1 Appraisal Committee's preliminary recommendations

1.1 Lapatinib or trastuzumab in combination with an aromatase inhibitor are not recommended as options for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2).

2 Clinical need and practice

2.1 Breast cancer is the most common type of cancer among women in the UK. Women have a one in nine lifetime risk of developing breast cancer. The incidence of breast cancer increases with age, doubling every 10 years until menopause, after which the rate of increase slows down. In the UK, 45,972 people were diagnosed with breast cancer in 2007, of whom 99% were women.

2.2 Metastatic breast cancer is an advanced stage of the disease when it has spread to other organs. It is estimated that approximately 5% of people present with metastatic breast cancer, and that approximately 30% of people who present with localised breast cancer will later develop metastatic breast cancer. Common sites of metastasis include bone, liver, lung and brain.

2.3 When clinicians manage breast cancer they consider various prognostic factors, including hormone receptor status and human epidermal growth factor receptor 2 (HER2) status. Hormone receptors include oestrogen receptors and progesterone receptors. Tumours that express either oestrogen receptors or progesterone receptors are commonly referred to as being hormone receptor positive (HR+). It is estimated that 60% and 80% of all breast cancers in premenopausal and postmenopausal women respectively are HR+. People with HR+ breast cancer generally have a better prognosis than those with HR− breast cancer.

2.4 Tumours that overexpress the HER2 protein (HER2+) grow and divide more quickly. Approximately 30% of people with metastatic breast cancer have HER2+ tumours, of which about 50% will also be HR+. It is estimated that 350–500 women per year with newly diagnosed metastatic breast cancer have tumours that are HER2+ and HR+.

2.5 After metastatic breast cancer is diagnosed the average length of survival has been reported to be 12 months for people receiving no treatment compared with 18–24 months for those receiving chemotherapy. Survival is shortened by up to 50% in people with HER2+ breast cancer. The aim of treatment in metastatic breast cancer is to palliate symptoms, prolong survival and maintain a good quality of life with minimal adverse events.

2.6 Choice of treatment depends on previous therapy, HR status, HER2 status and the extent of the disease. NICE clinical guideline 81 (’Advanced breast cancer: diagnosis and treatment’, 2009) recommends that if the disease is not imminently life threatening, or does not require early relief of symptoms because of significant visceral organ involvement, women who are postmenopausal and have HR+ breast cancer should be offered an aromatase inhibitor such as anastrozole or letrozole. There is variation in clinical practice for people with tumours that are both HER2+ and HR+.

3 The technologies

3.1 Lapatinib (Tyverb, GlaxoSmithKline) is a protein kinase inhibitor that blocks the tyrosine kinase components of the epidermal growth factor receptors (ErbB1 and ErbB2) which are implicated in the growth of various tumours. Lapatinib has conditional marketing authorisation (that is, further evidence on this medicinal product is being awaited) in the UK. Lapatinib is ‘indicated for the treatment of patients with breast cancer, whose tumours overexpress HER2 (ErbB2); in combination with an aromatase inhibitor for postmenopausal women with hormone receptor positive metastatic disease, not currently intended for chemotherapy’. The conditional marketing authorisation states that 'patients in the registration study were not previously treated with trastuzumab or an aromatase inhibitor'.

3.2 The summary of product characteristics (SPC) states that the most common adverse events during therapy with lapatinib are diarrhoea, nausea, vomiting and rash. For full details of side effects and contraindications, see the SPC.

3.3 Lapatinib is administered orally at a dosage of 1500 mg (six tablets) per day. The net price per pack of 70 tablets is £804.30 (excluding VAT; British national formulary [BNF], edition 60). The acquisition cost for a lifetime of treatment with lapatinib plus the aromatase inhibitor letrozole is £28,524 (£27,346 for lapatinib and £1188 for letrozole), assuming a mean treatment duration of 55.2 weeks and excluding administration costs. Costs may vary in different settings because of negotiated procurement discounts.

3.4 Trastuzumab (Herceptin, Roche Products) is a recombinant humanised IgG1 monoclonal antibody directed against HER2. Trastuzumab is indicated for the treatment of patients with HER2+ metastatic breast cancer ‘in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive metastatic breast cancer, not previously treated with trastuzumab’.

3.5 The SPC states that the most common adverse events associated with trastuzumab therapy are cardiotoxicity, infusion-related reactions, haematotoxicity (in particular neutropenia) and pulmonary events. In the clinical trials, patients receiving trastuzumab were required to have a left ventricular ejection fraction of at least 55% and to have cardiac monitoring every 4 months. For full details of side effects and contraindications, see the SPC.

3.6 The recommended dosage of trastuzumab is a loading dose of 4 mg/kg by intravenous infusion, followed by a weekly maintenance dose of 2 mg/kg until disease progression. Alternatively, a loading dose of 8 mg/kg can be given, followed by 3-weekly maintenance doses of 6 mg/kg until disease progression. The net price per 150 mg vial is £407.40 (excluding VAT; BNF 60). Assuming an average patient weight of 67 kg, a mean treatment period of 15 months and excluding administration, monitoring and wastage costs, the acquisition cost for a lifetime of treatment with trastuzumab plus anastrozole is £26,018 (£24,852 for trastuzumab and £1166 for anastrozole) for a weekly schedule and £26,832 (£25,666 for trastuzumab and £1166 for anastrozole) for a 3-weekly schedule. Costs may vary in different settings because of negotiated procurement discounts.

4 Evidence and interpretation

The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).

4.1 Clinical effectiveness

4.1.1  Three randomised controlled trials were identified that considered lapatinib or trastuzumab used within their licensed indications. The studies compared:

• lapatinib plus letrozole with letrozole alone (the EGF30008 trial)
• trastuzumab plus anastrozole with anastrozole alone (the TAnDEM trial)
• trastuzumab plus letrozole with letrozole alone (the eLEcTRA trial).

All three trials were multicentre, multinational trials that included postmenopausal women receiving first-line treatment for metastatic breast cancer. In all three trials, patients received treatment until disease progression.

Lapatinib

4.1.2  The EGF30008 trial compared lapatinib plus letrozole with letrozole alone. All patients in the trial (n = 1286, the intention-to-treat population [ITT]) had HR+ metastatic breast cancer but only 219 out of 1286 had HER2+ breast cancer. The trial excluded patients considered by the investigators to have rapidly progressing or life-threatening disease. The median age of patients in the ITT population was 62 years for the lapatinib plus letrozole group and 63 years for the letrozole group (the ages were 60 years and 59 years respectively for patients with HER2+ breast cancer). The two treatment groups were broadly similar in Eastern Cooperative Oncology Group (ECOG) performance status (58% had an ECOG performance status of 0 in the lapatinib plus letrozole group compared with 54% in the letrozole alone group; the proportions were 53% and 47% respectively for patients with HER2+ breast cancer). The median number of metastatic sites was two in both treatment groups, including patients with HER2+ breast cancer. The proportion of patients with metastases only to bone was 15% in the lapatinib plus letrozole group and 13% in the letrozole alone group (14% and 17% respectively in patients with HER2+ breast cancer). The remainder had visceral or soft tissue metastases. Patients were randomised 1:1 to either lapatinib plus letrozole (n = 644, which includes 111 patients with HER2+ breast cancer) or to letrozole alone (n = 642, which includes 108 patients with HER2+ breast cancer).

