The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using erlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?

Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of gender, race, disability, age, sexual orientation, religion or belief?

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD)
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using erlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer in the NHS in England and Wales.

For further details, see the ‘Guide to the technology appraisal process’ (available at www.nice.org.uk).

The key dates for this appraisal are:

Closing date for comments: 7 July 2010

Second Appraisal Committee meeting: 27 July 2010

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

1 Appraisal Committee’s preliminary recommendations

1.1 Erlotinib monotherapy is not recommended for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer with stable disease after platinum-based first-line chemotherapy.

2 The technology

2.1 Erlotinib (Tarceva, Roche Products) is an orally active inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. It has a UK marketing authorisation ‘as monotherapy for maintenance treatment in patients with locally advanced or metastatic non-small cell lung cancer with stable disease after 4 cycles of standard platinum-based first-line chemotherapy’. For further information see the summary of product characteristics.

2.2 Undesirable effects of erlotinib treatment include diarrhoea, rash, anorexia, gastrointestinal bleeding, liver-function test abnormalities and keratitis. For full details of side effects and contraindications, see the summary of product characteristics.

2.3 Erlotinib is given orally at a recommended dose of 150 mg/day. The normal acquisition cost of a pack of 30 tablets (150 mg) is £1631.53 (excluding VAT; ‘British national formulary’ [BNF] 59th edition). The manufacturer of erlotinib proposed a patient access scheme to the Department of Health in which the acquisition cost of erlotinib is reduced by 14.5% (that is, £1394.96 for a pack of 30 tablets [150 mg]). Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer’s submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of erlotinib and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The key evidence for the clinical effectiveness of erlotinib came from a randomised double-blind controlled trial comparing erlotinib with placebo in patients with advanced or metastatic non-small-cell lung cancer whose disease had not progressed following platinum-based chemotherapy (SATURN). Results of the SATURN trial were provided for the whole study population (that is, the intention-to-treat population) and two subgroups: patients with non-squamous disease and patients with stable disease after first-line chemotherapy. Stable disease was defined using the Response Evaluation Criteria in Solid Tumours (RECIST) criteria. According to these criteria, stable disease is when tumour shrinkage is not sufficient to be defined a partial response and tumour increase is not sufficient to be defined as progressive disease’. The results for the subgroups of patients with non-squamous disease and stable disease came from post-hoc analyses. Patients were included in the SATURN trial if their disease had not progressed after 4 cycles of a standard, platinum-based chemotherapy doublet (two chemotherapy drugs, one of which is platinum based), if they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 and a life expectancy of at least 12 weeks. The primary outcome of the trial was progression-free survival, defined as the time between randomisation and the date of the first documented disease progression, or death from any cause. Secondary outcomes included overall survival, time to disease progression, response rates (assessed by the RECIST criteria) and quality of life (assessed by the Functional Assessment of Cancer Therapy – Lung [FACT-L] questionnaire).

3.2 The SATURN trial included a total of 889 patients with a mean age of 60 years. At baseline, 69% of patients had an ECOG performance status of 1, 55% were current smokers, 70% had tumours with a positive EGFR immunohistochemistry (IHC) status, 60% had non-squamous disease and 55% had stable disease. The most common first-line treatments were gemcitabine plus carboplatin (28%), gemcitabine plus cisplatin (26%), and paclitaxel plus carboplatin (19%). The majority of patients (48%) were from Eastern Europe, 21% were from Southeast Asia and 1% were recruited from the UK.

3.3 For the subgroup of patients with stable disease after first-line chemotherapy, erlotinib was associated with statistically significant increases in progression-free survival (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.56 to 0.83; p < 0.0001) and overall survival (HR 0.72; 95% CI 0.59 to 0.89; p = 0.0019) compared with placebo. For the subgroup of patients with non-squamous disease, erlotinib was also associated with a greater progression-free survival (HR 0.68; 95% CI 0.56 to 0.82) and overall survival (HR 0.79; 95% CI 0.64 to 0.96) than placebo (p-value not stated). Median progression-free and overall survival and further outcomes, such as response rates and quality of life, were not provided for the subgroups of patients with stable disease and non-squamous disease. There were a number of statistically significant results in the intention-to-treat population. Median progression-free survival was 12.3 weeks in the erlotinib group and 11.1 weeks in the placebo group (HR 0.71; 95% CI 0.62 to 0.82; p < 0.0001). Median overall survival was 12.0 months in the erlotinib group and 11.0 months in the placebo group (HR 0.81; 95% CI 0.70 to 0.95; p = 0.0088). The proportion of patients in the intention-to-treat population who had a partial or complete response after maintenance treatment was 11.9% (95% CI 9.0 to 15.3) in the erlotinib group compared with 5.4% (95% CI 3.5 to 7.9) in the placebo group (p = 0.0006). For quality of life, there were no statistically significant differences between the erlotinib and placebo groups for time to symptom progression, time to deterioration in trial outcome index, and time to deterioration in quality of life.

