1 Appraisal Committee's preliminary recommendations

1.1 Erlotinib is recommended as an option for treating locally advanced or metastatic non-small-cell lung cancer in people who have received non-targeted chemotherapy because of delayed confirmation that their tumour is epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation-positive, only if the manufacturer provides erlotinib with the discount agreed in the patient access scheme.

1.2 Gefitinib is recommended as an option for treating locally advanced or metastatic non-small-cell lung cancer in people who have received non-targeted chemotherapy because of delayed confirmation that their tumour is EGFR-TK mutation-positive, only if the manufacturer provides gefitinib at the fixed price agreed in the patient access scheme.

1.3 Erlotinib is not recommended for treating locally advanced or metastatic non-small-cell lung cancer in people with EGFR-TK mutation-negative tumours after the failure of at least 1 prior non-targeted chemotherapy regimen.

1.4 Erlotinib is recommended as an option for treating locally advanced or metastatic non-small-cell lung cancer that has progressed after chemotherapy in people with tumours of unknown EGFR-TK mutation status, only if:

• the result of a EGFR-TK mutation diagnostic test is unobtainable because of an inadequate tissue sample or poor quality DNA and
• the tumour is very likely to be EGFR-TK mutation-positive based on patient characteristics and
• the person's disease responds to the first 2 cycles of treatment with erlotinib and
• the manufacturer provides erlotinib with the discount agreed in the patient access scheme.

1.5 People currently receiving treatment initiated within the NHS with erlotinib that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.

 

2 Clinical need and practice

2.1 Approximately 32,000 people are diagnosed with lung cancer in England each year. Around 72% of lung cancers are non-small-cell lung cancers, which can be further classified into 3 histological sub-types: large-cell undifferentiated carcinoma, squamous cell carcinoma and adenocarcinoma. Most lung cancers are diagnosed in the later stages, with 21% of people presenting with locally and regionally advanced disease (stage IIIB) and 48% presenting with advanced disease (stage IV) in which the cancer has spread to other parts of the body. The 5-year survival rates for people presenting with stage IIIB or stage IV non-small-cell lung cancer are around 7–9% and 2–13% respectively.

2.2 Non-small-cell lung cancer can either test positive or negative for an epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation. EGFR-TK is a selective target for inhibiting cancer: in normal cells, EGFR-TK is controlled, but the overexpression of EGFR-TK caused by the mutation is considered a critical factor in the development and malignancy of non-small-cell lung cancer tumours. Overexpression of EGFR-TK has been detected in 10–15% of non-small-cell lung cancers.

2.3 For most people with non-small-cell lung cancer, the aims of therapy are to prolong survival and improve quality of life. For people with locally advanced or metastatic non-small-cell lung cancer that has relapsed after prior chemotherapy, Lung cancer (NICE clinical guideline 121) recommends that docetaxel monotherapy should be considered if second-line therapy is appropriate. Erlotinib for the treatment of non-small-cell lung cancer (NICE technology appraisal guidance 162) recommends erlotinib with a patient access scheme as a second-line treatment option for non-small-cell lung cancer as an alternative to docetaxel. It does not recommend erlotinib for the second-line treatment of locally advanced or metastatic non-small-cell lung cancer in patients for whom docetaxel is unsuitable (that is, where there is intolerance of or contraindications to docetaxel) or for third-line treatment after docetaxel therapy. In Gefitinib for the second-line treatment of locally advanced or metastatic non-small-cell lung cancer (terminated NICE technology appraisal 175) NICE was unable to make a recommendation for gefitinib as a second-line treatment option for people with non-small-cell lung cancer because the manufacturer did not provide an evidence submission.

2.4 Clinical practice has changed since the publication of Erlotinib for the treatment of non-small-cell lung cancer (NICE technology appraisal 162) because the identification of a tumour’s EGFR-TK mutation status has become an important prognostic factor. In the NHS, most people with non-small-cell lung cancer obtain a histological diagnosis for their tumour before first-line therapy to ensure that the most appropriate treatment regimen is considered. People with non-small-cell lung cancer are now also tested for EGFR-TK mutation status at diagnosis. NICE recommends first-line treatment with an EGFR-TK inhibitor (either erlotinib or gefitinib) in people with non-small-cell lung cancer whose tumour tests positive for EGFR-TK mutations (see Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer [NICE technology appraisal guidance 192] and Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer [NICE technology appraisal guidance 258]). In clinical practice, re-treatment with an EGFR-TK inhibitor is unlikely to be considered for patients whose tumour tests negative for EGFR-TK mutations and has progressed after first-line treatment. Consequently, EGFR-TK mutation status is increasingly being considered in the design of lung cancer clinical trials (for example, prospective recruitment of EGFR-TK mutation-positive or EGFR-TK mutation-negative populations, or using EGFR-TK mutation status as a stratification factor).

3 The technologies

Erlotinib

3.1 Erlotinib (Tarceva, Roche Products) is an inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK). It blocks the signal pathways involved in cell proliferation and helps to slow the growth and spread of tumours. Erlotinib has a UK marketing authorisation for the ‘treatment of patients with locally advanced or metastatic non-small-cell lung cancer after the failure of at least 1 prior chemotherapy regimen’.

3.2 The summary of product characteristics lists the following as the most common adverse reactions for erlotinib: infection, anorexia, keratoconjunctivitis sicca, conjunctivitis, dyspnoea, cough, diarrhoea, nausea, vomiting, stomatitis, abdominal pain, rash, pruritus, dry skin and fatigue. For full details of adverse reactions and contraindications, see the summary of product characteristics.

3.3 Erlotinib is given orally at a recommended dosage of 150 mg once daily. The cost for a 30-tablet pack of 150-mg tablets is £1631.53 (excluding VAT; ‘British National Formulary’ [BNF] edition 66). Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of erlotinib has agreed a patient access scheme with the Department of Health, with a simple discount applied at the point of purchase or invoice. The level of discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.

Gefitinib

3.4 Gefitinib (Iressa, AstraZeneca) is an EGFR-TK inhibitor. It blocks the signal pathways involved in cell proliferation and helps to slow the growth and spread of tumours. Gefitinib has a UK marketing authorisation for the treatment of adults with ‘locally advanced or metastatic non-small-cell lung cancer with activating mutations of EGFR-TK’.

3.5 The summary of product characteristics states that when assessing the EGFR-TK mutation status of a patient, it is important that a well-validated and robust method is chosen to avoid false-negative and false-positive determinations.

3.6 The summary of product characteristics lists the following as common and very common adverse reactions for gefitinib: diarrhoea, skin reactions, anorexia, conjunctivitis, blepharitis, dry eye, haemorrhage, interstitial lung disease, vomiting, nausea, stomatitis, dehydration, dry mouth, elevations in alanine aminotransferase, elevations in total bilirubin, nail disorder, alopecia, asymptomatic laboratory elevations in blood creatinine, proteinuria, cystitis and asthenia. For full details of adverse reactions and contraindications, see the summary of product characteristics.

3.7 Gefitinib is given orally at a recommended dosage of 250 mg once daily. The cost for a 30-tablet pack of 250-mg tablets is £2167.71 (excluding VAT; ‘British National Formulary’ [BNF] edition 66). Costs may vary in different settings because of negotiated procurement discounts. The manufacturer has agreed with the Department of Health a patient access scheme in which gefitinib for treating of non-small-cell lung cancer will be available at a single fixed cost of £12,200 per patient irrespective of the duration of treatment. The manufacturer will not invoice the NHS until the third monthly pack of gefitinib is supplied. This means that patients who need less than 3 months of treatment will not incur a charge. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.

4 Evidence and interpretation

The Appraisal Committee (section 8) considered evidence from a number of sources (section 9).

4.1 Clinical effectiveness

4.1.1 The Assessment Group conducted a systematic review of the literature to identify studies evaluating the clinical effectiveness and safety of erlotinib and gefitinib for treating adults with locally advanced or metastatic non‑small‑cell lung cancer that has progressed after prior chemotherapy. It identified 12 randomised controlled trials: 2 trials comparing erlotinib with docetaxel (DELTA, n=301; TAILOR, n=222), 1 trial comparing erlotinib with chemotherapy (TITAN, n=424), 1 trial comparing erlotinib with best supportive care (BR21, n=731), 1 trial comparing gefitinib with erlotinib (Kim et al. 2012, n=96), 6 trials comparing gefitinib with docetaxel (Bhatnagar et al. 2012, n=30; INTEREST, n=1466; ISTANA, n=161; Li et al. 2010, n=98; SIGN, n=141; V‑15‑32, n=490) and 1 trial comparing gefitinib with best supportive care (ISEL, n=1692). The Assessment Group did not identify any additional trials relevant to the scope that were not identified in the manufacturers’ submissions.

4.1.2 The Assessment Group commented that overall the trials were of reasonable methodological quality. Two of the studies were reported in conference abstracts (Bhatnagar et al. 2012; DELTA) and therefore limited details were available about each of the trial designs and methods used. The Assessment Group highlighted that, of the published randomised controlled trials, only BR21 and ISEL were double‑blind and the remaining randomised controlled trials were open‑label. In all of the published randomised controlled trials, patient characteristics were comparable between trial groups and included more than 80% of randomised patients in their final analyses. However, the Assessment Group noted that in Kim et al. (2012), the patient characteristics for the historical control group that was used to estimate the efficacy of erlotinib and gefitinib (rather than directly comparing both groups) were not reported. All but 1 of the published randomised controlled trials (Li et al. 2010) stated that an intention‑to‑treat analysis was conducted.

