Treasury Minister to review financial support for care home costs

It concluded that the data for the aromatase inhibitor alone group from EGF30008 were more likely to represent the progression-free survival of people receiving this treatment in clinical practice. All three trials were multicentre, multinational trials that included postmenopausal women receiving first-line treatment for metastatic breast cancer. Cap, capecitabine; ICER, incremental cost-effectiveness ratio; Lap, lapatinib; Ner, neratinib, OS, overall survival, PD, progressive disease, PFS, progression-free survival; PPES, palmar-plantar erythrodysesthesia syndrome; QALY, quality-adjusted life year. 4.2.13 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.

Is this guidance up to date?

A probabilistic sensitivity analysis was undertaken using the base-case scenario over a 20-year time horizon. This showed no measurable probability of trastuzumab plus anastrozole being cost effective at £40,000 for an additional QALY, and a 3.2% probability of being cost effective at £50,000 for an additional QALY. This generated 266 progression-free survival days for lapatinib plus letrozole and 199 progression-free survival days for letrozole alone, giving a progression-free survival gain of 67 days per patient attributable to lapatinib. The Assessment Group reported that, following disease progression, patients in both groups of the trial were at the same risk of death, which appeared to be constant over time.

Clinical application

4.2.16 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 £26,150 per patient compared with letrozole alone, resulting in an ICER in excess of £220,000 per QALY gained. The results from regorafenib price philippines deterministic 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 which estimated the ICER to be in excess of £2,000,000 per QALY gained.

Data availability statement

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 QALY gains. Objective Neratinib plus capecitabine (Ner+Cap) were proved to be clinically beneficial as a third-line treatment for women with human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer (MBC).

Patient consent for publication

• B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators.
• Adverse events leading to dose reductions occurred in more than 20% of patients in both treatment groups.
• Alternatively, a loading dose of 8 mg/kg can be given, followed by 3-weekly maintenance doses of 6 mg/kg until disease progression.
• But he told members the department looked at income support regulations each year to «keep up» with the situation on the Isle of Man including the costs of care.

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. The corrected values for post-progression survival were 810 days for trastuzumab plus anastrozole and 870 days for anastrozole alone, a loss of 60 post-progression survival days attributable to trastuzumab. 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.

Related NICE guidance

• 4.2.15 Based on a study by Lloyd et al. (2006), slightly 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).
• Conversely, the Committee noted that the percentages of people alive and progression free for the comparator arms were different, and that this was the explanation for the difference in gain between treatment and comparator between the two trials.
• Both lapatinib and trastuzumab provided benefit in terms of progression-free survival but the overall survival benefit was small and/or uncertain.
• Trastuzumab in combination with an aromatase inhibitor is not recommended for first-line treatment in postmenopausal women with metastatic hormone-receptor-positive breast cancer that overexpresses HER2.
• 4.3.21 The Committee considered whether lapatinib plus an aromatase inhibitor for the treatment of metastatic hormone-receptor-positive and HER2+ metastatic breast cancer fulfilled the criteria for consideration as a life-extending, end-of-life treatment.
• It noted that the manufacturer presented an ICER of £74,400 per QALY gained (representing incremental costs of £34,700 and incremental QALYs gained of 0.47).
• On this basis the Committee accepted that trastuzumab plus an aromatase inhibitor fulfilled the small population criterion.

After consultation the Committee noted the Assessment Group’s revised estimate of £228,900 per QALY gained for the mean probabilistic ICER. On the basis of previous discussions regarding post-progression survival (section 4.3.9) the Committee concluded that the most plausible ICER would be higher than £74,000 per QALY gained. It noted a statistically significant difference of 5.2 months in median survival with lapatinib when compared with letrozole alone. In the subgroup of HER2 positive patients there was a non-statistically significant median increase of 1 month in overall survival for patients receiving lapatinib. The Committee concluded that lapatinib offered a benefit in progression-free survival but only a small and uncertain overall survival gain.

Appendix B: Sources of evidence considered by the Committee

The objective of this study was to evaluate the cost-effectiveness of Ner+Cap from the Chinese healthcare perspective. 4.3.7 The Committee considered the manufacturer’s and Assessment Group’s economic models for lapatinib. The Committee noted that there were some differences between the Assessment Group’s and the manufacturer’s estimates of progression-free survival and post-progression survival. In the base case, it was reported that trastuzumab plus anastrozole compared with anastrozole alone gave an incremental QALY gain 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.

