab was administered once every 3 weeks in 88% of the people receiving treatment. The updated analysis also used the actual list price of £11.49 per lapatinib tablet.
3.15 The revised base-case analysis showed that when lapatinib plus capecitabine was compared with capecitabine monotherapy, the QALY gain was 0.150 at an incremental cost of £14,015, giving an ICER of £93,825 per QALY gained. When compared with vinorelbine monotherapy, the QALY gain was 0.150 at an incremental cost of £11,726, giving an ICER of £78,503 per QALY gained. When compared with trastuzumab monotherapy, the QALY gain was 0.26 at an incremental cost of £638, giving an ICER of £24,227 per QALY gained. However, the revised base-case analysis suggested that lapatinib plus capecitabine was still more effective and less costly when compared with trastuzumab combination regimens, so it dominated the latter.
3.16 The manufacturer also presented an economic analysis that compared lapatinib plus capecitabine with a ‘blended comparator', using the same data that were used in the revised base case. This analysis was carried out in recognition of the uncertainties in identifying a subgroup of people who would be likely to have trastuzumab combination therapies in clinical practice. The blended comparator consisted of a weighted average of both the costs and QALYs of the three main treatment options: capecitabine monotherapy (estimated to be provided in 44% of patients), and trastuzumab in combination with either capecitabine (provided in 29% of patients) or vinorelbine (provided in 27% of patients). The proportions used were based on the results of the updated market research (described in section 3.13). The QALY gain for lapatinib plus capecitabine compared with the ‘blended comparator' was 0.080 at an incremental cost of £4887, giving an ICER of £60,730 per QALY gained.
3.17 The manufacturer also provided details of a proposed patient access scheme in which people who qualify for treatment with lapatinib have the initial treatment costs for lapatinib paid by the manufacturer for up to 12 weeks. For those people responding to lapatinib therapy, the NHS would then pay for the costs of continued treatment with lapatinib beyond 12 weeks. Criteria for continuation of therapy beyond 12 weeks would be determined by the individual person's clinician, based on reduction in size of lesion, presence of stable disease or improvement in other response criteria such as symptoms. The manufacturer reports that the scheme would continue until the release of updated guidance from NICE.
3.18 Incorporating the patient access scheme into the economic model suggested that the ICER for lapatinib plus capecitabine against the ‘blended comparator' was reduced from £60,730 to £16,384 per QALY gained. Against the individual comparators, the ICER for lapatinib plus capecitabine compared with capecitabine was reduced from £93,825 to £69,932 per QALY gained and against vinorelbine was reduced from £78,503 to £54,610 per QALY gained. Against trastuzumab combination regimens, lapatinib plus capecitabine was both more effective and less costly when compared with trastuzumab combination regimens, so it dominated the latter.
  Evaluation of additional data and economic analysis by the Decision Support Unit (DSU)
3.19 The DSU evaluated the additional clinical-effectiveness data and the updated economic analysis from the manufacturer.