4.1.3 Five trials were conducted internationally, 1 was a multicentre trial in Italy (TAILOR) the remaining 6 trials were conducted in Asian countries (Bhatnagar et al. 2012; DELTA; ISTANA; Kim et al. 2012; Li et al. 2010; V‑15‑32), 3 of which were multicentre (DELTA; ISTANA; V‑15‑32). Across the trials, the dosages of erlotinib and gefitinib were consistent with the licensed dosages. In the 9 trials that included docetaxel as a comparator, the dosages were: 75 mg/m² every 3 weeks in 6 of the trials (Bhatnagar et al. 2012; INTEREST; ISTANA; Li et al. 2010; SIGN; TAILOR); 60 mg/m² every 3 weeks (which is the standard dose in Japan) in 2 of the trials (DELTA; V‑15‑32); and at the treating physician’s discretion in the TITAN trial. Because the choice of chemotherapy (docetaxel or pemetrexed) was at the discretion of the physician, patients were not randomised in the TITAN trial. The TITAN trial investigators only published aggregated outcomes for chemotherapy and considered any disaggregated comparison of erlotinib with docetaxel or pemetrexed to be unreliable. Across all 12 trials, median follow-up ranged from 7.2 months (ISEL) to 33 months (TAILOR).

4.1.4 The median age of patients in the randomised controlled trials ranged from 48 to 67 years. Most patients: were male (except for Kim et al. 2012); had stage IV disease (except for Li et al. 2010); had received 1 prior chemotherapy (except for BR21 and ISEL); and had a performance status of 0 or 1 assessed by the Eastern Cooperative Oncology Group (ECOG) scoring system. The main histological type across the randomised controlled trials was adenocarcinoma but the ratio of adenocarcinoma to other histological subtypes varied. Patients included in the Kim et al. (2012) and TAILOR trials were tested for EGFR-TK mutation status before study entry, but it was unclear if EGFR-TK status was known at the time of randomisation in the DELTA trial. The 6 randomised controlled trials conducted in Asia exclusively included patients of East Asian ethnicity but most patients included in the remaining trials were white (except for SIGN).

4.1.5 The Assessment Group considered the overall population (people whose tumours are of unknown EGFR-TK mutation status) and 2 subgroups based on EGFR-TK mutation status (positive or negative). Clinical practice has changed since the publication of Erlotinib for the treatment of non-small-cell lung cancer (NICE technology appraisal guidance 162) because the identification of a tumours EGFR-TK mutation status has become an important prognostic factor. Many of the published trials conducted in patients with non-small-cell lung cancer therefore did not consider mutation status in their design or recruitment, and consequently were limited to retrospective subgroup analyses of the EGFR-TK mutation-positive or EGFR-TK mutation-negative populations. The manufacturer of gefitinib focused its evidence submission on the EGFR-TK mutation-positive population because gefitinib is only licensed for this population. The Assessment Group also considered that the 3 trials published since the European Medicines Agency granted the marketing authorisation for gefitinib were not sufficiently robust to make recommendations that could result in a change to current clinical practice (Bhatnagar et al. 2012; Kim et al. 2012; Li et al. 2010).

EGFR-TK mutation-positive population

Erlotinib

4.1.6 No trials of erlotinib were identified by the Assessment Group that were solely conducted in an EGFR-TK mutation-positive population. Two trials were identified that reported retrospective subgroup analyses of the EGFR-TK mutation-positive population (BR21; TITAN). Only 1 of the 2 trials reported results for progression‑free survival. No statistically significant differences in median progression‑free survival were found for erlotinib compared with docetaxel or pemetrexed (TITAN: median progression‑free survival in months not reported; hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.13 to 3.97). No statistically significant differences in median overall survival were found for erlotinib compared with:

• best supportive care (BR21: 10.9 months for erlotinib compared with 8.3 months for best supportive care; HR 0.55; 95% CI 0.25 to 1.19)
• docetaxel or pemetrexed (TITAN: 19.3 months for erlotinib, not reported for docetaxel or pemetrexed; HR 1.19; 95% CI 0.12 to 11.49).

Gefitinib

4.1.7 The Assessment Group did not identify any trials of gefitinib that were conducted solely in an EGFR-TK mutation-positive population. Four trials were identified that retrospectively reported a subgroup analysis of the EGFR-TK mutation-positive population (INTEREST; ISEL; Kim et al 2012; V‑15‑32). Limited data for progression‑free survival were available. The INTEREST trial showed statistically significantly longer median progression-free survival for patients receiving gefitinib than those receiving docetaxel (7 months compared with 4.1 months; HR 0.16; 95% CI 0.05 to 0.49). A smaller proportion of patients treated with gefitinib experienced disease progression compared with best supportive care in the ISEL trial (11 out of 21 patients compared with 4 out of 5 patients; median progression-free survival not reported; HR not reported).

4.1.8 No statistically significant differences in median overall survival were found between gefitinib and docetaxel in the INTEREST trial (14.2 months compared with 16.6 months respectively; HR 0.83; 95% CI 0.41 to 1.67). A smaller proportion of patients treated with gefitinib died compared with best supportive care in the ISEL trial (7 out of 21 patients compared with 3 out of 5 patients; median overall survival not reported; HR not reported). The manufacturer of gefitinib also presented the results of a post hoc analysis comparing patients whose disease had progressed on chemotherapy (paclitaxel and carboplatin) in the first-line IPASS trial and received subsequent EGFR-TK inhibitor treatment (n=83) with those who did not receive subsequent EGFR-TK inhibitor treatment (n=46). Median overall survival was lower in patients who did not receive subsequent EGFR-TK inhibitor treatment compared with patients who did (the manufacturer labelled the data as academic in confidence, so it cannot be presented here). The Assessment Group stated that the median overall survival results for patients treated with subsequent EGFR-TK inhibitor treatment after prior chemotherapy reported in the manufacturer’s post hoc analysis of the IPASS trial were longer than estimates previously reported in trials of gefitinib, erlotinib or chemotherapy treatment and therefore this finding needs to be validated by evidence from an independent randomised controlled trial because it would represent an important therapeutic advance.

4.1.9 Three of the 4 trials that retrospectively reported a subgroup analysis of the EGFR-TK mutation-positive population presented response rates for each treatment group (INTEREST; Kim et al. 2012; V‑15‑32). Results suggested that patients randomised to receive gefitinib had a higher response rate compared with those randomised to receive docetaxel or erlotinib, but results of statistical significance were only presented in 1 trial (INTEREST, gefitinib compared with docetaxel; p=0.04).

EGFR-TK mutation-negative population

Erlotinib

4.1.10 Four trials of erlotinib were identified by the Assessment Group that included patients known to be EGFR-TK mutation-negative (TAILOR), patients with and without EGFR-TK mutations whose EGFR-TK status was known before randomisation (DELTA), or patients whose EGFR-TK status was retrospectively reported in a subgroup analysis of the EGFR-TK mutation-negative population (BR21; TITAN).

4.1.11 Three of the 4 trials reported results for median progression‑free survival. This was statistically significantly lower with erlotinib compared with docetaxel in 2 of the 3 trials (TAILOR: 2.4 months compared with 2.9 months; HR 1.39; 95% CI 1.06 to 1.82, DELTA: 1.3 months compared with 2.9 months; HR 1.44; 95% CI 1.08 to 1.92). In the remaining trial, no statistically significant differences in median progression‑free survival were estimated between patients randomised to erlotinib compared with patients randomised to either docetaxel or pemetrexed (TITAN: median progression-free survival in months not reported; HR 1.25; 95% CI 0.88 to 1.78).

4.1.12 No statistically significant differences in overall survival were estimated between erlotinib compared with:

• best supportive care (BR21: 7.9 months for erlotinib compared with 3.3 months for best supportive care; HR 0.74; 95% 0.52 to 1.05)
• docetaxel (TAILOR: 5.4 months for erlotinib compared with 8.2 months for docetaxel; HR 1.28; 95% CI 0.95 to 1.96, DELTA: 9.0 months for erlotinib compared with 9.2 months for docetaxel; HR 0.98; 95% CI 0.69 to 1.39)
• docetaxel or pemetrexed (TITAN: 6.6 months for erlotinib compared with 4.4 months for docetaxel or pemetrexed; HR 0.85; 95% CI 0.59 to 1.22).

Only the TAILOR trial reported the response rates for each treatment group and the results showed a statistically significantly lower response rate for erlotinib compared with docetaxel (3.0% compared with 15.5%; p=0.003).

4.1.13 Because the TAILOR trial (conducted in 52 hospitals in Italy) is the only published study providing head‑to‑head evidence for erlotinib and docetaxel in the EGFR-TK mutation-negative population, the Assessment Group further considered its relevance to clinical practice in England. It noted that:

• Two regimens of docetaxel were administered (either 75 mg/m² every 3 weeks or weekly infusions of 35 mg/m²), and the latter regimen would not be used in clinical practice in England.
• A poorer performance status is linked to poorer outcomes, and a higher proportion of patients with a performance status of 2 would be treated in routine clinical practice in England than included in the TAILOR trial (7%).
• There are differences in other important prognostic factors between the erlotinib and docetaxel treatment groups that are possible modifiers of trial outcome in favour of docetaxel, including people who have: never smoked (17% compared with 27%); squamous cell histology (28% compared with 21%); and adenocarcinoma histology (63% compared with 75%).
• The manufacturer of erlotinib considered the rates of haematological toxicity in the docetaxel group to be low compared with other trials. The manufacturer commented that this may be related to the inclusion of a fitter patient population or the use of weekly treatment schedules. However, the Assessment Group considered that because docetaxel has been used for many years it is likely that its associated adverse reactions are better managed and more frequently avoided than in the past because of increased clinical awareness.

The Assessment Group concluded that the TAILOR study is a large, high-quality randomised controlled trial, but it is uncertain about the extent to which it reflects clinical practice in England and whether the results are likely to be mirrored in the clinical population. The Assessment Group also noted that the primary end point of TAILOR changed at the first planned interim analysis from ‘biomarkers of EGFR-TK amplification, protein expression and KRAS mutations’ to ‘overall survival’ because these biomarkers were found to have no effect.

Gefitinib

4.1.14 Gefitinib is not licensed for the treatment of adult patients with locally advanced or metastatic non‑small‑cell lung cancer whose tumours test negative for EGFR-TK mutations (see section 3.4). NICE can only appraise treatments within their licensed indications, so the trial evidence available for gefitinib in this population is not applicable to this technology appraisal.