3 Consideration of the evidence

Overall survival was calculated as progression-free survival plus post-progression survival. After adjusting post-progression survival to exclude patients who died at or before disease progression, the overall survival was 983 days for lapatinib plus letrozole and 928 days for letrozole alone, resulting in an overall survival gain of 55 days per patient attributable to lapatinib. 4.3.9 The Committee then considered the modelled estimates of post-progression survival. The Committee understood that patients would have stopped treatment with lapatinib at this stage. It noted that the Assessment Group’s model resulted in a lower estimate for lapatinib (717 days) than for the aromatase inhibitor (742 days). This resulted in a negative number of days gain in post-progression survival (−25 days) with lapatinib treatment.

Appraisal Committee’s preliminary recommendations

That was something Allinson said could lead to a situation where those services were no longer available for the «majority of people» on the island, but said it was «right» to monitor costs to «make sure they are proportionate». Any potential changes to financial support for people’s care home costs would be brought forward as part of the next budget, the treasury minister has said. An annual discount rate of 3% was applied to both cost and health utilities to reflect net current values.

Support for care home costs to be reviewed

It heard from the Assessment Group that it was not possible to combine the EGF30008 and TAnDEM trials in a meta-analysis because of the different populations included in the trials, and that the results of the manufacturer’s meta-analyses should be interpreted with caution. The Committee noted that the Assessment Group had not compared the clinical and cost effectiveness of lapatinib plus an aromatase inhibitor with trastuzumab plus an aromatase inhibitor in one model. The Committee accepted that it would need to consider the clinical and cost effectiveness of lapatinib plus an aromatase inhibitor and trastuzumab plus an aromatase inhibitor independently. It first considered the case for lapatinib plus an aromatase inhibitor (hereafter referred to as lapatinib) and then it considered the case for trastuzumab plus an aromatase inhibitor (hereafter referred to as trastuzumab).

Appendix A: Appraisal Committee members and NICE project team

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. 1.1 Lapatinib in combination with an aromatase inhibitor is not recommended for first-line treatment in postmenopausal women with metastatic hormone-receptor-positive breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2). (A) The cost-effectiveness acceptability curve; (B) Scatter plots of 1000 Monte Carlo simulated patients. Cap, capecitabine; Lap, lapatinib; Ner, neratinib; QALY, quality-adjusted life years; WTP, willingness-to-pay. The Committee noted that a range of survival estimates were presented and that all the evidence indicated that patients receiving current standard NHS treatment would have an expected survival greater than 24 months.

• The results showed that at £30,000 for an additional 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.
• 4.3.17 The Committee considered whether trastuzumab met the criterion for a small population.
• It noted that for the lapatinib treatment group, the manufacturer’s estimate of progression-free survival was 431 days and the Assessment Group’s estimate was 343 days.
• 4.1.17 The Assessment Group considered that the findings of the indirect comparisons presented by the two manufacturers should be treated with caution.
• After adjusting post-progression survival to exclude patients who died at or before disease progression, the overall survival was 983 days for lapatinib plus letrozole and 928 days for letrozole alone, resulting in an overall survival gain of 55 days per patient attributable to lapatinib.
• It is estimated that 60% and 80% of all breast cancers in premenopausal and postmenopausal women respectively are hormone receptor positive.
• Participants Patients with confirmed HER2-positive MBC who previously received at least two HER2-targeted treatments and were aged ≥18 years with an Eastern Cooperative Oncology Group performance status 0 or 1.

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 carrying on with their lives easier. 4.2.8 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. 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).

• An estimated 5% of patients present with metastatic breast cancer, and approximately 30% of people who present with localised breast cancer will later develop metastatic breast cancer.
• This generated 266 progression-free survival days for lapatinib plus letrozole and 199 progression-free survival days for letrozole alone, giving a progression-free survival gain of 67 days per patient attributable to lapatinib.
• Compared with T + C, L + C is dominant in the base case and approximately equally likely to be cost-effective in probabilistic sensitivity analyses over a wide range of threshold values.
• This showed no measurable probability of trastuzumab plus anastrozole being cost effective at £40,000 for an additional QALY, and a 3.2% probability of being cost effective at £50,000 for an additional QALY.
• Neratinib under the current price may benefit more Chinese women with HER2-positive MBC.