4.1.3 The primary outcome was progression-free survival, and secondary outcomes included overall survival, time to progression and overall response rate. For patients with HR+ and HER2+ breast cancer, progression-free survival was 8.2 months for the lapatinib plus letrozole group and 3.0 months for the letrozole alone group (hazard ratio [HR] for progression 0.71, 95% confidence interval [CI] 0.53 to 0.96, p = 0.019). A Cox regression analysis was performed to adjust for known baseline prognostic factors. These factors included treatment group, site of disease, previous adjuvant endocrine therapy, performance status, number of metastatic sites and serum HER2 (extracellular domain) levels at baseline. From this analysis, the HR for progression was 0.65 (95% CI 0.47 to 0.89, p = 0.008). For the ITT population, progression-free survival was 11.9 months for the lapatinib plus letrozole group and 10.8 months for the letrozole alone group (HR for progression 0.86; 95% CI 0.76 to 0.98; p = 0.026).

4.1.4 Overall survival for patients with HR+ and HER2+ breast cancer was 33.3 months for the lapatinib plus letrozole group and 32.3 months for the letrozole alone group (HR for death 0.74, 95% CI 0.49 to 1.12 p = 0.113). Overall survival results for the ITT population were not reported. The overall response rate for patients with HR+ and HER2+ breast cancer was 28% for the lapatinib plus letrozole group and 15% for the letrozole alone group (odds ratio [OR] 0.4, 95% CI 0.2 to 0.9, p = 0.021). The overall response rate for the ITT population was 33% in the lapatinib plus letrozole group and 32% in the letrozole alone group (OR not reported, p = 0.726).

4.1.5 Quality of life was assessed using the Functional Assessment of Cancer Therapy – Breast (FACT-B) questionnaire. Quality of life scores for patients with HER2+ breast cancer were reported to be generally constant over time in both treatment groups. The difference between the two groups was not statistically significant.

4.1.6 Patients who received lapatinib pus letrozole were more likely to experience adverse events, although serious adverse events were rare in both treatment groups. The incidence of diarrhoea, rash and nausea was statistically significantly greater in the lapatinib plus letrozole group (68%, 46% and 27% respectively) compared with the letrozole alone group (8%, 8% and 18% respectively, p<0.05).

Trastuzumab

4.1.7 The TAnDEM trial (n = 207) compared trastuzumab plus anastrozole with anastrozole alone. Patients included in the trial were postmenopausal women with HR+ and HER2+ metastatic breast cancer with an ECOG performance status of 0 or 1. The median age of patients was 56 years in the trastuzumab plus anastrozole group and 54 years in the anastrozole alone group. The median number of metastatic sites was two and 56% of patients had bone metastases. Patients were randomised 1:1 to either trastuzumab plus anastrozole (n = 103) or to anastrozole alone (n = 104). At disease progression, patients received second-line therapy, which included patients in the anastrozole alone group crossing over to receive trastuzumab plus anastrozole.

4.1.8 The primary outcome was progression-free survival. The secondary outcomes included overall survival, time to progression and overall response rate. Progression-free survival results were presented according to the ITT population, centrally confirmed results (confirmed by a blinded Response Evaluation Committee) and results updated at a later cut-off point (April 2008). For the ITT population, the median progression-free survival was 4.8 months (95% CI 3.7 to 7.0) for the trastuzumab plus anastrozole group and 2.4 months (95% CI 2.0 to 4.6) for the anastrozole alone group (HR for progression 0.63, 95% CI 0.47 to 0.84, p = 0.0016). For the centrally confirmed results, the progression-free survival was 5.6 months (95% CI 3.8 to 8.3) for the trastuzumab plus anastrozole group and 3.8 months (95% CI 2.0 to 6.3) for the anastrozole alone group (HR for progression 0.62, 95% CI not reported, p = 0.006). For the updated results, the progression-free survival was 5.8 months (95% CI 4.6 to 8.3) for the trastuzumab plus anastrozole group and 2.9 months (95% CI 2.1 to 4.5) for the anastrozole alone group (HR for progression 0.55, 95% CI 0.41 to 0.74, p < 0.0001).

4.1.9 Overall survival results were presented according to the ITT population, centrally confirmed results and results adjusted for crossover. For the ITT population, the overall survival was 28.5 months (95% CI 22.8 to 42.4) for the trastuzumab plus anastrozole group and 23.9 months (95% CI 18.2 to 37.4) for the anastrozole alone group (HR for death 0.84, 95% CI 0.59 to 1.20 p=0.325). For the centrally confirmed results, the overall survival was 34.1 months (95% CI 23.9 to 52.0) for the trastuzumab plus anastrozole group and 28.6 months (95% CI 17.4 to 40.0) for the anastrozole alone group (HR for death 0.85, 95% CI not reported    p=0.451).

4.1.10 The manufacturer attempted to account for crossover by conducting a post-hoc analysis of overall survival. The rank preserving structural failure time (RPSFT) approach was used to account for crossover (70% of the patients randomised to anastrozole alone subsequently received trastuzumab plus anastrozole). In this analysis, the manufacturer reported that the overall survival was 28.52 months (95% CI not reported) for the trastuzumab plus anastrozole group and 21.98 months (95% CI not reported) for the anastrozole alone group (HR for death 0.73, 95% CI 0.51 to 1.04, p value not reported). The Assessment Group commented that no statistical methods were described to address the issue of crossover and there was no agreement about the best method to use. It stated that RPSFT might not be appropriate when imbalances occur after randomisation, such as when there is an unequal distribution of patients receiving second-line treatment across the groups. The Assessment Group noted that in the TAnDEM trial, the proportion of patients who crossed over was relatively high, and this increased the likelihood of bias. The Assessment Group stated that, ideally, different methods for accounting for cross over should have been tested.

4.1.11 Patient utility data were not collected in the TAnDEM trial. Patients who received trastuzumab plus anastrozole were more likely to experience adverse events compared with patients who received anastrozole alone (87% compared with 65%), including serious adverse events (23% compared with 6%). Fatigue, diarrhoea and vomiting were among the most common adverse events (21%, 20% and 21% respectively in the trastuzumab plus anastrozole group compared with 10%, 8% and 5% in the anastrozole alone group).

4.1.12 The eLEcTRA trial aimed to compare trastuzumab plus letrozole with letrozole alone. However, only 92 patients with HR+ metastatic breast cancer were enrolled (out of a planned 370 patients) and so the study was stopped early because of slow recruitment.

Indirect comparisons

4.1.13 The manufacturer of lapatinib (GlaxoSmithKline) performed adjusted indirect comparisons in which data from five studies were incorporated: EGF30008, TAnDEM, one study comparing letrozole with tamoxifen and two studies comparing anastrozole with tamoxifen. The eLEcTRA study was not included because only an abstract had been published. Overall survival data suggested that the HR for death with lapatinib plus letrozole was 0.85 (95% CI 0.47 to 1.54) when compared with trastuzumab plus anastrozole, 0.77 (95% CI 0.52 to 1.14) when compared with letrozole alone, 0.71 (95% CI 0.45 to 1.14) when compared with anastrozole alone and 0.74 (95% CI 0.49 to 1.12) when compared with tamoxifen.