EGFR-TK mutation-unknown population

Erlotinib

4.1.15 Three trials of erlotinib were identified by the Assessment Group that presented outcome data for the EGFR-TK mutation-unknown population. No statistically significant differences in median progression‑free survival were estimated between erlotinib and docetaxel (DELTA: 2.0 months compared with 3.2 months respectively; HR 1.22; 95% CI 0.97 to 1.55) and erlotinib compared with either docetaxel or pemetrexed (TITAN: 6.3 weeks compared with 8.6 weeks respectively; HR 1.19; 95% CI 0.97 to 1.46). The BR21 trial showed a statistically significantly longer median progression‑free survival with erlotinib compared with best supportive care (2.2 months compared with 1.8 months respectively; HR 0.61; 95% CI 0.51 to 0.74).

4.1.16 No statistically significant differences in median overall survival were estimated between erlotinib compared with docetaxel (DELTA: 14.8 months compared with 12.2 months respectively; HR 0.91; 95% CI 0.68 to 1.22) and erlotinib compared with either docetaxel or pemetrexed (TITAN: 5.3 months compared with 5.5 months respectively; HR 0.96; 95% CI 0.78 to 1.19). The BR21 trial showed a statistically significantly longer median overall survival with erlotinib compared with best supportive care (6.7 months compared with 4.7 months; HR 0.7; 95% 0.58 to 0.85).

4.1.17 Response rates were reported for 2 of the 3 trials (BR21; TITAN). The response rates were higher for erlotinib compared with best supportive care (BR21: 8.9% compared with <1%) and erlotinib compared with either docetaxel or pemetrexed (TITAN: 7.9% compared with 6.3%).

4.1.18 Patients treated with erlotinib experienced a statistically significantly higher health‑related quality of life score compared with patients receiving best supportive care when measured by the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) in the BR21 trial. No statistically significant differences in health‑related quality of life were estimated between erlotinib and docetaxel when measured by the Functional Assessment of Cancer Therapy-Lung (FACT‑L) questionnaire in the TITAN trial.

4.1.19 The manufacturer of erlotinib stated that the most common grade 3 to 4 adverse reactions associated with erlotinib are skin rash (approximately 5–9%) and diarrhoea (approximately 0.6–6%) but are easily manageable. It commented that life‑threatening adverse reactions are very rare and erlotinib is better tolerated than chemotherapy. The Assessment Group stated that it considered that the adverse reactions reported in the trials appear to be consistent with the information available for erlotinib in its summary of product characteristics (see section 3.2).

Gefitinib

4.1.20 Gefitinib is only licensed for treating adult patients with locally advanced or metastatic non‑small‑cell lung cancer who test positive for EGFR-TK mutations (see section 3.4). NICE can only appraise treatments within their licensed indications, therefore the trial evidence available for gefitinib in the EGFR-TK mutation-unknown population is not applicable to this technology appraisal.

Mixed treatment comparison

4.1.21 The manufacturers and the Assessment Group did not conduct a mixed treatment comparison. The manufacturer of gefitinib and the Assessment Group commented that it would be inappropriate to estimate the relative treatment effectiveness of erlotinib or gefitinib using a mixed treatment comparison because the presence of heterogeneity in important clinical factors between the trials would be likely to increase rather than reduce uncertainty. Clinical and statistical weaknesses stated by the Assessment Group that precluded conducting a mixed treatment comparison included:

• Patient characteristics between trials that were not considered sufficiently similar. For example, ethnicity (Asian populations compared with non-Asian populations), the proportion of patients with a performance status of 0 or 1 compared with a performance status of 2 or more, and the proportion of patients who had received 1 prior chemotherapy compared with 2 or more prior chemotherapies.
• A lack of outcome data for each of the patient populations.
• Several trials that only reported either unadjusted or adjusted analyses, and combining these results, may not be directly comparable.
• The use of a Cox proportional hazards model to estimate hazard ratios in trials of erlotinib and gefitinib compared with the comparator treatment appeared to be violated in 6 of the trials because the Kaplan‑Meir plot crossed, which is a sufficient condition to reject proportionality.

4.2 Cost effectiveness

Published studies

4.2.1 The Assessment Group carried out a systematic review of existing cost-effectiveness evidence and identified 11 papers for inclusion in its review, but did not quality assess these studies because they were not directly relevant to UK decision-making. Only the manufacturer of erlotinib provided an economic model to support its submission. Both the manufacturer of erlotinib and the Assessment Group’s economic models only considered the population with EGFR-TK mutation-unknown status and 1 of the 2 subgroups relevant to the technology appraisal (that is, the EGFR-TK mutation-negative population). The EGFR-TK mutation-positive population was not considered because no trials were identified that solely assessed the relative effectiveness of erlotinib or gefitinib for treating non‑small‑cell lung cancer that has progressed after prior chemotherapy in this population (see sections 4.1.6 and 4.1.7). This meant it was not possible to assess the cost effectiveness of gefitinib because it is only licensed for the treatment of EGFR-TK mutation-positive locally advanced or metastatic non‑small‑cell lung cancer.

Manufacturer's economic model (Roche Products: erlotinib)

4.2.2 The manufacturer submitted a partitioned survival model that only assessed the cost effectiveness of erlotinib compared with best supportive care. The manufacturer stated that it was not possible to demonstrate that erlotinib is cost effective compared with docetaxel following the availability of generic docetaxel and so this comparison was excluded from the analyses. The manufacturer conducted the economic analysis from an NHS and personal social services perspective and the model had a cycle length of 1 week and a time horizon of 6 years. Costs and health effects were discounted at an annual rate of 3.5%.

4.2.3 The manufacturer’s economic model included 3 health states: progression‑free disease, progressed disease and death. The population was assumed to be the same as that recruited to the BR21 trial, and data from this study were used to estimate progression‑free survival and overall survival. No extrapolation of progression-free survival data was required because by 18 months all patients on best supportive care had disease progression and only 2 patients on erlotinib had progression-free disease. These 2 patients were assumed to experience disease progression at the next cycle. For overall survival, data were extrapolated from weeks 70 and 78 for erlotinib and best supportive care respectively.

4.2.4 The manufacturer’s economic model incorporated the patient access scheme for erlotinib and took into account the mean treatment duration based on the BR21 trial (19.57 weeks). Other costs considered in the manufacturer’s economic model were related to: a pharmacist dispensing a prescription of erlotinib every 30 days (£18.20); supportive care for progression-free disease (£85 per week) and progressed disease (£220 per week); and managing adverse reactions (the manufacturer only included adverse reactions that occurred in more than 5% of patients in the BR21 trial).

4.2.5 The manufacturer used pooled chemotherapy EQ-5D utility values from the PROFILE‑1007 trial of crizotinib for both the erlotinib and best supportive care treatment groups (see Crizotinib for previously treated non-small-cell lung cancer associated with an anaplastic lymphoma kinase fusion gene [NICE technology appraisal guidance 296]). The manufacturer noted that the utility values were relatively high for people with non‑small-cell lung cancer and that the population in PROFILE‑1007 included anaplastic lymphoma kinase (ALK)-positive patients who were younger and less fit than patients enrolled in the BR21 trial. The utility values used for the progression‑free disease and progressed disease health states were 0.747 and 0.610 respectively.

4.2.6 The manufacturer presented deterministic pairwise incremental cost‑effectiveness ratios (ICERs) for erlotinib compared with best supportive care for: the overall population (EGFR-TK mutation‑unknown); and a subgroup analysis of the EGFR-TK mutation-negative population. For the overall population, the manufacturer’s economic model estimated incremental costs and incremental quality‑adjusted life years (QALYs) of £7529 and 0.148 respectively, resulting in an ICER of £51,036 per QALY gained. For the EGFR-TK mutation-negative population, the incremental costs and incremental QALYs were £7490 and 0.128 respectively, resulting in an ICER of £58,579 per QALY gained.

4.2.7 The manufacturer carried out univariate sensitivity analysis to determine the impact on the ICER from changes in the parameters included in its economic model for the EGFR-TK mutation-unknown population. The results of the univariate sensitivity analysis showed that the ICER was most sensitive to changes in the utility values used for the ‘progression‑free disease’ and ‘progressed disease’ health states. The manufacturer also presented the results of a probabilistic sensitivity analysis that showed that at £30,000 per QALY gained, there is a 0% probability of erlotinib being cost effective compared with best supportive care in the EGFR-TK mutation-unknown population. The probabilistic sensitivity analysis estimated incremental costs and incremental QALYs of £7490 and 0.147 respectively, resulting in an ICER of £50,825 per QALY gained. The manufacturer did not carry out any sensitivity analyses for its economic model that included the EGFR-TK mutation-negative population.

Assessment Group's economic model

4.2.8 The Assessment Group did not undertake a detailed examination of the manufacturer’s economic model. Instead it developed a partitioned survival model to assess the cost effectiveness of erlotinib compared with:

• best supportive care in the EGFR-TK mutation-unknown population
• docetaxel in the EGFR-TK mutation-negative population
• best supportive care in the EGFR-TK mutation-negative population.

4.2.9 The model had a cycle length of 3 days and a lifetime time horizon. The model included 3 health states: progression‑free disease, progressed disease and death. The Assessment Group conducted the economic analysis from an NHS and personal social services perspective. Costs and health effects were discounted at an annual rate of 3.5% and a half-cycle correction was applied.

4.2.10 Using the manufacturer’s Kaplan‑Meier data from the intent-to-treat analysis of the BR21 trial, the Assessment Group estimated progression‑free survival and overall survival for the EGFR-TK mutation‑unknown population treated with erlotinib and best supportive care. The Assessment Group noted that the use of standard parametric functions were not appropriate because they assumed a single continuous disease and treatment effect throughout the duration of the trial, and data from BR21 showed that different disease and treatment effects were occurring during certain periods of the trial. Therefore it fitted a piecewise survival model with 3 phases after examining the cumulative hazard plots. The Assessment Group chose a 'piecewise approach' to reflect the change in event risk it observed: after treatment had started (erlotinib); and after disease progression when treatment stops. The Assessment Group noted that the transitions between phases in the treatment groups occur at different time points between the first 2 phases but at a common time point between phases 2 and 3. The event risk (progression or death) within each phase was found to be approximately constant in both treatment groups and for both the progression‑free survival and overall survival models, the long‑term event risk (phase 3) showed the same hazard rate for both groups in the trial.