3.4 The manufacturer conducted pre-planned subgroup analyses for the following factors: EGFR status, stage of disease, first-line chemotherapy, smoking status and geographical region. Erlotinib was associated with a statistically significant benefit in both progression-free survival (HR 0.69; 95% CI 0.58 to 0.82; p < 0.0001) and overall survival (HR 0.77; 95% CI 0.64 to 0.93; p = 0.0063) compared with placebo for patients with EGFR IHC positive tumours, but not for patients with EGFR IHC negative tumours (progression-free survival HR 0.77; 95% CI 0.51 to 1.14 and overall survival HR 0.91; 95% CI 0.59 to 1.38; p-values not reported).

3.5 In the SATURN trial, the most common adverse events associated with erlotinib were rash (49% in the erlotinib group and 6% in the placebo group) and diarrhoea (20% in the erlotinib group and 5% in the placebo group). More patients in the erlotinib group had an adverse event of any kind than in the placebo group (79% compared with 54%) and more patients in the erlotinib group had a grade 3 or 4 adverse event (25% compared with 12% in the placebo group).

3.6 The manufacturer conducted an indirect analysis of erlotinib and pemetrexed in patients with non-squamous disease using data from a randomised controlled trial of pemetrexed maintenance treatment versus placebo in patients with locally advanced or metastatic non-small-cell lung cancer (JMEN). The JMEN trial included patients who had a response after standard platinum-based chemotherapy and patients who had stable disease. The trial reported a statistically significant increase in progression-free survival (HR 0.44; 95% CI 0.36 to 0.55; p < 0.0001) and overall survival (HR 0.70; 95% CI 0.56 to 0.88; p = 0.002) with pemetrexed compared with placebo. The results of the indirect analysis of erlotinib and pemetrexed were marked commercial-in-confidence.

3.7 The manufacturer submitted economic analyses for three different patient populations because of uncertainty about the licensed indication at the time of the submission. The three populations were: the intention-to-treat population of the SATURN trial, the subgroup of patients with stable disease (erlotinib compared with best supportive care) and the subgroup of patients who had non-squamous disease (erlotinib compared with pemetrexed). The manufacturer used a three-state area under the curve model with a cycle length of 1 month and a 5-year time horizon. The health states in the model were progression-free survival, progressed (defined as the time from first treatment relapse until death), and death. All patients were assumed to start in the progression-free survival health state (after first-line chemotherapy). At the end of each cycle they could remain in this state, move to the progressed health state or die.

3.8 The risk of disease progression was taken from the SATURN trial for the direct comparison of erlotinib with best supportive care in the intention-to-treat population and the subgroup of patients with stable disease. For the subgroup of patients with non-squamous disease, the risk of disease progression came from the indirect comparison of pemetrexed with erlotinib from the SATURN and JMEN trials. Evidence on health-related quality of life for the progression-free survival state came from the FACT-L questionnaire in the SATURN trial. Utility values for the progression-free survival health state were 0.695 for the intention-to-treat population and 0.685 for the subgroups of patients with stable disease and non-squamous disease. Because health-related quality of life for the progressed state was not measured in the SATURN trial, the utility value for this state (0.47) was taken from a study on the second-line treatment of non-small-cell lung cancer by Nafees et al. (2008).

3.9 Costs included in the model were drug costs for erlotinib and pemetrexed, costs of best supportive care, costs for adverse events associated with erlotinib and pemetrexed, and costs for post-progression treatment. Costs for erlotinib were based on a proposed patient access scheme that consisted of a 14.5% discount of the list price (BNF 59) to be deducted at the time of supply to the NHS. The proposed patient access scheme was based on a discount arrangement already in place after NICE technology appraisal guidance 162 was published. Erlotinib doses were based on those given in the SATURN trial and the model assumed no wastage of the drug. The total average per-patient costs for erlotinib were £6430 for the intention-to-treat poulation, £6396 for the subgroup of patients with stable disease and £6617 for the subgroup of patients with non-squamous disease. For pemetrexed, costs were based on the list price to the NHS (BNF 58) and doses were based on the average body surface area for patients in the JMEN trial (1.8 m²). The total average per-patient cost for pemetrexed was £17,853. Data on post-progression treatment were collected in the SATURN trial and costs came from various sources including the BNF 58 and other NICE technology appraisal guidance. Because there was a lack of data on post-progression treatment from the JMEN study, the manufacturer assumed that the costs associated with pemetrexed would be the same as those for the placebo group of the SATURN study.