4.1.14 GlaxoSmithKline reported that the HR for progression with lapatinib plus letrozole was 0.89 (95% CI 0.54 to 1.47) when compared with trastuzumab plus anastrozole, 0.65 (95% CI 0.47 to 0.89) when compared with letrozole alone, 0.53 (95% CI 0.36 to 0.80) when compared with anastrozole alone and 0.45 (95% CI 0.32 to 0.65) when compared with tamoxifen.

4.1.15 The manufacturer of trastuzumab (Roche) performed an indirect network meta-analysis in which a number of different analyses were performed for overall survival (12 trials) and progression-free survival (7 trials). Roche used the overall survival findings from the TAnDEM trial, which adjusted for crossover and assumed that aromatase inhibitors hold a ‘class effect’ (that is, letrozole is equivalent to anastrozole). In the base case, Roche reported that the HR for death with trastuzumab plus aromatase inhibitors was 0.98 (95% CI 0.58 to 1.67) when compared with lapatinib plus aromatase inhibitors and 0.73 (95% CI 0.51 to 1.04) when compared with aromatase inhibitors. The HR for death with lapatinib plus aromatase inhibitors compared with aromatase inhibitors was 0.74 (95% CI 0.50 to 1.10). When the results were not adjusted for crossover, the HR for death with trastuzumab plus aromatase inhibitors was 1.13 (95% CI 0.67 to 1.92) compared with lapatinib plus aromatase inhibitors and 0.84 (95% CI 0.59 to 1.19) compared with aromatase inhibitors. The HR for death with lapatinib plus aromatase inhibitors compared with aromatase inhibitors was 0.74 (95% CI 0.50 to 1.10).

4.1.16 The HR for progression with trastuzumab plus aromatase inhibitors was 0.78 (95% CI 0.52 to 1.18) when compared with lapatinib plus aromatase inhibitors and 0.55 (95% CI 0.42 to 0.74) when compared with aromatase inhibitors. The HR for progression with lapatinib plus aromatase inhibitors compared with aromatase inhibitors was 0.71 (95% CI 0.53 to 0.95).

4.1.17 The Assessment Group considered that the findings of the indirect comparisons presented by the two manufacturers should be treated with caution. It stated that the populations in the EGF30008 and TAnDEM trials differed substantially and that neither of the manufacturers’ indirect comparisons met the basic requirement for indirect comparisons – that is, exchangeability of relative treatment effect between trials could not be assumed. The Assessment Group noted that the proportion of patients with HR+ and HER2+ metastatic breast cancer included in the other trials in the indirect comparisons was unclear. It also noted that the length of follow-up and the proportion of patients receiving first-line treatment differed between trials.

4.2 Cost effectiveness

4.2.1 The Assessment Group did not identify any published economic analyses that were considered relevant to the appraisal. The manufacturer of trastuzumab identified one study that it considered to be relevant. This was a poster presented in June 2010 at the American Society of Clinical Oncology by Hastings et al. The poster described an indirect comparison of the cost effectiveness of lapatinib plus letrozole versus trastuzumab plus anastrozolein postmenopausal women with HR+ and HER2+ metastatic breast cancer who had not received previous treatment. The Assessment Group considered that the studies that made up the evidence network addressed different populations and the analysis could not provide a reliable estimate of relative cost effectiveness.

4.2.2 Both manufacturers provided economic analyses to support their submissions in which the technologies under assessment were compared with each other and with letrozole and anastrozole as monotherapies.

GlaxoSmithKline (lapatinib plus an aromatase inhibitor)

4.2.3 The manufacturer’s economic model had three states: alive and no disease progression, alive with progression, and dead. The model had a time horizon of 10 years and both costs and benefits were discounted at 3.5% per year. The analysis was carried out from the perspective of the NHS and personal social services. The key clinical data comparing lapatinib plus letrozole with letrozole alone came from the EGF30008 trial. To compare lapatinib plus letrozole with other technologies, the manufacturer used the results of the indirect comparison. The utility value for the ‘alive and no disease progression’ state was estimated using data from the FACT-B questionnaire administered during the EGF30008 trial. The utility value for the ‘alive with progression’ state was taken from the results of a study by Lloyd et al. (2006) of societal preferences for different stages of metastatic breast cancer in the UK. The utility value used for the ‘alive and no disease progression’ state was 0.86 and the value for ‘alive with progression’ was 0.62. The utility decrements applied in the economic model included: nausea (0.1); vomiting (0.1); diarrhoea (0.1); alopecia (0.11); asthenia, fatigue or lethargy (0.12); skin and nail disorders (0.15).

4.2.4 In the base case, the incremental cost of lapatinib plus letrozole compared with letrozole alone was £34,737 and the incremental quality-adjusted life year (QALY) was 0.467. This generated an incremental cost-effectiveness ratio (ICER) of £74,448 per QALY gained. The ICER for lapatinib plus letrozole compared with trastuzumab plus anastrozole was £21,836 per QALY gained (incremental cost of £5513 and incremental QALY of 0.252) while the ICER for lapatinib plus letrozole compared with anastrozole alone was £59,895 per QALY gained (incremental cost of £35,995 and incremental QALYs of 0.601).

4.2.5 The manufacturer examined 51 scenarios in deterministic sensitivity analyses. The analyses showed that the ICERs were most sensitive to the utility value for the ‘alive and no disease progression’ health state, the discounting rate and the time horizon. Using different assumptions, the ICER for lapatinib plus letrozole compared with letrozole alone ranged from £41,877 per QALY gained to lapatinib plus letrozole being dominated by letrozole alone. The ICER for lapatinib plus letrozole compared with anastrozole alone ranged from £38,170 to £378,674 per QALY gained. The ICER for lapatinib plus letrozole compared with trastuzumab plus anastrozole ranged from lapatinib plus letrozole dominating the comparator to £45,106 per QALY gained. The manufacturer also performed a probabilistic sensitivity analysis. The results showed that at a maximum acceptable amount to pay for an additional QALY of £30,000 per QALY, the probability of lapatinib plus letrozole being cost effective was less than 25% when compared with any aromatase inhibitor, and about 50% when compared with trastuzumab plus anastrozole.

Roche (trastuzumab plus an aromatase inhibitor)

4.2.6 The manufacturer's economic model had three states: progression-free survival, progressive disease and death. The model had a time horizon of 15 years and discounted both costs and benefits at 3.5% per year. The key clinical data used for trastuzumab plus anastrozole compared with anastrozole alone were taken from the TAnDEM trial. All model inputs were from the latest data available, with an April 2008 cut-off point. On the basis of the results from the indirect comparison it was assumed that letrozole and anastrozole hold a ‘class effect’ and therefore the progression-free survival and overall survival curves for anastrozole were used for letrozole. The clinical estimates for lapatinib plus letrozole came from the EGF30008 trial. The manufacturer used utility values reported by Cooper et al. (2003) that assigned a utility of 0.73 to progression-free survival and 0.45 to progressive disease. Only grade 3 or 4 adverse events were considered in the model and disutilities resulting from adverse events were not modelled.