4.2.11 The Assessment Group used published Kaplan‑Meier data from the TAILOR trial to estimate progression‑free survival and overall survival for patients treated with erlotinib and docetaxel in the EGFR-TK mutation-negative subgroup. The Assessment Group noted that the progression‑free survival and overall survival data from the TAILOR trial showed similar relationships to that observed in the BR21 trial and therefore applied a similar 3‑phase piecewise model. The Assessment Group explained that:

• in the first phase the event risks were very similar in both treatment groups
• in the second phase, patients in both treatment groups had an increased event risk compared with their event risk in the first phase, but the event risk was different for patients treated with erlotinib and patients treated with docetaxel leading to the survival curves diverging
• in the final phase the event risks reduced substantially in both treatment groups.

It commented that the transitions between phases occurred at similar times from randomisation in both treatment groups. The main structural differences between the survival models for each treatment group were observed in the final phase. The Assessment Group stated that the event risk for progression‑free survival remained higher in the erlotinib group, suggesting that progression‑free survival outcomes continued to diverge indefinitely. For overall survival, the mortality risk stabilised at the same level between treatment groups once all patients experienced disease progression, suggesting that post‑progression survival is unrelated to previous treatments.

4.2.12 Using the manufacturer’s data from the post hoc subgroup analysis of the BR21 trial, the Assessment Group were able to estimate progression‑free survival and overall survival for the EGFR-TK mutation-negative population treated with erlotinib and best supportive care. The Assessment Group commented that the analysis for the EGFR-TK mutation-negative population was less reliable than the results for the EGFR-TK mutation‑unknown population because of the risk of imbalances between baseline patient characteristics and its smaller sample size.

4.2.13 The Assessment Group’s economic model included the patient access scheme for erlotinib. The cost of generic docetaxel was taken from the electronic Market Information Tool (eMIT), which includes information on the average prices paid by approximately 95% of NHS trusts in England for generic medicines. Therefore the eMIT price reflected the price of docetaxel relevant to the NHS. The dose of docetaxel was also estimated based on mean body surface area for males and females, and a weighted average cost used. Resource use and unit costs for administering erlotinib and docetaxel were based on a nurse‑led outpatient visit and in the day‑case setting respectively. For the comparison of erlotinib with docetaxel, the Assessment Group assumed that treatment continued until disease progression or death. For the comparison of erlotinib with best supportive care, the mean treatment duration was based on the BR21 trial data but the Assessment Group noted that no statistically significant differences were estimated between the length of progression‑free survival and the time‑on‑treatment. Other costs considered in the Assessment Group’s economic model were related to: supportive care for progression-free disease (£72 per week), progressed disease (£135 per week) and for terminal disease assumed to last 14 days per patient (£3952 per patient); and managing adverse reactions.

4.2.14 The Assessment Group noted several concerns with the utility values from the PROFILE‑1007 trial used by the manufacturer:

• Results were not published or peer reviewed.
• No assessment of bias was possible because no information was available on the patients completing the EQ-5D.
• The utility values included the effects of treatment‑related adverse reactions for a treatment not considered in this technology appraisal and are measured in a different population (adults with non‑small‑cell lung cancer associated with an ALK fusion gene).

The Assessment Group used alternative utility values from Nafees et al. (2008), which were measured in a sample of the UK general population (n=100) using the standard gamble technique. The Assessment Group adjusted the utility values for progression-free disease for each treatment based on the degree of response and the incidence of adverse reactions. This provided utility values of 0.6450 and 0.6225 for the ‘progression‑free disease’ health state for erlotinib and docetaxel respectively in the EGFR-TK mutation-negative subgroup, and 0.6351 and 0.6353 for erlotinib and best supportive care respectively in the EGFR-TK mutation‑unknown population and the EGFR-TK mutation-negative subgroup. Utility values for the ‘progressed disease’ health state and the ‘terminal period’ (last 2 weeks of life) were independent of treatment: 0.4734 and 0.2488 respectively. In its base case, no adjustment to the utility values was made by the Assessment Group to reflect potential differences in patient preferences for oral therapy compared with intravenous therapy.

4.2.15 The Assessment Group’s economic model included costs and disutilities associated with 7 adverse reactions: diarrhoea, fatigue, neutropenia, febrile neutropenia, hair loss, nausea and skin rash. The Assessment Group pooled the available grade 3 and 4 adverse reaction data from all published trials to estimate the incidence rate for each adverse reaction in the EGFR-TK mutation-unknown population. It used the incidence rate for each adverse reaction from the TAILOR trial for the EGFR-TK mutation-negative population.

4.2.16 Deterministic pairwise ICERs were presented in the Assessment Group’s base-case analyses. In the analysis for erlotinib compared with best supportive care for the EGFR-TK mutation‑unknown population, the Assessment Group’s economic model estimated an incremental overall survival benefit of 2.1 months, of which 1.7 months occurred before disease progression. The estimated incremental costs and incremental QALYs were £6314 and 0.103 respectively, resulting in an ICER of £61,132 per QALY gained. The results of the univariate sensitivity analysis showed that the ICER was not sensitive to changes in most parameters. The ICER was most sensitive to changes in baseline utility value for ‘progression‑free disease’ taken from Nafees et al. (2008). The Assessment Group carried out a probabilistic sensitivity analysis that showed that at £30,000 per QALY gained, there is a 0% probability of erlotinib being cost effective compared with best supportive care in the EGFR-TK mutation‑unknown population. The Assessment Group estimated a probabilistic ICER of £59,973 per QALY gained.

4.2.17 The Assessment Group’s base-case analysis for erlotinib compared with docetaxel for the EGFR-TK mutation-negative subgroup estimated an incremental overall survival loss of 2.5 months, of which 1.5 months occurred before disease progression. It estimated incremental cost savings of £1653 and an incremental QALY loss of 0.108. Despite the availability of generic docetaxel, the total costs per patient were higher for docetaxel compared with erlotinib because of increased costs for treatment administration and managing adverse reactions. For erlotinib compared with docetaxel, the Assessment Group estimated an ICER of £15,359 saved per QALY lost (that is, erlotinib was less effective but also less costly than docetaxel). The results of the univariate sensitivity analysis showed that the ICER was not sensitive to changes in most parameters. The ICER was most sensitive to changing the incidence and cost of febrile neutropenia. The Assessment Group carried out a probabilistic sensitivity analysis that showed that at £30,000 per QALY gained, there is a 9% probability of erlotinib being cost effective compared with docetaxel in the EGFR-TK mutation-negative population. For erlotinib compared with docetaxel, the Assessment Group estimated a probabilistic ICER of £12,719 saved per QALY lost.

4.2.18 Additional exploratory analyses were undertaken before the first Appraisal Committee meeting because the ICER estimated in the Assessment Group’s economic model, for erlotinib compared with docetaxel in the EGFR-TK mutation-negative population, was highly sensitive to the incidence and cost of febrile neutropenia. This exploratory analysis estimated the impact to the Assessment Group’s base-case ICER from changing the incidence and cost of febrile neutropenia to the values reported by the NICE Decision Support Unit in the appraisal of Erlotinib for the treatment of non-small-cell lung cancer (NICE technology appraisal guidance 162). The NICE Decision Support Unit reported that: the incidence of febrile neutropenia was 5.95% for patients treated with docetaxel based on a random effects meta-analysis of 13 trials of docetaxel (including different regimens); and the cost per episode of febrile neutropenia was approximately £2286. Changing the incidence of febrile neutropenia in the docetaxel group from 3.85% to 5.95% but using the cost per episode from the Assessment Group’s base-case analysis (£5048), resulted in the Assessment Group’s base-case ICER increasing from £15,359 saved per QALY lost to £28,520 saved per QALY lost respectively. Changing the cost per episode of febrile neutropenia from £5048 to £2286 but using the incidence of febrile neutropenia from the Assessment Group’s base-case analysis (3.85% as reported in the TAILOR trial), resulted in the Assessment Group’s base-case ICER decreasing from £15,359 saved per QALY lost to £2,400 saved per QALY lost respectively. Changing both the incidence of febrile neutropenia in the docetaxel group and the cost per episode of febrile neutropenia from the values used in the Assessment Group’s base-case analysis to the values reported by the NICE Decision Support Unit, resulted in the Assessment Group’s base-case ICER decreasing from £15,359 saved per QALY lost to £8,328 saved per QALY lost respectively.

4.2.19 The Assessment Group conducted a scenario analysis exploring the potential impact of including a utility benefit associated with delivery of oral treatment, given that oral therapies are generally more preferable to patients than intravenous therapies. This scenario analysis is only relevant to the comparison of erlotinib (oral) with docetaxel (intravenous) and the utility benefit is intended to represent a reduction in pain, anxiety and disruption to everyday activities caused by switching to an oral treatment. The Assessment Group’s scenario analysis assumed that the utility value for the progression-free disease health state for erlotinib was equal to that of the general population at the equivalent mean age. This resulted in the ‘progression-free disease’ utility value for patients treated with erlotinib increasing from 0.645 to 0.8. When erlotinib was compared with docetaxel in the EGFR-TK mutation-negative subgroup the estimated ICER increased from £15,359 to £26,176 saved per QALY lost. The Assessment Group concluded that this scenario analysis is extremely optimistic and indicates that any realistic estimation of utility benefit associated with oral delivery is very unlikely to have a significant impact on the size of the estimated ICER when comparing docetaxel with erlotinib.

4.2.20 The Assessment Group’s base-case analyses for erlotinib compared with best supportive care for the EGFR-TK mutation-negative subgroup estimated an incremental overall survival benefit of 2.2 months and estimated that all of the survival benefit occurred before disease progression. It estimated incremental costs and incremental QALYs of £6362 and 0.116 respectively, resulting in an ICER of £54,687 per QALY gained. The results of the univariate sensitivity analysis showed that the ICER was most sensitive to changes in the choice of survival model parameters (especially for overall survival) and utility values. The Assessment Group carried out a probabilistic sensitivity analysis that showed that at £30,000 per QALY gained, there is a 0% probability of erlotinib being cost effective compared with best supportive care in the EGFR-TK mutation-negative population. The Assessment Group estimated a probabilistic ICER of £54,184 per QALY gained.