3.10 In the manufacturer’s base case, for the comparison of erlotinib with best supportive care in the subgroup of patients with stable disease, the incremental cost-effectiveness ratio (ICER) was £47,743 per quality-adjusted life year (QALY) gained (incremental cost £7747 and incremental benefit 0.162 QALYs). Probabilistic sensitivity analysis reported a 55% probability that the ICER would be less than £50,000 per QALY gained for the subgroup of patients with stable disease. The manufacturer presented sensitivity analyses in which the base-case ICER increased to a maximum ICER of £54,624 per QALY gained when the utility value was decreased by 20%. For the comparison of erlotinib with best supportive care in the intention-to-treat population, the ICER was £55,219 per QALY gained (incremental cost £5706 and incremental benefit 0.103 QALYs). This ICER was most sensitive to the utility values for the progression-free health state. The results of the comparison of erlotinib with pemetrexed in the subgroup of patients with non-squamous disease (which included patients with stable disease and those whose disease responded to treatment) were also provided.

3.11 The ERG reviewed the evidence for clinical effectiveness submitted by the manufacturer. It noted that the extent to which patients and investigators were truly blind to treatment allocation throughout the SATURN trial was uncertain because patients in the erlotinib group were significantly more likely to develop a rash and suffer from diarrhoea than patients in the placebo group. The ERG commented that the results of the post-hoc analyses on the subgroups of patients with stable disease and non-squamous disease should be considered with caution because the trial was not designed to perform this type of analysis. The ERG queried whether the SATURN study could be generalised to the UK because it included very few UK patients and the population was slightly younger and fitter than would be seen in UK clinical practice. It also commented that a greater proportion of patients had first-line treatment with paclitaxel than would occur in UK clinical practice and no patients had first-line treatment with pemetrexed, which is becoming a more common first-line treatment for patients with non-squamous disease. Lastly, the patients in the SATURN trial received a variety of post-progression treatments, many of which do not have marketing authorisations in the UK or are not approved by NICE (including pemetrexed, vinorelbine, gemcitabine and paclitaxel). Only docetaxel and erlotinib are recommended by NICE for second-line treatment of non-small-cell lung cancer. The ERG noted that this would affect overall survival results.

3.12 The ERG commented on the cost-effectiveness evidence submitted by the manufacturer and made a number of revisions to the manufacturer’s models. Its main criticism was that although the models used a Markov structure, they were not Markov models because movement between health states was governed by parametric projection models rather than transition probabilities. This approach allowed negative post-progression patient numbers to be generated, compromising both lifetime cost and outcome estimates. The ERG carried out exploratory analyses using the manufacturer’s models, which were changed to be genuine Markov models.

3.13 The ERG reviewed the methods used for extrapolation of progression-free survival and overall survival beyond the trial period in the manufacturer’s model. It noted that the manufacturer had not modelled post-progression survival directly, and had instead calculated it as the difference between overall survival and progression-free survival. The ERG performed an exploratory analysis using an alternative approach in which post-progression survival was estimated directly based on data provided by the manufacturer. It pointed out that an advantage of this approach is that it takes account of the influence of subsequent courses of second-line chemotherapy on post-progression survival, and differences between treatment arms in the proportions of patients who received second-line chemotherapy. The ERG also explored an alternative approach to the manufacturer in modelling post-progression survival. The manufacturer used the area under the curve value after exploring several parametric models and finding none of them to be sufficiently accurate. The ERG noted that fitting standard parametric functions to full clinical trial data sets often does not correspond well with underlying data. The ERG’s approach used area under the curve data for 12 months, followed by projection using an exponential curve beyond 12 months. The ERG’s preferred method of extrapolation over a lifetime horizon resulted in an overall survival gain of 4.2 months in the stable disease population. This was greater than the 3.3 months (0.277 life years) estimated in the manufacturer’s base case. The manufacturer’s base-case ICER decreased from £47,743 to £47,574 per QALY gained when the ERG approach to estimating overall survival was used.

3.14 The ERG noted that the costs of erlotinib in the manufacturer’s models assumed that no wastage of erlotinib occurred. However erlotinib is dispensed in packs of 30 tablets to be taken at home and when a patient discontinues treatment any part-used packs are discarded. To address this issue, the ERG estimated the amount of wastage based on the timing of disease progression in the SATURN trial. This increased the mean cost of treatment with erlotinib by 14% in the intention-to-treat population. The ERG criticised the approach that the manufacturer used to calculate post-progression treatment costs. It commented that converting the estimated total costs of treatments in the SATURN trial to a monthly average and then reapplying them to survival estimates may distort the resulting incremental costs. The ERG corrected this by using a fixed cost per course of treatment multiplied by the proportion of progressed patients receiving second-line chemotherapy in the SATURN trial, spread pro-rata over the post-progression survivors in each cycle.

3.15 The ERG noted that the manufacturer’s method of generating utility values involved a number of steps (transformation of FACT-L scores into EQ-5D visual analogue scores and then to EQ-5D utility scores) and that each step introduced uncertainty. In its revisions to the model, the ERG used the same utility values used in the ongoing NICE technology appraisal ‘Pemetrexed for the maintenance treatment of non-small-cell lung cancer’. The utility values used by the ERG for the progression-free survival health state were 0.6732 for the erlotinib arm and 0.6628 for the placebo arm, compared with 0.685 for both treatment arms assumed by the manufacturer in the stable disease model. The utility value for the progressed health state was 0.53 in the ERG’s exploratory analyses compared with 0.47 in the manufacturer’s submission.