3.20 The DSU noted that the updated lapatinib clinical-effectiveness data were for overall survival and that TTP data were not provided. The DSU reported that the same methodological limitations applied to the updated pooled estimate of trastuzumab efficacy as had applied to the original pooled estimate. The DSU also noted that the RCT comparing trastuzumab plus capecitabine with capecitabine monotherapy reported results for overall survival and TTP that favoured trastuzumab. However, the DSU stated that neither lapatinib nor trastuzumab had demonstrated statistically significant gains in overall survival. The DSU commented that the hazard ratio for TTP for trastuzumab derived from pooling non-RCT data was similar to that derived from the trastuzumab plus capecitabine trial, but that both methods were associated with methodological limitations because neither maintained randomisation.
3.21 The DSU stated that the updated assumptions in the economic analysis were implemented as described by the manufacturer. The DSU provided analyses that explored the sensitivity of the ICERs to the assumptions about trastuzumab wastage and administration. These showed that if the wastage was 10% rather than 15%, then lapatinib plus capecitabine would still dominate trastuzumab combination therapies, but the incremental costs would be reduced. For example, the incremental costs of trastuzumab plus capecitabine compared with lapatinib plus capecitabine would be reduced from £1075 to £478. Alternatively, if 92% of people had trastuzumab administered every 3 weeks rather than 88%, then the incremental cost for the trastuzumab plus capecitabine combination compared with lapatinib plus capecitabine would be reduced from £1075 to £952.
3.22 The DSU commented that the ‘blended comparator' assumed that all the comparator treatments were used in routine practice and that it would be appropriate for any one of them to be displaced from NHS practice. The DSU provided analyses that explored how the ICERs changed if the proportion of trastuzumab use changed using a variety of market research estimates provided by the manufacturers of lapatinib and trastuzumab. Using estimates from the manufacturer of lapatinib, if trastuzumab was used to treat 49% of people rather than 56%, then the ICER increased from £60,730 to £67,050 per QALY gained. If trastuzumab was used to treat 12% of people, as suggested by the manufacturer of trastuzumab, the ICER increased further to £89,545 per QALY gained. The DSU also explored how the ICERs would change when the patient access scheme was applied to the different estimates of the proportion of trastuzumab use beyond progression. The DSU showed that when the proportion of women continuing trastuzumab-containing regimens beyond disease progression was estimated to be 56% (as in the manufacturer base case), the ICER was £16,387 per QALY gained. When the estimate was 54%, the ICER was £19,108 per QALY gained, an estimate of 49% gave an ICER of £26,993 per QALY gained and an estimate of 12% gave an ICER of £63,034 per QALY gained.
3.23 The DSU commented that a more appropriate approach to economic analysis in the context of the NICE guide to the methods of technology appraisal and general economic literature would have been to consider all treatment options in a single incremental analysis comparing each successive alternative from the least costly to the most. Using the data provided by the manufacturer of lapatinib, the DSU estimated that the most cost-effective treatment option was capecitabine monotherapy. Vinorelbine monotherapy was dominated by capecitabine, having greater costs and the same QALYs. Trastuzumab monotherapy compared with capecitabine monotherapy gave an ICER of £108,748 per QALY gained. Trastuzumab combination regimens were dominated by trastuzumab monotherapy, having greater costs and the same QALYs. The ICER for lapatinib plus capecitabine in comparison with capecitabine monotherapy was £93,825 per QALY gained and against trastuzumab monotherapy £24,227 per QALY gained.
3.24 Full details of all the evidence are in the manufacturer's submission, the manufacturer's response to the appraisal consultation document (ACD), the ERG report and DSU report available in the appraisal consultation folder
 