4.2.7 The manufacturer presented the results based on an incremental analaysis. In the base case, it reported that trastuzumab plus anastrozole compared with anastrozole alone gave an incremental QALY of 0.58 at an incremental cost of £31,408, giving an ICER of £54,312 per QALY gained. The manufacturer also reported the results of a pairwise analysis with the remaining two comparisons. In comparison with letrozole alone the ICER was £54,336 per QALY gained (an incremental QALY of 0.58 and an incremental cost of £31,422). In comparison with lapatinib plus letrozole the ICER was £18,347 per QALY gained (an incremental QALY of 0.16 and an incremental cost of £2866).

4.2.8 A univariate sensitivity analysis showed that the ICERs were most sensitive to the utility value for progression-free survival. When the base-case utility value of 0.73 was varied between 0.803 and 0.657 the ICER ranged from £50,099 to £59,355 per QALY gained for trastuzumab plus anastrozole compared with anastrozole alone. The manufacturer also described three multivariate scenario analyses. In these analyses, when the HRs for progression and for death from the indirect comparisons were used in the model, anastrozole represented a cost-effective treatment option up to a maximum acceptable amount to pay for an additional QALY of £3594; letrozole was the most cost-effective treatment option from £3594 to £57,773 per QALY gained; and trastuzumab plus anastrozole represented the most cost-effective treatment option above £57,773 per QALY gained.

4.2.9 The manufacturer conducted a probabilistic sensitivity analysis. This analysis showed that at a maximum acceptable amount to pay for an additional QALY of £30,000, the combination therapies were not cost effective. At a maximum acceptable amount to pay for an additional QALY of £55,000, trastuzumab plus anastrozole was cost effective in approximately 35% of simulations.

Independent economic assessment by the Assessment Group

4.2.10 Because of potential differences between the EGF30008 and TAnDEM trials in the baseline characteristics of patients, the Assessment Group performed two separate cost-effectiveness analyses. These analyses used directly observed progression-free survival and post-progression survival data from the trials to generate expected overall survival. The analyses had common parameter values, but took effectiveness data from a single randomised controlled trial (either TAnDEM or EGF30008). Days spent in ‘progression-free survival’ and ‘progressive disease’ from the trials were used to calculate health service costs and expected future patient utility values. Costs and outcomes were discounted at 3.5% per year.

Assessment Group model for lapatinib plus letrozole versus letrozole alone

4.2.11 The Assessment Group calculated the mean progression-free survival by applying the difference between the Kaplan–Meier area under the curve estimates up to the time of convergence (505 days) and then applying a single exponential model of progression-free survival to both the intervention and the comparator. This generated 266.2 progression-free survival days for lapatinib plus letrozole and 198.5 progression-free survival days for letrozole alone, giving a progression-free survival gain of 67.6 days per patient attributable to lapatinib. The Assessment Group reported that the survival curves for post-progression survival in the two groups appeared graphically very similar, and were therefore fitted by a single combined exponential function that gave a mean survival of 764.8 days. Overall survival was obtained by summing progression-free survival and post-progression survival. After adjusting post-progression survival to exclude patients who died at or before disease progression, the overall survival was 982.8 days for lapatinib plus letrozole and 928 days for letrozole alone, resulting in an overall survival gain of 54.8 days per patient attributable to lapatinib.

4.2.12 Based on a study by Lloyd et al. (2006), different utility values for the ‘progression-free survival’ state were assigned to the lapatinib plus letrozole group (0.766) and  to the letrozole alone group (0.762). A utility of 0.496 was assigned to the ‘post-progression survival’ state. Disutility of adverse events was not included in the base case but was examined in a sensitivity analysis.

4.2.13 In the base case, the Assessment Group stated that lapatinib plus letrozole provided less than 0.12 additional QALYs at an additional cost of more than £25,000 per patient compared with letrozole alone, resulting in an ICER in excess of £220,000 per QALY gained. The results from a sensitivity analysis showed that the ICER is most sensitive to the health state utility values, and to the cost of lapatinib. The Assessment Group conducted a probabilistic sensitivity analysis that showed that there is no measurable probability of lapatinib plus letrozole being cost effective at a maximum acceptable amount to pay for an additional QALY of £40,000 per, and the probability does not reach 50% until a maximum acceptable amount to pay for an additional QALY of nearly £3,000,000. 

Assessment Group model for trastuzumab plus anastrozole versus anastrozole alone

4.2.14 The mean progression-free survival was calculated using the Kaplan–Meier area under the curve estimate up to the last recorded event in each group, and then adding the area under the projected long-term Weibull curve. This generated 514.8 progression-free survival days for trastuzumab plus anastrozole and 189.6 progression-free survival days for anastrozole alone, a gain of 325.1 progression-free survival days attributable to trastuzumab. Mean post-progression survival was calculated using the Kaplan–Meier area under the curve estimate up to the last recorded event in each group, and then adding the area under the projected long-term Weibull model as applied for progression-free survival. This generated 649.6 post-progression survival days for trastuzumab plus anastrozole and 869.6 post-progression survival days for anastrozole alone, a loss of 220.0 post-progression survival days attributable to trastuzumab.

4.2.15 The estimate for overall survival was obtained by combining estimates of mean progression-free survival and mean post-progression survival in each group, and adjusting for the patients who died at or before progression (5.8% in the anastrozole alone group and 9.3% in the trastuzumab plus anastrozole group). This generated 1101.3 overall survival days for trastuzumab plus anastrozole and 1009.0 overall survival days for anastrozole alone, with a gain of 92.2 overall survival days attributable to trastuzumab.

4.2.16 The Assessment Group adjusted for crossover and second-line therapy for patients in the TAnDEM trial by fitting two separate exponential models from which mean survival gain in the post-progression phase was estimated. After adjusting for patients who died at or before progression (91% of the total), the net benefit of crossover was estimated as 137.5 days and that of second-line therapy as 5.9 days. Combining the adjustments for crossover and second-line chemotherapy generated 1101.3 overall survival days for trastuzumab plus anastrozole and 861.2 overall survival days for anastrozole alone, with a gain of 240.1 overall survival days attributable to trastuzumab.

4.2.17 Based on the study by Lloyd et al. (2006), different utility values for progression-free survival were assigned to the trastuzumab plus anastrozole group (0.769 [standard error 0.113]) and to the anastrozole alone group (0.764 [standard error 0.114]). A health state utility value of 0.496 (standard error 0.160) was assigned to the post-progression survival state. Disutility of adverse events was not included in the base case, but was examined in a sensitivity analysis.