3.16 Additional issues identified by the ERG related to the time horizon, the discounting logic, the costs of pemetrexed and the reference costs. The ERG provided a revised model in which the issues described above were addressed. The combined effect of all of the revisions was to increase the ICER for the subgroup of patients with stable disease from £47,743 per QALY gained in the manufacturer’s base case to £59,336 per QALY gained. The revisions that had the greatest affect on the ICERs for the subgroup of patients with stable disease were the inclusion of wastage in the costs of erlotinib, and corrections to the costs of post-progression treatments.

3.17 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of erlotinib, having considered evidence on the nature of non-small-cell lung cancer and the value placed on the benefits of erlotinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee was aware that during the course of the appraisal erlotinib had received a marketing authorisation for the maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer with stable disease after standard platinum-based first-line chemotherapy. It noted that because of uncertainty about the licensed indication at the time of submission, the manufacturer had included three analyses in their submission: comparisons of erlotinib with best supportive care in the intention-to-treat population and in the subgroup of patients with stable disease and a comparison of erlotinib with pemetrexed in the subgroup of patients with non-squamous disease.

4.3 The Committee considered the three analyses provided by the manufacturer, taking into account that the marketing authorisation for erlotinib is for the maintenance treatment of patients with stable disease. It first discussed the comparison of erlotinib with best supportive care in the intention-to-treat population of the SATURN trial. It noted that this analysis included patients with stable disease after first-line treatment as well as a substantial proportion of patients (45%) whose disease had responded after first-line treatment (this indication is not included in the marketing authorisation for erlotinib). The Committee discussed the comparison of erlotinib with pemetrexed in patients with non-squamous disease and noted that this analysis also included patients with stable disease and patients whose disease had responded to treatment. It therefore considered that the analyses of the intention-to-treat and non-squamous disease populations were not sufficiently applicable to the licensed population to be relevant to this appraisal of erlotinib. The Committee concluded that only the analysis of patients with stable disease was directly relevant to this appraisal.

4.4 The Committee noted that the analysis of patients with stable disease included patients with squamous and non-squamous disease. It considered that the decision problem for these two groups was different because pemetrexed is an option for the maintenance treatment of non-squamous disease but best supportive care is currently the only option for patients with squamous disease. However, no data for the stable disease subgroup were provided to allow separate consideration of the use of erlotinib in squamous and non-squamous disease. Furthermore, no evidence was provided comparing erlotinib with pemetrexed in patients with non-squamous disease who have stable disease after first-line treatment.

4.5 The Committee considered current UK practice for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer. It heard from clinical specialists that first-line treatment is usually with a platinum doublet of carboplatin or cisplatin plus gemcitabine, paclitaxel, vinorelbine or docetaxel, or cisplatin plus pemetrexed for patients with non-squamous disease. If disease progresses, patients have the option of receiving second-line systemic treatment if they have a good performance status. In the UK, second-line treatment is normally docetaxel or erlotinib. The Committee was aware that maintenance treatment after first-line treatment is still a relatively new concept in lung cancer and that its aim is to prolong the benefits of treatment and to maximise quality of life for as long as possible. The Committee was aware of the ongoing NICE technology appraisal ‘Pemetrexed for the maintenance treatment of non-small-cell lung cancer’. It noted that the final appraisal determination consultation document recommends pemetrexed as an option for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology if disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel. The Committee noted that patients are only eligible for maintenance treatment with this drug if they have not received it as first-line treatment in combination with cisplatin. It heard from clinical specialists that the number of patients who would be eligible for maintenance treatment with pemetrexed would progressively decrease as more patients receive first-line treatment with pemetrexed.

4.6 The Committee heard from clinical specialists that a clinical trial of docetaxel as maintenance treatment for non-small-cell lung cancer has been conducted. The trial compared maintenance treatment with docetaxel with second-line treatment with docetaxel (that is, patients received best supportive care until disease progression and were then treated with docetaxel). This showed a statistically significant benefit in progression-free survival but not in overall survival with docetaxel maintenance treatment. The clinical specialists commented that docetaxel may also be a relevant comparator for this appraisal. The Committee considered that the scope was developed through a consultative process and noted that docetaxel was not identified as a treatment offered in routine clinical practice in the NHS. It concluded that the comparator assessed by the manufacturer and the ERG for the stable disease population (best supportive care) reflected current practice in the NHS and was therefore appropriate.

4.7 The Committee noted views from clinical specialists that erlotinib is an oral drug with adverse effects that are well known and relatively well tolerated. The clinical specialists stated that a potential benefit of maintenance treatment is that it may increase the proportion of patients who receive subsequent treatment after first-line treatment. This is because many patients treated with first-line therapy are too unwell at relapse to receive subsequent treatment. The clinical specialists also commented that erlotinib may provide a maintenance treatment option for patients who are not suitable for pemetrexed maintenance treatment because they have squamous disease and/or they have had pemetrexed as a first-line treatment. The Committee noted that no statements were received from patient experts.