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 or 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 noted inconsistency in the market research data provided, which suggested a range of estimates of trastuzumab use beyond disease progression from approximately 10% to 50% of people. The Committee was aware of comments from the ERG that there was uncertainty in the market research data as set out in section 3.10. The Committee heard from clinical specialists that provision of trastuzumab varied considerably in England and Wales, but that they considered the higher estimates from the market research data to be more appropriate. The Committee concluded that there is no agreed standard treatment for patients whose disease progresses after treatment with trastuzumab, but that this could include capecitabine, vinorelbine and trastuzumab-containing regimens.
4.3 The Committee noted the inclusion of trastuzumab-containing regimens in the decision problem from the manufacturer. The Committee noted that the use of trastuzumab after disease progression was not currently licensed, but was mindful of comments from clinical specialists that it was being used in clinical practice. The Committee recognised that the NICE guide to the methods of technology appraisal allowed unlicensed comparators to be considered in appraisals, but was mindful that this was intended to reflect the inclusion of technologies used routinely on the basis of clinical experience for many years and for which a licence had not therefore been requested. The Committee considered that this was not the situation in this appraisal, but was persuaded by the testimony from the clinical specialists that it should consider the clinical- and cost-effectiveness analyses that included trastuzumab as a comparator.
4.4 The Committee considered the evidence for the clinical effectiveness of trastuzumab-containing regimens beyond progression in the advanced or metastatic settings. The Committee noted the availability of clinical-effectiveness data from an RCT of trastuzumab continued after progression, as well as an updated review of the trastuzumab clinical-effectiveness evidence provided by the manufacturer of lapatinib. The Committee heard from clinical specialists that evidence for the effect of continuation with trastuzumab treatment beyond disease progression was increasing but its effectiveness remained uncertain. The Committee was mindful of the draft NICE clinical guideline on the treatment and diagnosis of advanced breast cancer that provisionally recommends1 that people who are receiving treatment with trastuzumab should not continue trastuzumab at the time of disease progression outside the central nervous system. The Committee heard from clinical specialists that this recommendation reflected what they considered to be uncertain evidence about the effectiveness of trastuzumab when used at this point in the care pathway. The Committee was persuaded that trastuzumab may be of benefit after disease progression but that the clinical significance of continuing trastuzumab treatment in this situation has not been demonstrated.
4.5 The Committee discussed the clinical effectiveness of lapatinib plus capecitabine presented in the main RCT. It noted that lapatinib plus capecitabine was associated with an improved TTP, PFS and other secondary outcomes compared with capecitabine monotherapy. 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. 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 further investigate 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.
4.6 The Committee noted that adverse events reported in the main RCT by people in the lapatinib plus capecitabine group included diarrhoea and PPE. The lapatinib plus capecitabine group had a marginally higher incidence of diarrhoea and PPE than the capecitabine monotherapy group. Clinical specialists and patient experts commented that people at this stage of disease are often willing to accept side effects to have the benefits of lapatinib plus capecitabine treatment. The Committee also noted that, although the side effects were significant, they could be appropriately managed.
4.7 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 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 clinical specialists and patient experts.
4.8 The Committee considered the evidence on the cost effectiveness of lapatinib plus capecitabine presented in the manufacturer's submission as well as the revised base-case analysis provided. 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 clinical-effectiveness data used for the comparison with capecitabine monotherapy were based on the clinical trial and noted that the ICER presented in the revised base-case analysis by the manufacturer for this comparison was greater than £90,000 per QALY gained. The Committee concluded that this did not represent a cost-effective use of NHS resources.
4.9 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 people. The Committee considered that the data supporting this comparison were subject to considerable uncertainty. It noted additionally that in the revised base-case analysis the results of lapatinib plus capecitabine compared with vinorelbine monotherapy gave an ICER of approximately £79,000 per QALY gained and concluded that this did not represent a cost-effective use of NHS resources.
4.10 The Committee next considered the cost effectiveness of lapatinib plus capecitabine compared with trastuzumab-containing regimens presented by the manufacturer. The Committee noted that in the manufacturer's revised base-case analysis they had updated the assumptions about trastuzumab wastage and administration, assuming that 15% of trastuzumab was wasted instead of all excess trastuzumab, and that for 88% of people trastuzumab was administered once every 3 weeks, instead of once a week for all people. The Committee heard from clinical specialists that they considered that an assumption that 15% of trastuzumab was wasted may still be an overestimate, because vials are frequently shared. The Committee also heard that administration of trastuzumab once every 3 weeks was standard clinical practice. The Committee noted that the ICERs were sensitive to these assumptions and concluded that although the revised assumptions about trastuzumab wastage and administration reduced the overall costs of trastuzumab treatment, these costs may still be overestimated.