4.3 Consideration of the evidence

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

4.3.2 The Committee heard from the clinical specialists and patient expert about the nature of locally advanced and metastatic non-small-cell lung cancer that has progressed after prior chemotherapy. The patient expert emphasised that extending survival and improving quality of life are important to people with non-small-cell lung cancer, as is spending less time at the hospital because they have a short life expectancy. The clinical specialist commented that the number of people with non-small-cell lung cancer that has progressed after prior chemotherapy who are of good fitness is generally low, and very few of these patients have an ECOG performance status score of 0 or 1. First-line chemotherapy is suitable for only 50% of patients with a performance status of 2 and subsequently 25% of this population will go on to receive further treatment. The Committee recognised the importance of having clinically effective and tolerable treatment options that people with non-small-cell lung cancer.

4.3.3 The Committee discussed the role of EGFR-TK mutation testing. It was aware that the identification of a tumour’s EGFR-TK mutation status has recently become an important prognostic factor and determines treatment choice in the first-line setting. The clinical specialists stated that most patients now have a mutation test before starting first-line treatment and emphasised the importance of testing all patients. They explained that the time to diagnosis of EGFR-TK mutation status (and consequently treatment initiation) generally ranges from 7 to 10 days but varies between regions partly because some patients are managed at several hospitals rather than at 1 hospital. The clinical specialists further noted that at diagnosis and initiation of subsequent treatments, the patient is informed that EGFR-TK inhibitors are a targeted therapy for tumours that test positive for EGFR-TK mutations. The Committee concluded that a timely diagnosis of EGFR-TK mutation status has an important role in ensuring that patients are given the most appropriate treatment.

4.3.4 The Committee considered the clinical pathway for the EGFR-TK mutation-positive population. The clinical specialists stated that most patients receive an EGFR-TK inhibitor (that is, erlotinib or gefitinib) as first-line treatment in line with Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (NICE technology appraisal guidance 192) and Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer (NICE technology appraisal guidance 258). The Committee was aware that gefitinib only has a marketing authorisation for treating the EGFR-TK mutation-positive population. The clinical specialists commented that erlotinib and gefitinib are very similar treatments with comparable efficacy and side effects. The Committee also heard from the clinical specialists that the adverse reactions associated with both these treatments are much less common than those associated with chemotherapy, although rash may be more common with erlotinib and interstitial lung disease may be more common with gefitinib. The clinical specialists stated that the use of EGFR-TK inhibitors for re-treating non-small-cell lung cancer after the failure of first-line EGFR-TK inhibitor treatment is not common in clinical practice in England because of reduced sensitivity of the tumour to these treatments. They further noted that the EGFR-TK mutation-positive population generally includes people who have never smoked and who are younger and fitter than the EGFR-TK mutation-negative population, which means platinum doublet chemotherapy is still suitable for them after first-line treatment. The Committee understood from the clinical specialists that some patients have stable disease and it is possible to wait for 2 weeks for the diagnostic test result, but a small proportion of the EGFR-TK mutation-positive population who do not receive a timely diagnosis need immediate treatment because their disease is progressing. The clinical specialists explained that these patients will complete a course of platinum doublet chemotherapy and receive an EGFR-TK inhibitor thereafter, that is, in effect second-line. The Committee concluded that although most patients with EGFR-TK mutation-positive tumours receive first-line treatment with an EGFR-TK inhibitor and their disease is unlikely to be re-treated with these agents, a small number of patients may receive a delayed diagnosis of EGFR-TK mutation status. For this subgroup, subsequent treatment with an EGFR-TK inhibitor after prior chemotherapy is considered appropriate in clinical practice.

4.3.5 The Committee considered the clinical pathway for the EGFR-TK mutation-negative population. The Committee understood from the clinical specialists that the EGFR-TK mutation-negative population receive first-line treatment with platinum doublet chemotherapy and not EGFR-TK inhibitors. The Committee was aware that gefitinib does not have a UK marketing authorisation for treating the EGFR-TK mutation-negative population. The clinical specialists explained that the choice of treatment in patients whose non-small-cell lung cancer has progressed after prior chemotherapy depends on their performance status. Patients with a performance status of 0 or 1 are offered a choice between erlotinib and docetaxel in line with Erlotinib for the treatment of non-small-cell lung cancer (NICE technology appraisal guidance 162). The Committee heard from the clinical specialists that in clinical practice docetaxel is preferred despite its toxicity because, in their opinion, docetaxel is clinically effective compared with erlotinib. However, the clinical specialists acknowledged that some clinicians and patients prefer erlotinib despite its mechanism of action being targeted at EGFR-TK mutation-positive tumours. They confirmed that in clinical practice, docetaxel is not suitable for patients with a performance status of 2 (that is, less fit than patients with a performance status of 0 or 1) because of the drug’s toxicity and therefore these people are offered erlotinib or best supportive care. The Committee noted, however, that Erlotinib for the treatment of non-small-cell lung cancer (NICE technology appraisal guidance 162) does not recommend erlotinib for treating patients for whom docetaxel is unsuitable. The clinical specialists explained that suitability of docetaxel is a grey area because of differing dosing possibilities and the importance of patient choice. The Committee concluded that in clinical practice treatment varies for patients depending upon performance status and does not fully reflect existing NICE guidance.

4.3.6 The Committee considered the clinical pathway for patients with unknown EGFR-TK mutation status. It understood from the clinical specialists that 30% of people with non-small-cell lung cancer do not have adequate tissue for diagnosis and up to 5% of samples sent for EGFR-TK mutation analysis fail because of insufficient or poor quality DNA. The clinical specialists commented that an element of clinical judgement is needed when treating these patients but they would generally follow the same clinical pathway as the EGFR-TK mutation-negative population (see section 4.3.5). Patients with a performance status of 2 or more in whom the disease has progressed after prior chemotherapy may receive best supportive care or erlotinib if their patient characteristics suggest that their tumour may be mutation-positive (for example, people who have never smoked or are light smokers, women, people of Asian ethnicity and people with adenocarcinoma histology). The Committee concluded that the EGFR-TK mutation-unknown population is diminishing because of the increasing role of EGFR-TK mutation testing but there is a small group of patients in whom diagnosis of EGFR-TK mutation status is not possible.

Clinical effectiveness

EGFR-TK mutation-positive population

4.3.7 The Committee discussed the clinical effectiveness evidence for gefitinib in the EGFR-TK mutation-positive population. It understood that there were no trials of gefitinib solely conducted in this population but some clinical effectiveness evidence is available from several retrospective analyses. The Committee discussed the retrospective analyses, including 2 from second-line trials of gefitinib (ISEL and INTEREST) and 1 from the first-line IPASS trial of gefitinib. The Committee was aware that the ISEL trial compared gefitinib and best supportive care but did not report the median survival for each treatment group and presented a pooled estimate, so the results were not meaningful for assessing the relative effectiveness. It noted that the INTEREST trial showed statistically significantly longer median progression-free survival with gefitinib compared with docetaxel but there was no statistically significant difference in median overall survival. The Committee also noted that in the post hoc analysis of the IPASS trial, the median overall survival of patients who received subsequent EGFR-TK inhibitor treatment was longer compared with those who did not receive it. The Committee heard from the Assessment Group that Fukuoka et al. (2011) reported that 37 of the 46 patients who did not receive subsequent EGFR-TK inhibitor treatment in the post hoc analysis of the IPASS trial did not receive any treatment at all and therefore the results were heavily weighted against the comparator group (that is, the no subsequent EGFR-TK inhibitor group). The Assessment Group considered that the evidence available for the EGFR-TK mutation-positive population was weak and not sufficiently robust to inform decision-making. The Committee agreed that these retrospective analyses were based on small patient numbers, were subject to imbalances in baseline patient characteristics (and so were highly selective) and lacked statistical power. The manufacturer of gefitinib acknowledged the limitations of the retrospective analyses. The Committee was aware that established practice is to treat patients with EGFR-TK mutation-positive tumours with EGFR-TK inhibitors in the first-line setting (see section 4.3.4). However, the Committee was mindful that a small proportion of the EGFR-TK mutation-positive population may have received a delayed diagnosis of EGFR-TK mutation status and, depending on their fitness, may need immediate treatment with non-targeted chemotherapy (see section 4.3.4). It heard from the clinical specialists that when a tumour tests positive for EGFR-TK mutations, the disease responds to treatment with EGFR-TK inhibitors to the same degree irrespective of whether the person has received prior non-targeted chemotherapy or not. The Committee was persuaded that the EGFR-TK mutation-positive population may gain a clinical benefit from treatment with EGFR-TK inhibitors if they have received prior chemotherapy in clinical practice because of a delayed diagnosis of EGFR-TK mutation status. The Committee concluded that second-line treatment with gefitinib is appropriate if a diagnosis of EGFR-TK mutation-positive status has been confirmed at the time of disease progression on first-line chemotherapy.

4.3.8 The Committee discussed the clinical effectiveness evidence for erlotinib in the EGFR-TK mutation-positive population. It understood that there were no trials of erlotinib solely conducted in this population but that clinical effectiveness evidence was available from 2 retrospective analyses of the BR21 and TITAN trials. The Committee noted that neither of these analyses reported statistically significant differences between erlotinib and the comparator group (that is, best supportive care in the BR21 trial and a pooled comparator of patients randomised to either docetaxel or pemetrexed in the TITAN trial). It recognised that these retrospective analyses of erlotinib were subject to the same weaknesses identified in the retrospective analyses of gefitinib but was persuaded by the clinical specialists that the EGFR-TK mutation-positive population would gain a clinical benefit from treatment with EGFR-TK inhibitors after prior chemotherapy  (see section 4.3.7). It Committee concluded that for the small proportion of the EGFR-TK mutation-positive population who may have received a delayed diagnosis and needed immediate treatment with non-targeted chemotherapy, second-line treatment with erlotinib is appropriate if EGFR-TK mutation-positive status has been confirmed at the time of disease progression on first-line chemotherapy.