4.8 The Committee discussed the RECIST criteria for determining disease response in the SATURN trial taking into account the marketing authorisation for erlotinib, which includes patients with stable disease only. It heard from clinical specialists that some centres, particularly those involved in clinical trials, use the RECIST criteria routinely but that centres less involved in research may not use RECIST criteria on a day-to-day basis.

Clinical effectiveness

4.9 The Committee discussed the clinical effectiveness evidence for maintenance treatment with erlotinib in the subgroup of patients with stable disease and noted that the only evidence for these patients came from one randomised controlled trial (SATURN). It was aware that the only results provided for patients with stable disease were the hazard ratios for the difference in progression-free survival and overall survival between the erlotinib and placebo groups. The duration of progression-free survival and overall survival and the response rates were not reported.

4.10 The Committee discussed whether the SATURN study could be generalised to UK clinical practice and noted that there were few UK patients and a high proportion of patients from Southeast Asia in the study. The Committee noted a comment from the ERG that Asian people are known to respond better to lung cancer treatments than other races. The Committee heard from the clinical specialists that there are no significant reasons why the relative benefit of erlotinib in the SATURN trial would not also be seen in the UK population. It also heard from clinical specialists that patients with EGFR mutations have a longer natural history of disease and a better prognosis than other patients with non-small-cell lung cancer. The clinical specialists also commented that the small proportion of patients with EGFR mutations in the SATURN trial would be similar to the UK population. The Committee noted that no one in the SATURN trial had received first-line treatment with pemetrexed and cisplatin, which is now becoming a commonly used combination chemotherapy regimen for patients with non-squamous disease. It therefore concluded that there was uncertainty about the clinical benefit of erlotinib in patients who had previously received pemetrexed and cisplatin.

4.11 The Committee also noted that a high proportion of patients (72%) in the SATURN trial received a range of post-progression treatments, some of which would not be routinely used in the UK. It also noted that only a small proportion of patients in the placebo group had received erlotinib after progression. It considered that the post-progression treatments and the small proportion of patients in the placebo group who had received erlotinib after progression would affect the estimates of overall survival in the erlotinib and placebo groups. The Committee was aware that it is unclear whether patients would benefit most from receiving erlotinib as maintenance treatment or for treatment of relapsed disease. It was also aware that the small number of patients in the placebo group receiving erlotinib after progression could favour the erlotinib maintenance arm. The Committee also noted that patients in the SATURN trial were younger, had a better performance status and a longer duration of overall survival than would be seen in routine clinical practice in the UK. The Committee concluded that the relative effectiveness of erlotinib reported in the SATURN trial may be seen in clinical practice in the UK, but there was considerable uncertainty that the absolute gains of treatment seen in the trial would be translated into routine UK practice.

4.12 The Committee discussed the results of the SATURN trial for the stable disease population. It concluded that the trial showed that erlotinib was associated with a statistically significant improvement in progression-free survival and overall survival compared with placebo. It noted that the adverse events associated with erlotinib (most commonly, rash and diarrhoea) were well known and that most patients in the SATURN trial did not require their treatment to be changed or stopped because of adverse events.

Cost effectiveness

4.13 The Committee was aware that a patient access scheme had been proposed by the manufacturer. It noted that this is a simple scheme in which erlotinib is supplied to the NHS at a discount of 14.5% of the list price. The Committee concluded that it was appropriate to appraise the cost effectiveness of erlotinib maintenance treatment on the basis of ICERs that take into account this discount.

4.14 The Committee noted that the evidence for the cost effectiveness of erlotinib in patients with stable disease was based on the manufacturer’s economic evaluation in which the ICER was £47,743 per QALY gained. It considered the ERG’s critique of the analysis and considered that the factors that had the greatest effect on the ICER were the calculation of erlotinib and post-progression treatment costs, the progression-free survival utility value used and the approach used to model progression-free survival and overall survival.

4.15 The Committee considered the ERG’s revised cost calculations for erlotinib taking into account wastage, which increased the per-patient costs of erlotinib by £2000 and the ICER by £12,300 per QALY gained compared with the manufacturer’s base-case estimate for the stable disease population. It heard from the manufacturer that wastage was an important component of the revised cost calculations. The Committee heard from the manufacturer that they had patient level data from the SATURN trial which allow a more accurate estimation of wastage. This was about 9% in the trial, compared with 14% wastage estimated by the ERG. The Committee noted that patients enrolled in clinical trials are usually more compliant in taking their treatment than the general population and that wastage is likely to be between 9% and 14% in clinical practice. On balance, the Committee was persuaded that the costs of erlotinib in the manufacturer’s model had been underestimated and that the ERG’s revisions more closely estimated the true costs than those in the manufacturer's submission.