4.11 The Committee understood that the economic analysis comparing lapatinib plus capecitabine with trastuzumab-containing regimens had been revised to reflect the new clinical-effectiveness data available. The Committee recognised that two estimates had been provided: one from the RCT of trastuzumab used after progression and another from an updated pooled analysis of trastuzumab studies. The Committee noted that both were 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 experimental and observational studies. Data from an unpublished RCT in this patient group were available and were expected to provide methodologically robust evidence for the efficacy of trastuzumab. However, the Committee concluded that the subsequent use of these data as an unadjusted indirect comparison was associated with considerable uncertainty around the relative effectiveness of lapatinib plus capecitabine compared with trastuzumab-containing regimens.
4.12 The Committee also discussed the relevance of trastuzumab-containing regimens as comparators in the economic analysis. The Committee was mindful of comments from clinical specialists about the extent of the use of trastuzumab (described in section 4.2). However, the Committee also noted the uncertainty regarding the clinical effectiveness of trastuzumab and the method of its inclusion in the economic model (described in sections 4.3 and 4.11). The Committee examined the incremental analysis to evaluating cost effectiveness provided by the DSU. The Committee noted that in this analysis capecitabine monotherapy represented the most cost-effective use of NHS resources, and that the ICER for lapatinib plus capecitabine in comparison with capecitabine monotherapy was approximately £94,000 per QALY gained. The Committee noted that the ICER for lapatinib plus capecitabine in comparison with trastuzumab monotherapy was approximately £24,000 per QALY gained, but that this did not take into account the comparison of trastuzumab monotherapy with capecitabine for which the ICER was approximately £109,000 per QALY gained. The Committee considered 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, the incremental analysis in which the costs and effects of each technology were considered successively from the least costly to the most costly demonstrated that it was based on a comparison of capecitabine with trastuzumab which was not primarily cost effective. Therefore, the Committee concluded that the results of the manufacturer's cost-effectiveness analysis in this situation were unsupportable, and the Committee could not, on this basis, recommend lapatinib plus capecitabine as a cost-effective use of NHS resources.
4.13 The Committee examined the economic analysis from the manufacturer using a ‘blended comparator', which weighted the costs and QALYs of the lapatinib comparators (that is, capecitabine, vinorelbine and trastuzumab-containing regimens) to produce a single ICER of approximately £61,000 per QALY gained for lapatinib plus capecitabine in comparison with all comparators included in the economic analyses. The Committee noted that the analysis was completed because the manufacturer recognised that at present it was difficult to identify a subgroup of patients who in current clinical practice would be likely to continue trastuzumab beyond disease progression. The Committee noted that the ‘blended comparator' assumed that all comparators were in routine use, and that it was appropriate for lapatinib to displace any of the comparators. The Committee was also aware that the analyses assumed that lapatinib would displace all of the other comparators. The Committee noted comments from the DSU that the ‘blended comparator' was sensitive to assumptions about the proportion of people who were receiving each of the comparators. The Committee noted that estimates for the proportion of people continuing trastuzumab-containing regimens were subject to uncertainty, and ranged between 12% and 55%, giving ICERs of approximately £90,000 and £61,000 per QALY gained, respectively. The Committee was also mindful that the ‘blended comparator' incorporated assumptions about the administration of trastuzumab and its efficacy in comparison with lapatinib that were uncertain. The Committee was not persuaded that economic analyses that compared lapatinib plus capecitabine with a ‘blended comparator' were appropriate when cost-ineffective comparators were included in the blending. Therefore, the Committee did not consider that the cost-effectiveness analyses using a ‘blended comparator' could form the basis of a decision on the appropriate use of NHS resources.
4.14 The Committee considered the proposed patient access scheme (section 3.17). The Committee noted that the manufacturer proposed to pay for the costs of lapatinib for the first 12 weeks of treatment, for all people eligible for treatment as part of the patient access scheme. The Committee noted that the reduced costs associated with the patient access scheme had been incorporated into economic analyses with both the ‘blended comparator' and each individual comparator. The Committee was mindful that including the patient access scheme reduced the ICER, using the blended comparator, from £61,000 to £16,000. However, it noted that the ICERs were sensitive to changes in the proportions of people continuing trastuzumab-containing regimens and that when different estimates of the proportion of people continuing trastuzumab were used the ICERs increased up to as much as £63,000 per QALY gained. The Committee did not consider that application of the patient access scheme to the blended comparator was appropriate because of the limitations of the ‘blended comparator' approach (described in section 4.13).
4.15 The Committee specifically considered the estimates of cost effectiveness that included the patient access scheme against capecitabine and vinorelbine monotherapy. The Committee noted that the ICERs were approximately £70,000 and £55,000 per QALY gained, respectively. The Committee was mindful of the factors that inform judgements about the acceptability of the technology as an effective use of NHS resources within, and above, the £20,000 to £30,000 per QALY gained range to be accepted, but concluded that lapatinib plus capecitabine could not be judged to be a cost-effective use of NHS resources, even taking into account the proposed patient access scheme.
4.16 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 concluded that trials to establish the effectiveness of lapatinib in subgroups of patients, that included all appropriate treatment comparisons, should be considered.
  1 The consultation for this guideline ends on October 2008 and publication of the final version is expected in February 2009
 