EGFR-TK mutation-negative population

4.3.9 The Committee discussed the clinical effectiveness evidence available for the EGFR-TK mutation-negative population comparing the EGFR-TK inhibitors with best supportive care. It noted that gefitinib does not have a UK marketing authorisation for treating the EGFR-TK mutation-negative population and therefore it could not be considered as a treatment option for this population. The Committee understood that only 1 retrospective analysis was available from the BR21 trial comparing erlotinib and best supportive care in the EGFR-TK mutation-negative population. It was aware that the BR21 trial was completed in 2004 before EGFR-TK mutation testing became established practice and part of clinical decision-making. It also noted that the trial formed part of the evidence base for Erlotinib for the treatment of non-small-cell lung cancer (NICE technology appraisal guidance 162). The Committee heard from the manufacturer that many of the patients enrolled in the BR21 trial had already received first-line or second-line chemotherapy and were unsuitable for docetaxel because of their poor performance status. The Committee acknowledged that the BR21 trial did not report statistically significant differences in median overall survival between erlotinib and best supportive care but median overall survival was numerically longer for erlotinib (see section 4.1.12). It heard from the Assessment Group that the sample sizes were larger in the retrospective analysis of the BR21 trial in the EGFR-TK mutation-negative population compared with the retrospective analyses of the trials in the EGFR-TK mutation-positive population, but the results were still less reliable than the main intention-to-treat analysis of the BR21 trial because of the risk of imbalances in baseline patient characteristics. The Committee heard from the clinical specialists that erlotinib is now essentially regarded as a targeted therapy for mutation-positive patients only. It concluded that the evidence only weakly suggests that erlotinib may be clinically effective compared with best supportive care in the EGFR-TK mutation-negative population for whom docetaxel is unsuitable.

4.3.10 The Committee considered the clinical effectiveness evidence available for the EGFR-TK mutation-negative population comparing erlotinib with docetaxel. It understood that clinical effectiveness evidence was available from 2 retrospective subgroup analyses of the DELTA and TITAN trials and the recently completed TAILOR trial conducted specifically in the EGFR-TK mutation-negative population. The Committee noted that:

• DELTA showed statistically significantly longer median progression-free survival in patients treated with docetaxel compared with erlotinib, but TITAN did not show any statistically significant differences between groups for median progression-free survival
• no statistically significant differences were estimated between erlotinib and the comparator group for median overall survival in both DELTA and TITAN.

It again acknowledged the weaknesses of retrospective subgroup analyses (see section 4.3.7) and noted that the TITAN trial presented the results of erlotinib compared with a pooled comparator (that is, patients were randomised to either docetaxel or pemetrexed in the comparator group), and that pemetrexed was not specified in the scope of this technology appraisal. The Committee was aware that the TAILOR trial showed statistically significantly longer median progression-free survival and longer (but not statistically significant) median overall survival with docetaxel compared with erlotinib (see sections 4.1.11 to 4.1.12). It acknowledged that the TAILOR trial confirmed the Committee’s conclusions on the clinical effectiveness of erlotinib compared with docetaxel in NICE technology appraisal guidance 162. Without head-to-head evidence comparing erlotinib with docetaxel in NICE technology appraisal 162, the Committee concluded that ‘erlotinib could not reasonably be considered to have an overall survival benefit when compared with docetaxel, and that a progression-free survival benefit with docetaxel was more probable’. The Committee further considered the generalisability of the TAILOR trial to clinical practice in England. The Committee discussed the concern that the TAILOR trial enrolled a lower proportion of patients with a performance status of 2 or more (approximately 7%) than is treated in clinical practice. It understood from the clinical specialists that patients with a performance status of 2 or more would not be offered docetaxel (see section 4.3.5) and therefore the low proportion of patients with a performance status of 2 or more in the TAILOR trial reflects clinical practice. The Committee acknowledged that the TAILOR trial included a docetaxel weekly regimen that is not used in clinical practice in England and understood from the clinical specialists that using a weekly dose (and consequently weekly hospital visits) may lead to fewer episodes of febrile neutropenia. However, the Committee heard from the clinical specialists that increasing the frequency of docetaxel infusion had become more common in clinical practice in the preceding 12 months because of the results from the TAILOR trial. The Committee considered that the results of the TAILOR trial were relevant to people in England with non-small-cell lung cancer whose disease had progressed after prior chemotherapy and whose tumours tested negative for EGFR-TK mutations. The Committee concluded that based on the available evidence and clinical practice in England, docetaxel is more clinically effective compared with erlotinib in the EGFR-TK mutation-negative population.

EGFR-TK mutation-unknown population

4.3.11 The Committee discussed the clinical effectiveness evidence available for the EGFR-TK mutation-unknown population. It noted that gefitinib does not have a UK marketing authorisation for treating this population and therefore it could not be considered as a treatment option for this population. For erlotinib, it understood that clinical effectiveness evidence was available from 3 trials (BR21, DELTA and TITAN) whose intention-to-treat populations included patients whose tumours were not tested before randomisation. For the EGFR-TK mutation-unknown population, the Committee noted that the BR21 trial showed statistically significantly longer median progression-free survival and median overall survival for erlotinib compared with best supportive care. It also noted that the DELTA and TITAN trials showed no statistically significant differences between erlotinib and docetaxel for median progression-free survival and median overall survival. The Committee understood from the clinical specialists that, despite most patients being tested for mutation status at diagnosis, tumour mutation status can be difficult to obtain in a small population because of inadequate tissue samples or poor quality DNA (see section 4.3.6). Therefore, the Committee concluded it should consider further the generalisability of the EGFR-TK mutation-unknown BR21 trial population with the EGFR-TK mutation-unknown clinical population.

4.3.12 The Committee discussed the BR21 intent-to-treat population and its relevance to decision-making. It understood from the clinical specialists that certain clinical characteristics are strong predictors of mutation status (see section 4.3.6). It noted that the overall results of the BR21 intent-to-treat population are likely to be poorer than the results of an EGFR-TK mutation-unknown population whose tumours have a high probability of testing positive for EGFR-TK mutations. The Committee concluded that, in the EGFR-TK mutation-unknown population, it is likely that erlotinib compared with best supportive care is more clinically effective in people who have clinical characteristics similar to those with confirmed EGFR-TK mutation-positive status than in those who do not.

Cost effectiveness

4.3.13 The Committee discussed the cost-effectiveness analyses presented by the manufacturer of erlotinib and the Assessment Group. It noted that:

• the manufacturer and Assessment Group did not present any cost-effectiveness estimates for the EGFR-TK mutation-positive population because of the weaknesses in clinical effectiveness data (see sections 4.3.7 to 4.3.8)
• no cost-effectiveness estimates were presented for gefitinib because it only has a UK marketing authorisation for treating the EGFR-TK mutation-positive population
• the manufacturer of erlotinib did not present cost-effectiveness estimates comparing erlotinib with docetaxel because it was not possible to show that erlotinib was cost effective following the availability of generic docetaxel.

The Committee concluded that it could only consider the cost effectiveness of erlotinib in the EGFR-TK mutation-negative and EGFR-TK mutation-unknown populations.

EGFR-TK mutation-negative population

4.3.14 The Committee discussed the Assessment Group’s ICERs for the comparison of erlotinib with docetaxel in the EGFR-TK mutation-negative population. The Committee was aware of the conclusion in Erlotinib for the treatment of non-small-cell lung cancer (NICE technology appraisal guidance 162) stating ‘while the difference in benefit between docetaxel and erlotinib was uncertain in the absence of direct comparisons, erlotinib could be acceptable if the total costs of treatment were lower or equal to those of docetaxel’. It noted that since the publication of NICE technology appraisal guidance 162, the results of the first published trial directly comparing erlotinib with docetaxel in patients whose tumours test negative for EGFR-TK mutations had become available (that is, the TAILOR trial). Additionally, the price of docetaxel reduced by approximately 90%, and the patient access scheme for erlotinib changed from the manufacturer providing erlotinib at an overall treatment cost (including administration, adverse events and monitoring costs) equal to that of docetaxel to a simple discount scheme. The Committee commented that the Assessment Group’s economic model estimated that erlotinib resulted in cost savings (because of administration and adverse-reaction management) but fewer QALYs compared with docetaxel. It acknowledged that the direct evidence from the TAILOR trial showed that erlotinib was less clinically effective compared with docetaxel (see section 4.3.10). The Committee noted that the Assessment Group’s base-case ICER comparing erlotinib with docetaxel showed that erlotinib was less effective and less costly with an ICER of £15,400 saved per QALY lost. Based on this, the Committee agreed that this suggested erlotinib did not represent a cost-effective use of NHS resources for this population. It heard from the Assessment Group that the estimated ICERs for the comparison of erlotinib with docetaxel in the EGFR-TK mutation-negative population were robust to most parameters in its economic model but were highly sensitive to the incidence and cost of febrile neutropenia. The Committee concluded that further consideration of the incidence and cost of febrile neutropenia was needed before it could make a judgement on the cost effectiveness of erlotinib compared with docetaxel in the EGFR-TK mutation-negative population.