4.16 The Committee discussed the costs of post-progression treatments used in the manufacturer’s model. It noted the ERG’s concerns that the costs were based on the SATURN trial, which included very few UK patients and that many of the post-progression treatments in the trial were not recommended for use in the UK. The Committee considered the ERG’s revisions to the post-progression costs of treatment, in which a fixed cost per course of treatment was used (see section 3.12). It noted that this correction increased the ICER by £6,320 per QALY gained compared with the manufacturer’s base-case estimate. The Committee concluded that although there is considerable uncertainty about the true costs of post-progression treatments in UK clinical practice, they are likely to be closer to those calculated by the ERG than those in the manufacturer’s model.

4.17 The Committee considered the estimates of utility values assigned to different health states of the model. It agreed with the ERG’s concern about deriving utility values by mapping the FACT-L disease specific measure to the EQ-5D. Therefore the Committee considered the ERG’s revised utility values to be more appropriate and noted that these increased the QALYs by 0.0091, reducing the base-case ICER by £2,550 per QALY gained.

4.18 The Committee considered the method used by the manufacturer to model progression-free survival and overall survival. It noted the ERG’s criticism of this method and considered the ERG’s revised estimates of progression-free survival and overall survival to be plausible. It noted that the ERG’s estimates were higher than those estimated by the manufacturer and that these revisions had the effect of decreasing the manufacturer’s base-case ICER by between £169 and £2090 per QALY gained.

4.19 The Committee considered the cumulative impact of the ERG’s revisions to the manufacturer’s model. It noted that although some of the ERG’s revisions reduced the ICER for erlotinib compared with best supportive care in the subgroup of patients with stable disease, the combined effect of all revisions to the model was to increase the ICER from £47,700 in the manufacturer’s base case to £59,300 per QALY gained. The Committee concluded that this was the most plausible ICER.

4.20 The Committee considered 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.

4.21 The Committee considered that the life expectancy of patients with non-small-cell lung cancer who receive best supportive care after first-line chemotherapy is between 7 and 11 months. The Committee discussed the extension to life offered by erlotinib in the stable disease population. The manufacturer estimated the overall survival benefit for patients receiving erlotinib to be 3.3 months over placebo and the ERG estimated the overall survival benefit to be 4.2 months. However, the Committee noted that these were based on the modelled estimate of overall survival and that the actual duration of survival of patients in each treatment arm of the SATURN trial had not been provided in the manufacturer’s submission. The Committee did not consider the evidence provided by the manufacturer to be robust enough to meet the extension to life criterion. The Committee discussed the size of the population for whom erlotinib was licensed. The manufacturer estimated that about 3000 patients would be eligible for maintenance treatment with erlotinib (that is, patients with stable disease after first-line treatment). However, the Committee was aware that erlotinib was also licensed for second-line treatment of non-small-cell lung cancer and for treatment of metastatic pancreatic cancer. It considered that the total population for whom erlotinib was licensed was therefore not small enough to allow the end-of-life advice to apply.

4.22 The Committee was persuaded that the ERG’s revised ICER of £59,300 per QALY gained for erlotinib compared with best supportive care was the most plausible ICER and that despite some uncertainty about the estimation of erlotinib costs, the ICER would be well above £50,000 per QALY gained. The Committee had previously concluded that the end-of-life considerations did not apply to this appraisal, but it noted that even if they were taken into account, the most plausible ICER was higher than that normally considered to be cost effective. Therefore, the Committee concluded that erlotinib could not be considered a cost-effective use of NHS resources for the maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer who have stable disease following platinum-based chemotherapy.