4.2.18 In the base case, the Assessment Group reported that there was a mean health gain per patient of 0.51 QALYs at an additional cost of about £37,500 per patient. The resulting ICER exceeds £73,000 per QALY gained for trastuzumab plus anastrozole compared with anastrozole alone. A sensitivity analysis showed that the ICER is most sensitive to the utility values for the different states, the cost of trastuzumab and discounting rates. A probabilistic sensitivity analysis was undertaken using the base-case scenario over a 20-year time horizon. This showed that there is no measurable probability of trastuzumab plus anastrozole being cost effective at a maximum acceptable amount to pay for an additional QALY of £40,000, and a 3.2% probability at a maximum acceptable amount to pay for an additional QALY of £50,000.

4.3 Consideration of the evidence

4.3.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of lapatinib and trastuzumab, having considered evidence on the nature of metastatic HR+ and HER2+ breast cancer and the value placed on the benefits of lapatinib and trastuzumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

Clinical effectiveness

4.3.2 The Committee discussed current clinical practice in the UK in the treatment of metastatic HR+ and HER2+ breast cancer and the position of lapatinib and trastuzumab in the treatment pathway. The Committee heard from clinical specialists that in current UK clinical practice, people with advanced HER2+ breast cancer are more likely to receive trastuzumab plus chemotherapy than trastuzumab or lapatinib plus an aromatase inhibitor. Aromatase inhibitors alone are currently offered to people who prefer not to receive chemotherapy and to those who are either not fit enough to receive chemotherapy or who have contraindications. The clinical specialists stated that trastuzumab or lapatinib plus an aromatase inhibitor is therefore likely to be offered to people who are not fit enough to receive chemotherapy or who opt not to receive it. However, the clinical specialists also stated that trastuzumab or lapatinib plus an aromatase inhibitor might be preferred in some cases where chemotherapy would currently be offered because it was more effective than aromatase inhibitor therapy alone and has a better adverse events profile than chemotherapy. The Committee heard from patient experts that for some women, chemotherapy was particularly difficult to cope with and treatment with lapatinib or trastuzumab in combination with an aromatase inhibitor may make it easier for them to carry on with their lives. The Committee also noted comments from patient representatives that women wish to have access to the newer therapies because these may increase progression-free survival, and that this benefit  outweighed concerns about potential adverse events associated with adding these agents to aromatase inhibitor monotherapy. The Committee was aware that the relevant marketing authorisation for trastuzumab in combination with an aromatase inhibitor was for people not previously treated with trastuzumab. It heard from clinical specialists that up to 70% of people with metastatic HR+ and HER2+ breast cancer will not previously have received adjuvant treatment with trastuzumab. The Committee also heard from the manufacturer of lapatinib that although the conditional marketing authorisation states that patients in the registration study were not previously treated with trastuzumab or an aromatase inhibitor, this does not exclude these people from receiving treatment with lapatinib. The Committee heard from clinical specialists that people who receive trastuzumab or lapatinib plus an aromatase inhibitor may subsequently receive chemotherapy. The Committee therefore concluded that lapatinib or trastuzumab plus an aromatase inhibitor are likely to be used in people who, in consultation with their clinicians, consider that chemotherapy is not the best option for first-line treatment.

4.3.3 The Committee discussed the population for whom lapatinib or trastuzumab plus an aromatase inhibitor is suitable. The Committee was aware that this had been estimated as 50 patients per year by both manufacturers in their submissions. The Committee was also aware of the comments from consultees made during the consultation on the assessment report that the eligible population is likely to be at least 350 patients per year. The Committee concluded that the population for whom these treatments are suitable was uncertain but was likely to be more than 50 patients per year.

4.3.4 The Committee discussed the TAnDEM and EGF30008 trials. The Committee considered that both trials were well designed and were of good quality but did not include large numbers of patients who were HR+ and HER2+. It was aware that the baseline characteristics of patients in the two trials were reported differently. The Committee was also aware that the exclusion criteria for the two trials were reported differently, although it noted comments from consultees during the consultation on the assessment report that the populations in the two trials were broadly similar. In particular, the Committee noted that the EGF30008 trial excluded patients considered by the investigators to have disease that was rapidly progressing or life threatening. The clinical specialists stated that patients with serious intercurrent illness were excluded from the TAnDEM trial and these patients could have had similar disease to the patients excluded from the EGF30008 trial. The Committee also noted that the progression-free survival of patients with HER2+ breast cancer in the comparator groups of both trials was broadly similar, suggesting that the populations in the two trials were unlikely to be substantially different. The Committee noted that there appeared to be differences between the trials in the subsequent treatments received by patients following progression. It was reported that a large number of patients in the aromatase inhibitor group of the TAnDEM trial crossed over to receive trastuzumab plus an aromatase inhibitor. In addition, a proportion of patients in the TAnDEM trial received second-line chemotherapy on disease progression. However, in the EGF30008 trial, second-line treatments were at the investigators’ discretion and were not clearly reported. The clinical specialists thought that it was likely that second-line chemotherapy was made available to patients in the EGF30008 trial but was not clearly reported. The Committee concluded that the two trials were similar in most aspects and any differences were likely to be because of reporting.

4.3.5 The Committee discussed the generalisability of the evidence presented to routine UK clinical practice. It noted that participants in the two trials were younger than the average age of people with metastatic breast cancer in the UK. The Committee also noted that the trials included some women who were not postmenopausal. It considered whether women whose menopause was medically induced could be considered as menopausal in clinical practice and in relation to the licensed use of these technologies. The Committee heard from clinical specialists that metastatic breast cancer is treated in the same way whether menopause is natural or treatment induced. In both situations women would receive trastuzumab or lapatinib if the treatment was considered suitable. The Committee was assured by the clinical specialists that the patient populations in the trials broadly represented those in UK clinical practice. The Committee concluded that the evidence from the two trials was largely generalisable to UK clinical practice.

4.3.6 The Committee discussed the results of the TAnDEM and EGF30008 trials. The Committee noted that the gains in progression-free survival presented by the manufacturers for their technologies were statistically significant compared with an aromatase inhibitor alone. The Committee also noted that the overall survival results presented by both manufacturers were not statistically significant for the technologies relative to the comparators according to the ITT analyses. The Committee noted that the manufacturer of trastuzumab had performed a separate analysis that adjusted the overall survival results for patients who had crossed over from the aromatase inhibitor group to the trastuzumab plus aromatase inhibitor group. It noted that the Assessment Group had similarly adjusted for crossover in their overall survival results for trastuzumab and the results were not statistically significant. The Committee considered that it was appropriate to make adjustments for crossover, but was not certain that the methods used resulted in estimates that were robust. The Committee heard from the manufacturer of trastuzumab that the analysis in the original submission did not adjust for second-line therapy and that the manufacturer was in the process of conducting an analysis that made this adjustment. The Committee concluded that both trials showed evidence of statistically significant gains in progression-free survival as a result of adding lapatinib or trastuzumab to an aromatase inhibitor, but no statistically significant gains in overall survival.

4.3.7 The Committee discussed the indirect comparison meta-analysis performed by the manufacturers. It was aware of the Assessment Group’s concerns that the differences in the patient populations and the reporting in the EGF30008 and the TAnDEM trials could make indirect comparisons unreliable. The Committee was also aware of comments from consultees during the consultation on the assessment report that the two trials were broadly similar. The Committee agreed that the trials were largely similar and indirect comparisons may have been appropriate. However, the Committee considered that the preferred approach was to assess the cost-effectiveness of the treatments against aromatase inhibitors alone, before considering their cost-effectiveness against each other in an incremental analysis. It considered that the EGF30008 and TAnDEM trials provided sufficient evidence of clinical efficacy for this analysis and the manufacturers’ indirect comparisons contributed no further relevant information.