The Committee further noted that the manufacturer’s model resulted in a higher estimate of post-progression survival for lapatinib (810 days) than for an aromatase inhibitor (759 days). This resulted in a positive number of days gained during post-progression survival following lapatinib treatment (51 days). The Committee heard from clinical specialists that there is no reason why treatment with lapatinib prior to progression should result in either a shorter or longer duration of post-progression survival. The Committee agreed that it was not implausible that a longer time in progression-free survival might reduce the time in post-progression survival. The Committee concluded that the incremental gain in post-progression survival with lapatinib was most likely to be near zero difference.

Cost-effectiveness Analysis of Trastuzumab Emtansine as Second-line Therapy for HER2-Positive Breast Cancer in China

It also noted that the length of follow-up and the proportion of patients receiving first-line treatment differed between trials. 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’.

Views wanted on nursing and home care cost models

It noted the large differences in the estimates produced by the manufacturer and the Assessment Group’s models. In particular it noted that the Assessment Group’s model resulted in a negative value of −60 days in post-progression survival for trastuzumab compared with an aromatase inhibitor. The Committee noted comments from the manufacturer of trastuzumab that it would seem wrong that treatment with trastuzumab causes a shortened life expectancy following disease progression. The Committee heard from the Assessment Group that this does appear to be an anomaly but that it is caused by a problem in the data in the control arm of the trial, raising further questions of uncertainty in the data. For the same reason as discussed for lapatinib (section 4.3.9) the Committee concluded that the likely impact on post-progression survival with trastuzumab was most likely to be nearer to zero. 4.3.5 The Committee noted the mixed treatment comparisons presented by the manufacturers.

4.3.14 The Committee considered the ICERs for trastuzumab plus anastrozole compared with anastrozole alone. The Committee also noted that the Assessment Group’s revised estimate of the ICER was £69,500 per QALY gained. The Committee accepted that the manufacturer’s estimate was too low given that people in the aromatase inhibitor group appeared to progress much quicker than would be expected in clinical practice (sections 4.3.4 and 4.3.12). It considered that if the estimate of progression-free survival on an aromatase inhibitor was higher than 190 days, the ICER would be higher. On the basis of previous discussions (section 4.3.13), the Committee also considered that the manufacturer’s estimate of post-progression survival was too high and that if this estimate were lower, the ICER would be higher. The Committee concluded that the most plausible ICER for trastuzumab would be in excess of £51,000 per QALY gained.

The Committee concluded that all the evidence on survival indicated that patients receiving current standard NHS treatment would have an expected survival greater than 24 months. The Committee therefore concluded that the life expectancy of patients exceeded 24 months and that trastuzumab plus an aromatase inhibitor did not fulfil the criterion for short life expectancy. 4.2.17 In response to consultation comments, the Assessment Group in its deterministic sensitivity analysis revised the estimates of survival and the ICER for lapatinib. The revised estimates of pre-progression survival were 343 days and 255 days for lapatinib and an aromatase inhibitor respectively, giving a gain of 89 days of pre-progression survival with lapatinib treatment. The revised estimates of post-progression survival were 717 days and 742 days for lapatinib and an aromatase inhibitor respectively, giving a loss of 25 days of pre-progression survival with lapatinib treatment.

In a phase III trial of women with HER2+ metastatic breast cancer (MBC) previously treated with trastuzumab, an anthracycline, and taxanes (EGF100151), lapatinib plus capecitabine (L + C) improved time to progression (TTP) versus capecitabine monotherapy (C-only). In a trial including HER2+ MBC patients who had received at least one prior course of trastuzumab and no more than one prior course of palliative chemotherapy (GBG 26/BIG 03-05), continued trastuzumab plus capecitabine (T + C) also improved TTP. 4.3.21 The Committee considered whether lapatinib plus an aromatase inhibitor for the treatment of metastatic hormone-receptor-positive and HER2+ metastatic breast cancer fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee discussed the first criterion and noted that the evidence for life expectancy in this group of patients exceeded 24 months (see section 4.3.18).

The Appraisal Committee has considered the evidence submitted and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts. Main outcome measures The primary health outcomes of the model were costs, expected life-years (LYs), quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). Clinical specialists stated that lapatinib or trastuzumab plus an aromatase inhibitor might be preferred for some women in whom chemotherapy would currently be offered because the combination has a better adverse event profile than chemotherapy. Univariate sensitivity analyses were performed to determine the impact of each independent variable on the result, within a specific range.