5 Implementation
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.
5.3

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]

  • Slides highlighting key messages for local discussion.
  • Costing report and costing template to estimate the savings and costs associated with implementation.
  • Implementation advice on how to put the guidance into practice and national initiatives which support this locally.
  • Audit support for monitoring local practice.
 
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 that may particularly benefit from this treatment.
6.2 The Committee recommended that a study of the clinical and cost effectiveness of the use of trastuzumab continued following disease progression in the advanced or metastatic breast cancer should be carried out.
 
7 Related NICE guidance
7.1

Published

Gemcitabine for the treatment of metastatic breast cancer. NICE technology appraisal guidance 116 (2007). Available from www.nice.org.uk/TA116

Familial breast cancer: the classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care. NICE clinical guideline 41 (2006 ) . Available from www.nice.org.uk/CG41

Guidance on the use of capecitabine for the treatment of locally advanced or metastatic breast cancer. NICE technology appraisal guidance 62 (2003). Available from www.nice.org.uk/TA62

Guidance on cancer services. Improving outcomes in breast cancer. NICE clinical guideline manual update (2002). Available from www.nice.org.uk/CSGBC

Guidance on the use of vinorelbine for the treatment of advanced breast cancer. NICE technology appraisal guidance 54 (2002). Available from www.nice.org.uk/TA54

Guidance on the use of trastuzumab for the treatment of advanced breast cancer. NICE technology appraisal guidance 34 (2002). Available from www.nice.org.uk/TA34

Guidance on the use of taxanes for the treatment of breast cancer. NICE technology appraisal guidance 30 (2001). Available from www.nice.org.uk/TA30

Under development

NICE is developing the following guidance:

  • Bevacizumab for the first-line treatment of metastatic breast cancer. NICE technology appraisal (suspended)
  • Advanced breast cancer: diagnosis and treatment. NICE clinical guideline (publication expected February 2009).
 
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 It is proposed that the guidance on this technology is considered for review in May 2013 and will coincide with the publication of the anticipated extra work requested by the EMEA. The Institute would particularly welcome comment on this proposed date.
  David Barnett
Chair, Appraisal Committee
October 2008
 
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
Radiologist, St George's Hospital, London

Professor A E Ades
MRC Senior Scientist, MRC Health Services Research Collaboration, Department of Social Medicine, University of Bristol

Dr Amanda Adler
Consultant Physician, Cambridge University Hospitals Trust

Dr Tom Aslan
General Practitioner, Stockwell, London

Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester

Dr Matt Bradley
Head of HTA and Business Environment, Sanofi-Aventis Ltd

Mrs Elizabeth Brain
Lay Member

Mr David Chandler
Lay Member

Professor Karl Claxton
Professor of Health Economics, Department of Economics & Related Research, University of York

Dr Simon Dixon
Reader in Health Economics, University of Sheffield

Mrs Fiona Duncan
Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool

Dr Paul Ewings
Statistician, Taunton & Somerset NHS Trust, Taunton

Professor John Geddes
Professor of Epidemiological Psychiatry, University of Oxford