TAXXX (STA)	Appraisal title: Erlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer	ACD section
Key conclusion
Erlotinib monotherapy is not recommended for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer with stable disease after platinum-based first-line chemotherapy. The Committee concluded that the SATURN trial showed that erlotinib was associated with a statistically significant improvement in progression-free survival and overall survival compared with placebo and that the adverse events associated with erlotinib were well known and could be tolerated by most patients. The Committee was persuaded that the most plausible ICER would be well above £50,000 per QALY gained. It concluded that erlotinib could not be considered a cost-effective use of NHS resources for the maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer who have stable disease following platinum-based chemotherapy.		1.1 4.12 4.22
Current practice
Clinical need of patients including the availability of alternative treatments	The Committee noted that the final appraisal determination issued for consultation recommends pemetrexed as an option for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology if disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel. The Committee noted that patients are only eligible for maintenance treatment with this drug if they have not received it as first-line treatment in combination with cisplatin. Therefore the number of patients who would be eligible for maintenance treatment would progressively decrease as more patients receive first-line treatment with pemetrexed.
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?	The Committee was aware that maintenance treatment after first-line treatment is still a relatively new concept in lung cancer and that its aim is to prolong the benefits of treatment and to maximise quality of life for as long as possible. The Committee noted that pemetrexed is an option for the maintenance treatment of people with non-squamous disease but best supportive care is currently the only option for patients with squamous disease.	4.5 4.4
What is the position of the treatment in the pathway of care for the condition?	The Committee was aware that during the course of the appraisal erlotinib had received a marketing authorisation for the maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer with stable disease after standard platinum-based first-line chemotherapy.	4.2
Adverse effects	The Committee noted views from patient experts that erlotinib is an oral drug with adverse events that are relatively well tolerated. The Committee noted that the adverse events associated with erlotinib (most commonly rash and diarrhoea) were well known and that most patients in the SATURN trial did not require their treatment to be changed or stopped because of adverse events.	4.7 4.12
Evidence for clinical effectiveness
Availability, nature and quality of evidence	The Committee noted that the only evidence for maintenance treatment with erlotinib in patients with stable disease came from one randomised controlled trial (SATURN).	4.9
Relevance to general clinical practice in the NHS	The Committee noted that no one in the SATURN trial had received first-line treatment with pemetrexed and cisplatin, which is now becoming a commonly used combination chemotherapy regimen for patients with non-squamous disease. It concluded that there was uncertainty about the clinical benefit of erlotinib in patients who had received this combination. The Committee noted that patients in the SATURN trial were younger, had a better performance status and a longer duration of overall survival than would be seen in routine clinical practice in the UK. It concluded that the relative effectiveness of erlotinib reported in the SATURN trial may be seen in clinical practice in the UK, but there was considerable uncertainty that the absolute gains of treatment seen in the trial would be translated into routine UK practice.	4.10 4.11
Uncertainties generated by the evidence	See ‘Relevance to general clinical practice in the NHS’.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness	None considered.
Estimate of the size of the clinical effectiveness including strength of supporting evidence	The Committee concluded that the SATURN trial showed that erlotinib was associated with a statistically significant improvement in progression-free survival and overall survival compared with placebo.	4.12
Evidence for cost effectiveness
Availability and nature of evidence	The Committee noted the evidence for the cost effectiveness of erlotinib in patients with stable disease was based on the manufacturer’s economic evaluation in which the ICER was £47,743 per QALY gained.	4.14
Uncertainties around and plausibility of assumptions and inputs in the economic model	The Committee was persuaded that the costs of erlotinib in the manufacturer’s model had been underestimated and that the ERG’s revisions more closely estimated the true costs than those in the manufacturer's submission. The Committee concluded that there is considerable uncertainty about the true costs of post-progression treatments in UK clinical practice, but that they are likely to be closer to those calculated by the ERG than those in the manufacturer’s model. The Committee noted the ERG’s criticism of the method used to model progression-free survival and overall survival and considered the ERG’s revised estimates of progression-free survival and overall survival to be plausible.	4.15 4.16 4.18
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 noted the ERG’s concern about deriving utility values by mapping the FACT-L disease specific measure to the EQ-5D and considered the ERG’s revised utility values, which decreased the ICER, to be more appropriate. None considered.	4.17
Are there specific groups of people for whom the technology is particularly cost-effective?	None considered.
What are the key drivers of cost effectiveness?	The Committee considered the factors that had the greatest effect on the ICER were the calculation of erlotinib and post-progression treatment costs, the progression-free survival utility value used and the approach used to model progression-free survival and overall survival.	4.14
Most likely cost-effectiveness estimate (given as an ICER)	The Committee considered the cumulative impact of the ERG’s revisions to the manufacturer’s model which increased the ICER from £47,700 in the manufacturer’s base case to £59,300 per QALY gained. The Committee concluded that this was the most plausible ICER.	4.19
Additional factors taken into account
Patient access schemes (PPRS)	The Committee noted that the proposed patient access scheme is a simple scheme in which erlotinib is supplied to the NHS at a discount of 14.5% of the list price.	4.13
End of life considerations	The Committee considered that the total population for whom erlotinib was licensed was not small enough to allow the end-of-life advice to apply. It noted that even if the supplementary advice on end-of-life treatments was taken into account, the most plausible ICER was higher than that normally considered to be cost effective. The Committee did not consider the evidence provided by the manufacturer to be robust enough to meet the extension to life criterion.	4.21, 4.22
Equalities considerations, SVJ	None considered.

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must 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. The NHS is not required to fund treatments that are not recommended by NICE.

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 report and costing template to estimate the savings and costs associated with implementation.