4.3.15 The Committee discussed the cost and incidence of febrile neutropenia in the Assessment Group’s economic model. It was aware that while developing NICE technology appraisal guidance 162, NICE commissioned the NICE Decision Support Unit to explore the cost and incidence of febrile neutropenia. The Committee understood that the cost per episode of febrile neutropenia in the Assessment Group’s economic model (£5048) was higher than that estimated by the NICE Decision Support Unit (£2286). The clinical specialists approximated that an episode of febrile neutropenia costs between £4000 and £5000. The Committee was persuaded that the Assessment Group’s cost was more plausible and based on the most recent NHS Reference Cost for febrile neutropenia. It heard from the Assessment Group that it included adverse reaction data from a single trial (TAILOR) and that the patient populations in other trials were not sufficiently similar for a meta-analysis to be carried out. The Committee was aware that the manufacturer of erlotinib suggested during consultation on the Assessment Group report that using pooled adverse reaction data increased the ICER for erlotinib compared with docetaxel from £15,400 saved per QALY lost to over £40,000 saved per QALY lost. It was also aware that the NICE Decision Support Unit conducted a meta-analysis of 13 trials of docetaxel (including different regimens) to estimate the incidence of febrile neutropenia. The Committee heard from the Assessment Group that changing the incidence of febrile neutropenia from 3.85% (used in the base case and derived from the TAILOR trial) to 5.95% (derived from the NICE Decision Support Unit meta-analysis) resulted in ICERs of £15,400 saved per QALY lost and £28,500 saved per QALY lost respectively for erlotinib compared with docetaxel. The Committee noted that the TAILOR trial data were more recent than the meta-analysis data, and that the docetaxel dosing and frequency were not immutable. It acknowledged that both estimates were feasible but that the incidence of febrile neutropenia was likely to lie between the 2 estimates. Therefore, the Committee concluded that the ICER for erlotinib compared with docetaxel was likely to be between £15,400 and £28,500 saved per QALY lost.

4.3.16 The Committee discussed the estimated ICERs for the comparison of erlotinib and best supportive care in the EGFR-TK mutation-negative population for whom docetaxel is unsuitable. It noted that the Assessment Group’s economic model estimated lower incremental costs and fewer incremental QALYs compared with the manufacturer’s economic model but the estimated base-case ICERs were similar for the comparison of erlotinib with best supportive care (£54,700 per QALY gained and £58,600 per QALY gained respectively). The Committee understood that the ICERs were robust to changes in all parameters included in the respective economic models. The Committee therefore concluded that erlotinib is not a cost-effective use of NHS resources in the EGFR-TK mutation-negative population for whom docetaxel is unsuitable.

EGFR-TK mutation-unknown population

4.3.17 The Committee discussed the estimated ICERs for the comparison of erlotinib and best supportive care in the EGFR-TK mutation-unknown population. It acknowledged that the Assessment Group’s estimated base-case ICER was higher than the manufacturer’s base-case ICER but both were over £50,000 per QALY gained (£61,100 per QALY gained and £51,000 per QALY gained respectively). The Committee was aware that the intention-to-treat population of the BR21 trial used in the economic modelling may not reflect the EGFR-TK mutation-unknown population who are offered erlotinib in clinical practice after the failure of prior chemotherapy (see section 4.3.12). It concluded that the ICER for erlotinib compared with best supportive care is likely to be lower than those estimated by the manufacturer and the Assessment Group in the EGFR-TK mutation-unknown population with clinical characteristics suggestive of EGFR-TK mutation-positive tumours.

Overview of the Appraisal Committee’s conclusions and preliminary recommendations

EGFR-TK mutation-positive population

4.3.18 The Committee discussed the most plausible ICER for each of the populations. It noted that cost-effectiveness estimates were not presented for each population considered in the appraisal so had to use its judgement on whether erlotinib represented an equitable and cost-effective use of NHS resources in these circumstances. The Committee was aware that a small population with EGFR-TK mutation-positive tumours are offered erlotinib after prior chemotherapy in clinical practice because of a delayed diagnosis. It noted that no trials were solely conducted in this population and that the clinical effectiveness evidence was limited to retrospective subgroup analyses that were not sufficiently robust for decision-making. The Committee commented that it had not been presented with cost-effectiveness estimates for either gefitinib or erlotinib in the EGFR-TK mutation-positive population and therefore could not approximate the most plausible ICER. However, it considered that these patients were an extension of the first-line population for whom NICE has recommended erlotinib and gefitinib (see Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer [NICE technology appraisal guidance 192] and Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer [NICE technology appraisal guidance 258]). The Committee assumed that the fixed price patient access scheme already in place for gefitinib would apply in this circumstance and heard nothing to the contrary. The Committee concluded that if erlotinib and gefitinib are provided with their respective patient access schemes, the EGFR-TK mutation-positive population should have the option of treatment with erlotinib or gefitinib after prior chemotherapy because it would be unfair to disadvantage this small group of people because of a delayed diagnosis.

EGFR-TK mutation-negative population

4.3.19 The Committee considered the population whose tumours test negative for EGFR-TK mutations and for whom docetaxel is suitable (performance status of 0 or 1). It was aware that direct evidence comparing erlotinib with docetaxel showed erlotinib to be less clinically effective. The Committee noted that although erlotinib was considered to be better tolerated than docetaxel, the health-related quality of life and the cost associated with managing adverse reactions had been accounted for in the cost-effectiveness estimates. The Committee was aware that the price of erlotinib and docetaxel had both changed since the publication of NICE technology appraisal 162 but the Assessment Group’s economic model estimated erlotinib resulted in cost savings but at the detriment of fewer QALYs (that is, a health loss) compared with docetaxel. The Committee concluded that the most plausible ICER was likely to be between £15,400 and £28,500 saved per QALY lost comparing erlotinib with docetaxel. The Committee also heard from the clinical specialists that there is an unmet need for well-tolerated treatments for non-small-cell lung cancer that are more clinically effective compared with docetaxel. The Committee concluded that taking all these factors into account erlotinib could not be recommended for the EGFR-TK mutation-negative population for whom treatment with docetaxel is suitable.

4.3.20 The Committee considered the population of people whose tumours test negative for EGFR-TK mutations and for whom docetaxel is not suitable (that is, those with a performance status of 2). The Committee stated that without new evidence and consistent with the recommendation in NICE technology appraisal guidance 162, erlotinib after prior chemotherapy did not represent a cost-effective use of NHS resources in people with non-small-lung cancer whose tumours test negative for the EGFR-TK mutation and for whom docetaxel is unsuitable, with the most plausible ICER likely to be over £50,000 per QALY gained compared with best supportive care and therefore it could not be recommended for this population.

EGFR-TK mutation-unknown population

4.3.21 The Committee then went on to consider the EGFR-TK mutation-unknown population. It noted that this is a diminishing population because of the increasing role and advances in testing of EGFR-TK mutation-status. The Committee highlighted its conclusion that the ICER comparing erlotinib with best supportive care was likely to be lower than those estimated by the manufacturer and Assessment Group in the EGFR-TK mutation-unknown population with clinical characteristics suggestive of EGFR-TK mutation-positive tumours. The Committee acknowledged that a patient’s EGFR-TK mutation status genuinely may be unobtainable in clinical practice because of inadequate tissue samples. It heard from the clinical specialists that if a person’s disease is likely to respond to EGFR-TK inhibitor treatment, that it will do so by 2 cycles of treatment. The Committee considered that it would be unfair to disadvantage this small group of people. It therefore concluded that erlotinib should be recommended as a treatment option in the EGFR-TK mutation-unknown population with clinical characteristics suggestive of EGFR-TK mutation-positive tumours and should be able to continue treatment until disease progression provided that their tumours have responded after 2 cycles.

4.3.22 The Committee considered whether there were any health-related quality-of-life benefits that were not adequately captured in the QALY calculation. The Assessment Group’s report recognised that a drug taken orally may provide people with non-small-cell lung cancer with a valuable alternative to intravenous docetaxel. The benefit of an oral mode of treatment was not captured in the Assessment Group’s base-case analysis comparing erlotinib with docetaxel but was explored in a scenario analysis (see section 4.2.17). The Committee was aware of the Assessment Group’s comments that it was an extremely optimistic scenario analysis applying the maximum possible patient health utility increment and that any realistic estimation of utility benefit was very unlikely to have a significant impact on the size of the ICER. The Committee noted that the Assessment Group’s scenario analysis was not plausible but acknowledged that some people may have a preference for erlotinib because it is orally administered. However, it concluded that if the Assessment Group had used a more plausible estimation of the health-related quality-of-life benefit of oral treatment, it would not change its conclusion about the cost effectiveness of erlotinib in the EGFR-TK mutation-negative population for whom docetaxel is suitable.

4.3.23 The Committee considered supplementary advice from NICE, which 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 of the following criteria must be met:

• the treatment is indicated for patients with a short life expectancy, normally less than 24 months and
• 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 and
• the technology is licensed or otherwise indicated, for small patient populations normally not exceeding a cumulative total of 7000 for all licensed indications in England.

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

4.3.24 The Committee discussed whether erlotinib fulfilled the criteria for a life-extending end-of-life treatment. It was aware that the manufacturer of erlotinib did not make a case for erlotinib meeting the end-of-life criteria in its submission. The Committee noted that the median overall survival of patients with non-small-cell lung cancer after prior chemotherapy in the trials was 5–8 months. The Committee considered that the life expectancy of patients with non-small-cell lung cancer after prior chemotherapy was less than 24 months. The Committee went on to consider whether erlotinib met the extension-to-life criterion. It understood:

• in the TAILOR trial and the Assessment’s Group economic modelling patients treated with erlotinib experienced shorter progression-free survival and shorter overall survival compared with patients treated with docetaxel in the EGFR-TK mutation-negative population
• the clinical effectiveness evidence for erlotinib compared with best supportive care in the EGFR-TK mutation-negative population for whom docetaxel was not suitable was not sufficiently robust for decision-making and the Assessment Group’s economic analysis for this population estimated an incremental survival gain of 2.2 months.

The Committee was not convinced that the extension to life of patients to whom erlotinib could be offered was at least an additional 3 months. Having established that erlotinib did not meet the extension-to-life criterion, the Committee decided that it was not necessary to make a decision about the population size criterion. It concluded, on this basis, that erlotinib did not fulfil the criteria for being a life-extending, end-of-life treatment.