Mr John Goulston
Director of Finance, Barts and the London NHS Trust

Mr Adrian Griffin
Director of Health Policy, Johnson & Johnson Medical Ltd

Dr Richard Harling
Director of Health Policy, Worcestershire PCT and Worcestershire County Council

Dr Rowan Hillson
Consultant Physician, Diabeticare, The Hillingdon Hospital

Professor Philip Home (Vice Chair)
Professor of Diabetes Medicine, Newcastle University

Dr Vincent Kirkbride
Consultant Neonatologist, Regional Neonatal Intensive Care Unit, Sheffield

Dr Simon Maxwell
Senior Lecturer in Clinical Pharmacology and Honorary Consultant Physician, Queen's Medical Research Institute, University of Edinburgh

Dr Alec Miners
Lecturer in Health Economics, London School of Hygiene and Tropical Medicine

Dr Ann Richardson
Lay Member

Mrs Angela Schofield
Chairman, Bournemouth and Poole Teaching PCT

Mr Mike Spencer
General Manager, Clinical Support Services, Cardiff and Vale NHS Trust

Mr David Thomson
Lay Member

Mr William Turner
Consultant Urologist, Addenbrooke's Hospital, Cambridge

Dr Norman Vetter
Reader, Department of Epidemiology, Statistics and Public Health, College of Medicine, University of Wales, Cardiff

Dr Paul Watson
Director of Commissioning, East of England Strategic Health Authority

B. Guideline representative

The following individual, representing the Guideline Development Group responsible for developing the Institute's clinical guideline related to this topic, was invited to attend the meeting to observe and to contribute as an adviser to the Committee.

  • Dr Nick Murray, National Collaborating Centre for Cancer

C 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.

David Chandiwana
Technical Lead

Louise Longworth
Technical Adviser

Zoe Garrett (from July 2008)
Technical Adviser

Eloise Saile
Project Manager

Bijal Chandarana (from September 2008)
Project Manager

 
Appendix B. Sources of evidence considered by the Committee
A

The Evidence Review Group (ERG) report for this appraisal was prepared by the Southampton Health Technology Assessment Centre:

  • Jones J, Takeda A, Picot J et al. Lapatinib for HER2 over-expressing breast cancer, June 2007
B Evidence for this appraisal was also prepared by the NICE Decision Support Unit, Southampton Health Technology Assessment Centre and the University of Sheffield.
C

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 gave their expert views on lapatinib by providing a written statement to the Committee. Organisations listed in I and II have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

  • GlaxoSmithKline

II Professional/specialist and patient/carer groups:

  • Breakthrough Breast Cancer
  • Breast Cancer Campaign
  • Breast Cancer Care
  • British Association of Surgical Oncology
  • Cancerbackup
  • Cancer Research UK
  • National Collaborating Centre for Cancer
  • Royal College of Nursing
  • Royal College of Pathologists
  • Royal College of Physicians (Medical Oncology Joint Special Committee)
  • Welsh Assembly Governmen

Commentator organisations (did not provide written evidence and without the right of appeal):

  • British National Formulary
  • Department of Health, Social Services and Public Safety for Northern Ireland
  • Eli Lilly and Company Ltd
  • NHS Quality Improvement Scotland
  • Pierre Fabre Ltd
  • Roche
D

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.

  • Professor Dudley Sinnett, nominated by British Association of Surgical Oncology
  • Dr Justin Stebbing, nominated by Royal College of Physicians
  • Dr Rob Stein, nominated by Royal College of Physicians
  • Mrs Marie Wilby, patient expert, nominated by Breast Cancer Care
  • Ms Carolyn Rogers, patient expert, nominated by Breast Cancer Care
 

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Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.

Accessibility | Cymraeg | Freedom of information | Vision Impaired | Contact Us | Glossary | Data protection | Copyright | Disclaimer | Terms and conditions

Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.