Due to the lack of CI, the costs were assumed to vary by ±20%, and the utilities were assumed to vary by ±10%, based on their baseline values. 4.3.23 The Committee considered that the potential population covered by the marketing authorisation for lapatinib would not be as high as for trastuzumab (see 4.3.17) because lapatinib does not have a marketing authorisation for early breast cancer or for gastric cancer. Participants Patients with confirmed HER2-positive MBC who previously received at least two HER2-targeted treatments and were aged ≥18 years with an Eastern Cooperative Oncology Group performance status 0 or 1. However, because lapatinib had failed to meet the first and second criteria for consideration as a life-extending end-of-life treatment, the Committee concluded that lapatinib did not fulfil all the criteria for special consideration under the supplementary advice from NICE. 4.1.16 The HR for progression of 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 of lapatinib plus aromatase inhibitors compared with aromatase inhibitors was 0.71 (95% CI 0.53 to 0.95).

4.2.21 In response to consultation comments, the Assessment Group revised the estimates of survival and the ICER for trastuzumab, correcting for an error in the number of patients who died at or before progression in the trastuzumab group. The revised estimates of pre-progression survival were 510 days and 194 days for trastuzumab and an aromatase inhibitor respectively, giving a gain of 316 days pre-progression survival with lapatinib treatment. The revised estimates of post-progression survival were 612 days and 672 days for trastuzumab and an aromatase inhibitor respectively, giving a loss of 60 days pre-progression survival with trastuzumab treatment. Overall survival was estimated to be 1122 days with trastuzumab and 866 days with an aromatase inhibitor, giving an increase of 256 days with trastuzumab treatment.

Direct costs of anticancer agents, drug administration, routine follow-up and serious adverse events management were calculated in the model. When compared against capecitabine alone, the addition of lapatinib has a cost-effectiveness ratio exceeding the threshold normally used by NICE. Compared with T + C, L + C is dominant in the base case and approximately equally likely to be cost-effective in probabilistic sensitivity analyses over a wide range of threshold values.

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. 2.3 When clinicians manage breast cancer they consider various prognostic factors, including hormone receptor status and HER2 status.

The Committee concluded that lapatinib plus an aromatase inhibitor did not fulfil the criterion for short life expectancy. The Committee reviewed all the evidence for life expectancy in this group of patients, including historical published data and estimates of overall survival in the aromatase inhibitor arms of the trials. It considered that the best estimate of expected survival using current standard NHS treatment was demonstrated in the control arms of the trials. The Committee noted that additional information on survival with standard NHS treatment was also available from the aromatase inhibitor arm of the EGF30008 trial in which median overall survival was 32 months.

The sensitivity analysis showed that unless the cost of lapatinib was reduced by 70%, it was unlikely to change the final result. The target population for our economic analysis was clinically similar to the patients enrolled in the NALA trial. The hypothetical patients were women with confirmed HER2-positive MBC who previously received at least two HER2-targeted treatments and were aged ≥18 years with an Eastern Cooperative Oncology Group performance status 0 or 1. The dosage of capecitabine was calculated according to the average body surface area of Chinese women.15 Furthermore, patients in the Ner+Cap arm received loperamide (initial dose, 4 mg) with the first dose of neratinib, followed by 2 mg every 4 hours for the first 3 days. Thereafter, loperamide 2 mg was administered every 8 hours until the end of the first cycle.

4.3.25 The Committee considered the clinical and cost effectiveness of lapatinib plus an aromatase inhibitor and trastuzumab plus an aromatase inhibitor in light of the submitted evidence and the comments of the clinical specialists, the commissioning expert and the patient experts. The Committee agreed that the cost-effectiveness estimates for both technologies were high and subject to uncertainties which would increase, rather than decrease, the manufacturers’ ICERs. The Committee concluded that neither lapatinib nor trastuzumab would be a cost-effective use of NHS resources when combined with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2. 4.2.20 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 exceeded £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.

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 over 99% were women. Commissioners and/or providers have a responsibility to provide the funding required to enable the guidance to be applied when individual health professionals and their patients wish to use it, in accordance with the NHS Constitution. They should do so in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Cap, capecitabine; KM, Kaplan Meier; Lap, lapatinib; Ner, neratinib; OS, overall survival; PFS, progress-free survival.