Implementation advice on how to put the guidance into practice and national initiatives 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

• Pemetrexed for the first-line treatment of non-small-cell lung cancer. NICE technology appraisal guidance 181 (2009). Available from www.nice.org.uk/guidance/TA181
• Gefitinib for the second-line treatment of locally advanced or metastatic non-small-cell lung cancer (terminated appraisal). NICE technology appraisal guidance 175 (2009). Available from www.nice.org.uk/guidance/TA175
• Erlotinib for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 162 (2008). Available from www.nice.org.uk/guidance/TA162
• Bevacizumab for the treatment of non-small-cell lung cancer (terminated appraisal). NICE technology appraisal 148 (2008). Available from www.nice.org.uk/guidance/TA148
• Pemetrexed for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 124 (2007). Available from www.nice.org.uk/guidance/TA124
• Lung cancer: the diagnosis and treatment of lung cancer. NICE clinical guideline 24 (2005). Available from www.nice.org.uk/guidance/CG24

Under development

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

• Pemetrexed for the maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance (publication expected June 2010).
• Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer. NICE technology appraisal guidance (publication expected July 2010).
• The diagnosis and treatment of lung cancer (update). NICE clinical guideline (publication expected March 2011).
• Erlotinib (in combination with bevacizumab) for the maintenance treatment of advanced or metastatic non-small-cell lung cancer. NICE technology appraisal guidance (publication expected June 2011).
• Cetuximab for the treatment of advanced non-small-cell lung 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 June 2013. 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.

Peter Clark
Chair, Appraisal Committee
June 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 Darren Ashcroft
Senior Clinical Lecturer, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Dr Matthew Bradley
Value Demonstration Director, AstraZeneca

Professor Usha Chakravarthy
Professor of Ophthalmology and Vision Sciences, The Queen’s University of Belfast

Professor Peter Clark (Chair)
Consultant Medical Oncologist, Clatterbridge Centre for Oncology

Dr Ian Davidson
Lecturer in Rehabilitation, The University of Manchester

Professor Simon Dixon
Professor of Health Economics, University of Sheffield

Dr Martin Duerden
Medical Director, Conwy Local Health Board

Dr Alexander Dyker
Consultant Physician, Wolfson Unit of Clinical Pharmacology

Dr Jon Fear
Consultant in Public Health Medicine, Head of Healthcare Effectiveness NHS Leeds

Professor John Hutton
Professor of Health Economics, University of York

Dr Steven Julious
Senior Lecturer in Medical Statistics, University of Sheffield

Professor Jonathan Michaels (Vice Chair)
Professor of Vascular Surgery, University of Sheffield

Professor Oluwafemi Oyebode
Professor of Psychiatry and Consultant Psychiatrist, The National Centre for Mental Health

Mr Mike Pinkerton
Chief of Business Development, The Rotherham NHS Foundation Trust

Dr Phillip Rutledge
GP and Consultant in Medicines Management, NHS Lothian

Dr Brian Shine
Consultant Chemical Pathologist, John Radcliffe Hospital

Mr Paddy Storrie
Lay Member

Dr Cathryn Patricia Thomas
GP and Associate Professor, The University of Birmingham

Mr Mike Wallace
Health Economics and Reimbursement Director, Johnson and Johnson Medical Ltd

Dr Lok Yap
Consultant in Acute Medicine and Clinical Pharmacology, Whittington Hospitals NHS Trust

C NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Sally Gallaugher
Technical Lead

Eleanor Donegan
Technical Adviser

Kate Moore
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by Liverpool Reviews and Implementation Group (LRIG):

• Bagust A, Boland A, Blundell M, et al. Erlotinib monotherapy for the maintenance treatment of non-small cell lung cancer after previous platinum-containing therapy. March 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, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Roche Pharmaceuticals

II Professional/specialist and patient/carer groups:

• Macmillan Cancer Support
• Roy Castle Lung Cancer Foundation
• British Thoracic Society
• National Lung Cancer Forum for Nurses
• Royal College of Nursing
• Royal College of Physicians’ Intercollegiate Lung Cancer Group
• United Kingdom Oncology Nursing Society

III Other consultees:

• NHS Cornwall and the Isles of Scilly
• Department of Health
• NHS Dudley
• Welsh Assembly Government

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

• NHS Quality Improvement Scotland
• Eli Lilly and Company
• British Thoracic Oncology Group
• Liverpool Reviews and Implementation Group (LRIG)
• National Institute for Health Research Health Technology Assessment Programme
• National Collaborating Centre for Cancer

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on erlotinib by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Professor David Ferry, Consultant Medical Oncologist, nominated by Eli Lilly and Company – clinical specialist
• Dr Diane Parry, Consultant Physician and Lung Cancer Lead, nominated by Welsh Assembly Government – clinical specialist
• Dr Yvonne Summers, Honorary Lecturer, nominated by Royal College of Physicians – clinical specialist
• Dr Clive Mulatero, Senior Lecturer in Medical Oncology, nominated by Royal College of Physicians – clinical specialist

D The following individuals were nominated as NHS Commissioning experts by the selected PCT allocated to this appraisal. They gave their expert/NHS commissioning personal view on erlotinib by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Caroline Court, Consultant in Public Health Medicine and Public Health Lead for Cancer, NHS Cornwall, selected by NHS Cornwall and Isles Of Scilly – NHS Commissioning expert

E Representatives from the following manufacturer/sponsor attended Committee Meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Roche Pharmaceuticals