Cost effectiveness

4.3.8 The Committee discussed the approaches used in the cost-effectiveness analysis by the manufacturer of lapatinib, the manufacturer of trastuzumab and by the Assessment Group. The Committee noted that all three evaluations based the clinical-effectiveness estimates on the TAnDEM and EGF30008 trials and used modelling to extrapolate the data. It was aware that although the two manufacturers had each submitted a model comparing their technologies with each other and with aromatase inhibitors, the Assessment Group had modelled the cost effectiveness of lapatinib and trastuzumab separately, each in comparison with an aromatase inhibitor. The Committee was aware that the Assessment Group’s approach used estimates of progression-free survival and post-progression survival to calculate overall survival whereas the manufacturers had estimated post-progression survival from extrapolated estimates of overall survival and progression-free survival. The manufacturer of lapatinib stated that its approach more accurately reflected the overall survival gain. The manufacturer of trastuzumab stated that its approach was informed by previous NICE technology appraisals. The Assessment Group stated that progression-free survival and post-progression survival are different survival entities and modelling them separately is a more valid approach. The Assessment Group further stated that modelling progression-free survival and post-progression survival separately ensured that the models retained the actual trial data as much as possible and reduced the biases that could arise because of extrapolations. The Committee noted that the modelling approaches adopted by the manufacturers and by the Assessment Group had produced different ICERs. The Committee considered that the different approaches may have resulted in substantial differences in costs or QALYs. This appeared to be the case for lapatinib in particular because the differences between the ICERs calculated by the manufacturer and the Assessment Group were large. The Committee therefore explored possible reasons and areas of uncertainty that may have contributed to these differences

4.3.9 The Committee considered the ICERs for lapatinib plus letrozole compared with letrozole alone. It noted that the manufacturer presented an ICER of £74,400 per QALY gained (incremental cost £34,700 and incremental QALY 0.47). The Assessment Group presented an ICER in excess of £200,000 per QALY gained (incremental cost £25,000 and incremental QALY less than 0.12). The Committee also noted that the probabilistic sensitivity analysis presented by the Assessment Group produced an ICER of £960,800 per QALY gained. The Committee considered that the difference in the ICERs was mainly because of different incremental QALYs that resulted from the different PFS estimates. The Committee heard from the Assessment Group that the time in progression-free survival had been calculated using the Kaplan–Meier area under the curve estimates from the manufacturer’s trial data. The time in post-progression survival had been derived by fitting an exponential model to the post-progression survival data. The separate survival estimates were then used to derive the QALYs. The Committee heard that the manufacturer had fitted models to the progression-free survival data from the trial to derive the overall survival values used in calculating the QALYs. The Committee concluded that there were substantial uncertainties around the survival benefits provided by lapatinib as calculated by the manufacturer and considered that the area under the curve method used by the Assessment Group was likely to produce the more plausible results.

4.3.10 The Committee also noted that the cost of treatment with letrozole alone was £25,900 from the manufacturer’s model and £15,500 from the Assessment Group’s model. The Committee heard from the Assessment Group that most of the differences in costs (up to £7100) occurred during the period of post-progression survival. The Assessment Group stated that it had used the cost from a typical care package as presented in NICE clinical guideline 81 whereas the manufacturer had used the cost from the trial. The Committee considered that the costs used by the Assessment Group and those used by the manufacturer may be lower than the true costs incurred by the NHS if subsequent chemotherapy was used in these people. Taking into account uncertainties in the costs and the QALYs, the Committee concluded that the ICER for lapatinib plus letrozole compared with letrozole alone was likely to be between £74,400 and £1,000,000 per QALY gained.

4.3.11 The Committee considered the ICERs for trastuzumab plus anastrozole compared with anastrozole alone. It noted that the manufacturer presented an ICER of £54,300 per QALY gained (incremental cost £31,400 and incremental QALY 0.58). The Assessment Group presented an ICER of £73,100 per QALY gained (incremental cost £37,500 and incremental QALY 0.52). The Committee also noted that a probabilistic sensitivity analysis undertaken by the Assessment Group indicated that the ICER was £71,500 per QALY gained. The Committee noted that although the differences in these ICERs were smaller than those for lapatinib, they were mainly because of the costs associated with treatment with anastrozole alone. The Committee noted that the cost of treatment with anastrozole was £23,300 from the manufacturer’s model and £14,000 from the Assessment Group’s model. The Committee considered that there was substantial uncertainty around the costs associated with treatment with anastrozole alone and the sources of the costs were not clear. The Committee considered it possible that some of the costs in the anastrozole group could be attributed to trastuzumab because of crossover. It concluded that the most plausible ICER for trastuzumab plus anastrozole compared with anastrozole alone was likely to be between £54,300 and £73,100 per QALY gained.

4.3.12 The Committee considered the supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:

• The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
• There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
• The treatment is licensed or otherwise indicated for small patient populations.

In addition, when taking these into account, the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust.

4.3.13 The Committee discussed whether the benefit provided by lapatinib plus an aromatase inhibitor for the treatment of metastatic HR+ and HER2+ breast cancer fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee considered that because people with HER2+ status have a worse prognosis, they would be expected to have a life expectancy of less than 24 months, but noted that the mean overall survival in the aromatase inhibitor monotherapy arm of the EGF30008 trial and in the centrally confirmed results of the TAnDEM trial exceeded 24 months. The Committee considered the evidence on increased overall survival relative to current NHS treatment. The Committee considered that no robust evidence had been presented to indicate that lapatinib plus an aromatase inhibitor compared with an aromatase inhibitor alone offered a 3-month survival gain. The Committee also noted that the overall size of the population for whom lapatinib is licensed was uncertain. The Committee concluded that treatment with lapatinib plus an aromatase inhibitor did not fulfil the criteria for special consideration under the supplementary advice from NICE.

4.3.14 The Committee discussed whether trastuzumab plus an aromatase inhibitor fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee noted that the trial data did not show a statistically significant overall survival gain, but that the ITT analysis indicated a median overall survival benefit of 4.6 months, suggesting that trastuzumab plus an aromatase inhibitor compared with an aromatase inhibitor alone may offer a 3-month survival gain. The Committee noted that the population for whom trastuzumab is licensed across all the indications as reported by the manufacturer was 7158. The Committee noted that there was uncertainly around the number of people with metastatic HR+ and HER2+ breast cancer for whom trastuzumab is suitable under this new licensed indication (in combination with an aromatase inhibitor). The Committee considered that this was likely to be much higher in clinical practice than the figure presented by the manufacturer of 50 patients. The Committee concluded that there was uncertainty around the size of the population for whom trastuzumab is suitable under this new indication, and the total size of the population for whom trastuzumab is licensed, but noted that in combination, the number of people was likely to be too high for trastuzumab to fulfil the criteria for special consideration under the supplementary advice from NICE.

4.3.15 The Committee took into account the most plausible ICERs for the two technologies, the uncertainties about the modelling assumptions used by the manufacturer of lapatinib, the uncertainties about the treatment costs for aromatase inhibitors compared with trastuzumab and the uncertainties about the population eligible to receive trastuzumab. It concluded that lapatinib or trastuzumab in combination with an aromatase inhibitor would not be a cost-effective use of NHS resources for the first-line treatment of metastatic HR+ breast cancer that overexpresses HER2.

Summary of Appraisal Committee's key conclusions

TAXXX	Appraisal title: Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2	Section
Key conclusion
Lapatinib or trastuzumab in combination with an aromatase inhibitor are not recommended as options for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2). The Committee concluded that there were substantial uncertainties around the survival benefits provided by lapatinib as calculated by the manufacturer and that the ICER for lapatinib plus letrozole compared with letrozole alone was likely to be between £74,400 and £1,000,000 per QALY gained. The Committee considered that no robust evidence had been presented to indicate that lapatinib plus an aromatase inhibitor compared with an aromatase inhibitor alone offered a 3-month survival gain. The Committee also noted that the population for whom lapatinib was suitable was uncertain. The Committee concluded that the available evidence was not robust enough to show that treatment with lapatinib plus an aromatase inhibitor fulfilled the criteria for consideration as a life-extending end-of-life treatment under the supplementary advice from NICE. The Committee considered that there was substantial uncertainty around the costs assigned to people in the anastrozole arm and the sources of the costs were not clear. It concluded that the most plausible ICER for trastuzumab plus anastrozole compared with anastrozole alone was likely to be between £54,300 and £73,100 per QALY gained. The Committee concluded that there was uncertainty around the size of the population for whom trastuzumab is suitable under the new indication, and for the total size of the population for whom trastuzumab is licensed, but noted that in combination, the number of people was likely to be too high for trastuzumab to fulfil the criteria for special consideration under the supplementary advice from NICE.
Current practice
Clinical need of patients, including the availability of alternative treatments	The Committee heard from clinical specialists that in current UK clinical practice, people with advanced HER2+ breast cancer are more likely to receive trastuzumab plus chemotherapy than trastuzumab or lapatinib plus an aromatase inhibitor. Aromatase inhibitors alone are currently offered to people who prefer not to receive chemotherapy and to those who are either not fit enough to receive chemotherapy or who have contraindications. The clinical specialists stated that trastuzumab or lapatinib in combination with an aromatase inhibitor is therefore likely to be offered to people who are not fit enough to receive chemotherapy or who opt not to receive it.	4.3.2
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?	Clinical specialists stated that trastuzumab or lapatinib plus an aromatase inhibitor might be preferred in some cases where chemotherapy would currently be offered because it was more effective than aromatase inhibitor therapy alone and had a better adverse events profile than chemotherapy. The Committee heard from patient experts that for some women, chemotherapy was particularly difficult to cope with and treatment with lapatinib or trastuzumab in combination with an aromatase inhibitor may make it easier for them to carry on with their lives	4.3.2
What is the position of the treatment in the pathway of care for the condition?	The Committee concluded that lapatinib or trastuzumab plus an aromatase inhibitor are likely to be used in patients who, in consultation with their clinicians, consider that chemotherapy is not the best option for first-line treatment. The Committee heard from clinical specialists that people who receive trastuzumab or lapatinib plus an aromatase inhibitor may subsequently receive chemotherapy.	4.3.2
Adverse effects	Clinical specialists stated that trastuzumab or lapatinib plus an aromatase inhibitor might be preferred in some cases where chemotherapy would currently be offered because it was more effective than aromatase inhibitor therapy alone and had a better adverse events profile than chemotherapy	4.3.2
Evidence for clinical effectiveness
Availability, nature and quality of evidence	The Committee considered that both trials were well designed and were of good quality but did not include large numbers of patients who were HR+ and HER2+. The Committee noted that the gains in progression-free survival presented by the manufacturers for their technologies were statistically significant compared with an aromatase inhibitor alone. The Committee also noted that the overall survival results presented by both manufacturers were not statistically significant for the technologies relative to the comparators according to the ITT analysis.	4.3.4 4.3.6
Relevance to general clinical practice in the NHS	The Committee was assured by the clinical specialists that the patient populations in the EGF30008 and the TAnDEM trials broadly represented those in UK clinical practice. The Committee concluded that the evidence from the two trials was largely generalisable to UK clinical practice.	4.3.5
Uncertainties generated by the evidence	The Committee noted that the manufacturer of trastuzumab had performed a separate analysis that adjusted the overall survival results for patients who had crossed over from the aromatase inhibitor group to the trastuzumab plus aromatase inhibitor group. It noted that the Assessment Group had similarly adjusted for crossover in their overall survival results for trastuzumab and the results were not statistically significant. The Committee considered that it was appropriate to make adjustments for crossover, but was not certain that the methods used resulted in estimates that were robust. The Committee noted that the progression-free survival gains presented by both manufacturers for their technologies were statistically significant compared with an aromatase inhibitor alone The Committee noted that in the EGF30008 trial second-line treatments were not reported.	4.3.6 4.3.6
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?	No subgroups were identified in this appraisal.	–
Estimate of the size of the clinical effectiveness including strength of supporting evidence	The Committee concluded that both trials showed evidence of statistically significant gains in progression-free survival as a result of adding lapatinib or trastuzumab to an aromatase inhibitor, but no statistically significant gains in overall survival.	4.3.6
Evidence for cost effectiveness
Availability and nature of evidence	The Committee considered evidence on the cost effectiveness of lapatinib and trastuzumab compared with aromatase inhibitors, including the different models, the costs and ICERs presented by the manufacturers and the Assessment Group.	4.3.8 to 4.3.11
Uncertainties around and plausibility of assumptions and inputs in the economic model	The Committee considered the ICERs for lapatinib plus letrozole compared with letrozole alone. It noted that the manufacturer presented an ICER of £74,400 per QALY gained and the Assessment Group presented an ICER in excess of £200,000 per QALY gained and that the probabilistic sensitivity analysis presented by the Assessment Group produced an ICER of £960,800 per QALY gained. The Committee heard from the Assessment Group that time in progression-free survival had been calculated using the Kaplan–Meier area under the curve estimates from the manufacturer’s trial data and that the manufacturer had fitted models to the progression-free survival data from the trial to derive the overall survival values used in calculating the QALYs. The Committee concluded that there were substantial uncertainties around the survival benefits provided by lapatinib as calculated by the manufacturer and considered that the area under the curve method as used by the Assessment Group was likely to produce the more plausible results. The Committee noted that the manufacturer presented an ICER of £54,300 per QALY gained for trastuzumab plus anastrozole compared with anastrozole alone and that the Assessment Group presented an ICER of £73,100 per QALY gained. The Committee noted that the cost of treatment with anastrozole was £23,300 from the manufacturer’s model and £14,000 from the Assessment Group’s model. The Committee considered that there was substantial uncertainty around the costs assigned to patients in the anastrozole arm and the sources of the costs were not clear.	4.3.9 4.3. 9 4.3.9 4.3.11 4.3.11
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?	The Committee did not make a conclusion on the incorporation of health-related quality-of-life benefits and utility values.	–
Are there specific groups of people for whom the technology is particularly cost effective?	No subgroups were identified in this appraisal.	–
What are the key drivers of cost effectiveness?	The Committee considered that the difference in the ICERs was mainly because of different incremental QALYs that resulted from the different PFS estimates. The Committee considered that the difference in the ICERs presented by the manufacturer and the Assessment Group for trastuzumab plus anastrozole compared with anastrozole alone were mainly because of the costs associated with treatment with anastrozole alone.	4.3.9 4.3.11
Most likely cost-effectiveness estimate (given as an ICER)	The Committee concluded that the ICER for lapatinib plus letrozole compared with letrozole alone was likely to be between £74,400 and £1,000,000 per QALY gained. The Committee concluded that the most plausible ICER for trastuzumab plus anastrozole compared with anastrozole alone was likely to be between £54,300 and £73,100 per QALY gained.	4.3.10 4.3.11
Additional factors taken into account
Patient access schemes (PPRS)	Not applicable to this appraisal.	–
End-of-life considerations	The Committee considered that because people with HER2+ status have a worse prognosis,  can reduce life expectancy by up to 50%, they would be expected to have a life expectancy of less than 24 months. The Committee considered that no robust evidence had been presented to indicate that lapatinib plus an aromatase inhibitor compared with an aromatase inhibitor alone offered a 3-month survival gain. The Committee also noted that the overall size of the population for whom lapatinib is licensed was uncertain. It concluded that treatment with lapatinib plus an aromatase inhibitor did not fulfil the criteria for special consideration under the supplementary advice from NICE. The Committee noted that the trial data did not show a statistically significant overall survival gain, but that the ITT analysis indicated a median overall survival benefit of 4.6 months, suggesting that trastuzumab plus an aromatase inhibitor compared with an aromatase inhibitor alone may offer a 3-month survival gain. The Committee concluded that there was uncertainty around the size of the eligible population for whom trastuzumab is suitable under for the new indication (in combination with an aromatase inhibitor), and for the total size of the population for whom trastuzumab is licensed, but noted that in combination, the total number of people was likely to be too high for trastuzumab to fulfil the criteria for special consideration under the supplementary advice from NICE.	4.3.14 4.3.14 4.3.15 4.3.15
Equalities considerations and social value judgements	No equality issues were raised during the scoping exercise or through the course of this appraisal.	–

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Related NICE guidance

Published

• Advanced breast cancer: diagnosis and treatment. NICE clinical guideline 81 (2009). Available from www.nice.org.uk/guidance/CG81
• 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/guidance/CG41
• 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/guidance/TA34
• Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Trastuzumab as monotherapy and in combination with a taxane for the treatment of metastatic breast cancer (to include a review of TA34). NICE technology appraisal guidance (publication expected October 2011)
• Lapatinib for the treatment of women with previously treated advanced or metastatic breast cancer. NICE technology appraisal guidance (publication date to be confirmed).
• Lapatinib for the first-line treatment of metastatic hormone-sensitive breast cancer. NICE technology appraisal guidance (publication date to be confirmed).

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in May 2014. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Jane Adam
Chair, Appraisal Committee
November 2010

Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. 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. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

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 (Chair)
Department of Diagnostic Radiology, St George's Hospital

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

Professor A E Ades
Professor of Public Health Science, Department of Community Based Medicine, University of Bristol

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

Mr Christopher Earl
Surgical Care Practitioner, Renal Transplant Unit, Manchester Royal Infirmary

Mr John Goulston
Chief Executive, Barking, Havering and Redbridge Hospitals NHS Trust

Mr Adrian Griffin
VP Strategic Affairs, LifeScan, Johnson & Johnson

Professor Jonathan Grigg
Professor of Paediatric Respiratory and Environmental Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University London

Dr Ian Lewin
Consultant Endocrinologist, North Devon District Hospital

Dr Louise Longworth
Reader in Health Economics, HERG, Brunel University

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

Dr James Moon
Consultant Cardiologist and Senior Lecturer, University College London Hospital (UCLH) and UCL

Dr Ann Richardson
Lay member

Dr Paul Robinson
Medical Director, Merck Sharp & Dohme

Mr Stephen Sharp
Senior Statistician, MRC Epidemiology Unit

Mr Mike Spencer
Assistant Director Patient Experience, Cardiff and Vale University Health Board

Mr David Thomson
Lay member

Mr William Turner
Consultant Urologist, Addenbrooke’s Hospital

Dr Luke Twelves
General Practitioner, Ramsey Health Centre, Cambridgeshire

Dr John Watkins
Clinical Senior Lecturer/Consultant in Public Health Medicine, Cardiff University and National Public Health Service Wales  

Dr Anthony S Wierzbicki
Consultant in Metabolic Medicine/Chemical Pathology, Guy’s and St Thomas’ Hospitals NHS Trust

Dr Olivia Wu
Reader in Health Economics, University of Glasgow

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.

Raphael Yugi
Technical Lead

Joanne Holden
Technical Adviser

Bijal Joshi
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The assessment report for this appraisal was prepared by Liverpool Reviews and Implementation Group (LRiG):

• Fleeman N, Bagust A, Boland A, et al., Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor positive breast cancer which over-expresses HER2, September 2010

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, assessment report and the appraisal consultation document (ACD). Organisations listed in I, II and III were also invited to make written submissions and have the opportunity to appeal against the final appraisal determination.

I Manufacturers/sponsors:

• GlaxoSmithKline
• Roche Products

II Professional/specialist and patient/carer groups:

• Breast Cancer Campaign
• Breast Cancer Care
• Breast Cancer UK
• Cancer Networks Pharmacists Forum
• Cancer Research UK
• Macmillan Cancer Support
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians, Medical Oncology Joint Special Committee
• United Kingdom Oncology Nursing Society

III Other consultees:

• Betsi Cadwalader University
• Department of Health
• Welsh Assembly Government

IV Commentator organisations (without the right of appeal):

• AstraZeneca (anastrozole, tamoxifen)
• Commissioning Support Appraisals Unit
• Department of Health, Social Services and Public Safety for Northern Ireland
• Liverpool Reviews and Implementation Group, University of Liverpool
• Medicines and Healthcare Products Regulatory Agency
• National Collaborating Centre for Cancer
• National Institute for Health Research Health Technology Assessment Programme
• NHS Quality Improvement Scotland
• Pfizer (exemestane)

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee’s deliberations. They gave their expert personal view on lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2 by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

• Professor David Cameron, nominated by organisation representing NHS Quality Improvement Scotland – clinical specialist
• Dr Rob Stein, nominated by organisation representing Royal College of Physicians (NCRI/RCP/RCR/ACP/JCCO) – clinical specialist
• Mrs Emma Freeborn nominated by organisation representing Breast Cancer Care – patient expert
• Ms Maria Leadbeater nominated by organisation representing Breast Cancer Care – patient expert

D Representatives from the following manufacturers/sponsors attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• GlaxoSmithKline
• Roche Products