Summary of Appraisal Committee's key conclusions

TAXXX	Appraisal title: Erlotinib and gefitinib for treating non-small-cell lung cancer that has progressed after prior chemotherapy (review of NICE technology appraisal guidance 162 and 175)		Section
Key conclusion
Erlotinib is recommended as an option for treating locally advanced or metastatic non-small-cell lung cancer in people who have received non-targeted chemotherapy because of delayed confirmation that their tumour is epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation-positive, only if the manufacturer provides erlotinib with the discount agreed in the patient access scheme. Gefitinib is recommended as an option for treating locally advanced or metastatic non-small-cell lung cancer in people who have received non-targeted chemotherapy because of delayed confirmation that their tumour is EGFR-TK mutation-positive, only if the manufacturer provides gefitinib at the fixed price agreed in the patient access scheme. Erlotinib is not recommended for treating locally advanced or metastatic non-small-cell lung cancer in people with EGFR-TK mutation-negative tumours after the failure of at least 1 prior non-targeted chemotherapy regimen. Erlotinib is recommended as an option for treating locally advanced or metastatic non-small-cell lung cancer that has progressed after chemotherapy in people with tumours of unknown EGFR-TK mutation status, only if: ·         the result of a EGFR-TK mutation diagnostic test is unobtainable because of an inadequate tissue sample or poor quality DNA and ·         the tumour is very likely to be EGFR-TK mutation-positive based on patient characteristics and ·         the person’s disease responds to the first 2 cycles of treatment with erlotinib and ·         the manufacturer provides erlotinib with the discount agreed in the patient access scheme.			1.1 1.2 1.3 1.4
Current practice
Clinical need of patients, including the availability of alternative treatments		Extending survival and improving quality of life are important to people with non-small-cell lung cancer, as is spending less time at the hospital because they have a short life expectancy. The clinical specialists stated that the use of EGFR-TK inhibitors for re-treating non-small-cell lung cancer after the failure of first-line EGFR-TK inhibitor treatment is not common in clinical practice because of reduced sensitivity of the tumour to these treatments. Although most patients with EGFR-TK mutation-positive tumours receive first-line treatment with an EGFR-TK inhibitor, a small number of patients may receive a delayed diagnosis. For this subgroup, subsequent treatment with an EGFR-TK inhibitor after prior chemotherapy is appropriate. The clinical specialists explained that the choice of treatment in patients whose non-small-cell lung cancer has progressed after prior chemotherapy depends on their performance status. The Committee understood that the EGFR-TK mutation-unknown population is diminishing because of the increasing role of EGFR-TK mutation testing but there is a small group of patients in whom diagnosis of EGFR-TK mutation status is not possible.	4.3.2 4.3.4 4.3.5 4.3.6
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 Assessment Group’s report recognised that a drug taken orally may provide people with non-small-cell lung cancer with a valuable alternative to intravenous docetaxel. The Committee also heard from the clinical specialists that there is an unmet need for well-tolerated treatments for non-small-cell lung cancer that are clinically effective compared with docetaxel.	4.3.22 4.2.19
What is the position of the treatment in the pathway of care for the condition?		The Committee understood that a timely diagnosis of EGFR-TK mutation status has an important role in ensuring that patients are given the most appropriate treatment. Although most patients with EGFR-TK mutation-positive tumours receive first-line treatment with an EGFR-TK inhibitor, a small number of patients may receive a delayed diagnosis. For this subgroup, subsequent treatment with an EGFR-TK inhibitor after prior chemotherapy is appropriate. The Committee was aware that gefitinib only has a marketing authorisation for treating the EGFR-TK mutation-positive population. It understood that treatment for the EGFR-TK mutation-negative population varies depending on performance status and does not fully reflect existing NICE guidance. Patients with a performance status of 0 or 1 are offered a choice between erlotinib and docetaxel. Docetaxel is not suitable for patients with a performance status of 2 because of the drug’s toxicity and therefore these people are offered erlotinib or best supportive care. The clinical specialists commented that an element of clinical judgement is needed when treating patients with EGFR-TK mutation-unknown tumours but they would generally follow the same clinical pathway as the EGFR-TK mutation-negative population.	4.3.3 4.3.4 4.3.5 4.3.6
Adverse reactions		The Committee heard from the clinical specialists that the adverse reactions associated with both these treatments are much less common than those associated with chemotherapy, although rash may be more common with erlotinib and interstitial lung disease may be more common with gefitinib.	4.3.4
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee understood that there were no trials of gefitinib or erlotinib solely conducted in the EGFR-TK mutation-positive population but some clinical effectiveness evidence is available from several retrospective analyses. The Committee understood that only 1 retrospective analysis was available from the BR21 trial comparing erlotinib and best supportive care in the EGFR-TK mutation-negative population. It was aware that the BR21 trial was completed in 2004 before EGFR-TK mutation testing became established practice and part of clinical decision-making. For the comparison of erlotinib with docetaxel, the Committee understood that clinical effectiveness evidence was available from 2 retrospective subgroup analyses of the DELTA and TITAN trials and the recently completed TAILOR trial conducted specifically in the EGFR-TK mutation-negative population. The Committee understood that clinical effectiveness evidence was available from 3 trials (BR21, DELTA and TITAN) whose intention-to-treat populations included patients whose tumours were not tested before randomisation.	4.3.7 – 4.3.8 4.3.9 – 4.3.10 4.3.11
Relevance to general clinical practice in the NHS		The Committee considered that the results of the TAILOR trial were relevant to people in England with non-small-cell lung cancer whose disease had progressed after prior chemotherapy and whose tumours tested negative for EGFR-TK mutations.	4.3.10
Uncertainties generated by the evidence		The Assessment Group considered that the evidence available for the EGFR-TK mutation-positive population was weak and not sufficiently robust to inform decision-making. The Committee agreed that these retrospective analyses were based on small patient numbers, were subject to imbalances in baseline patient characteristics (and so were highly selective) and lacked statistical power. The Committee understood that the sample sizes were larger in the retrospective analysis of the BR21 trial in the EGFR-TK mutation-negative population compared with the retrospective analyses of the trials in the EGFR-TK mutation-positive population, but the results were still less reliable than the main intention-to-treat analysis of the BR21 trial because of the risk of imbalances in baseline patient characteristics. The Committee acknowledged that the TAILOR trial included a docetaxel weekly regimen that is not used in clinical practice in England. The Committee noted that the overall results of the BR21 intent-to-treat population are likely to be poorer than the results of an EGFR-TK mutation-unknown population whose tumours have a high probability of testing positive for EGFR-TK mutations.	4.3.7-4.3.8 4.3.9 4.3.10 4.3.12
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee heard from the clinical specialists that erlotinib is now essentially regarded as a targeted therapy for mutation-positive patients only.	4.3.9
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee concluded that the evidence only weakly suggests that erlotinib may be clinically effective compared with best supportive care in the EGFR-TK mutation-negative population for whom docetaxel is unsuitable. The Committee was aware that the TAILOR trial showed statistically significantly longer median progression-free survival and longer (but not statistically significant) median overall survival with docetaxel compared with erlotinib. The Committee concluded that based on the available evidence and clinical practice in England, docetaxel is more clinically effective compared with erlotinib in the EGFR-TK mutation-negative population. For the EGFR-TK mutation-unknown population, the Committee noted that the BR21 trial showed statistically significantly longer median progression-free survival and median overall survival for erlotinib compared with best supportive care. It also noted that the DELTA and TITAN trials showed no statistically significant differences between erlotinib and docetaxel for median progression-free survival and median overall survival. The Committee concluded that, in the EGFR-TK mutation-unknown population, it is likely that erlotinib compared with best supportive care is more clinically effective in people who have clinical characteristics similar to those with confirmed EGFR-TK mutation-positive status than in those who do not.	4.3.9 4.3.10 4.3.11-4.3.12
How has the new clinical evidence that has emerged since the original appraisals (TA162 and TA175) influenced the current (preliminary) recommendations?		The Committee acknowledged that the TAILOR trial confirmed the Committee’s conclusions on the clinical effectiveness of erlotinib compared with docetaxel in NICE technology appraisal guidance 162. Without head-to-head evidence comparing erlotinib with docetaxel in NICE technology appraisal 162, the Committee concluded that ‘erlotinib could not reasonably be considered to have an overall survival benefit when compared with docetaxel, and that a progression-free survival benefit with docetaxel was more probable’.	4.3.10
Evidence for cost effectiveness
Availability and nature of evidence		The Committee concluded that it could only consider the cost effectiveness of erlotinib in the EGFR-TK mutation-negative and EGFR-TK mutation-unknown populations.	4.3.13
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee heard from the Assessment Group that it included adverse reaction data from a single trial (TAILOR) and that the patient populations in other trials were not sufficiently similar for a meta-analysis to be carried out. It was also aware that the NICE Decision Support Unit conducted a meta-analysis of 13 trials of docetaxel to estimate the incidence of febrile neutropenia. It acknowledged that both estimates were feasible but that the incidence of febrile neutropenia was likely to lie between the 2 estimates. The Committee was aware that the intention-to-treat population of the BR21 trial used in the economic modelling may not reflect the EGFR-TK mutation-unknown population who are offered erlotinib in clinical practice after the failure of prior chemotherapy	4.3.15 4.3.17
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 acknowledged that some people may have a preference for erlotinib because it is orally administered. However, it concluded that using a realistic estimation of the health-related quality-of-life benefit of oral treatment did not change its conclusion about the cost effectiveness of erlotinib in the EGFR-TK mutation-negative population for whom docetaxel is suitable.	4.3.22
Are there specific groups of people for whom the technology is particularly cost effective?		N/A	-
What are the key drivers of cost effectiveness?		The Committee heard from the Assessment Group that the estimated ICERs for the comparison of erlotinib with docetaxel in the EGFR-TK mutation-negative population were robust to most parameters in its economic model but were highly sensitive to the incidence and cost of febrile neutropenia, and to the price of docetaxel.	4.3.14
Most likely cost-effectiveness estimate (given as an ICER)		The Committee concluded that the most plausible ICER was likely to be between £15,400 and £28,500 saved per QALY lost comparing erlotinib with docetaxel for the EGFR-TK mutation-negative population for whom treatment with docetaxel is suitable. In people with non-small-lung cancer whose tumours test negative for the EGFR-TK mutation and for whom docetaxel is unsuitable, the most plausible ICER likely to be over £50,000 per QALY gained compared with best supportive care. The Committee concluded that the ICER for erlotinib compared with best supportive care is likely to be lower than those estimated by the manufacturer and the Assessment Group in the EGFR-TK mutation-unknown population with clinical characteristics suggestive of EGFR-TK mutation-positive tumours.	4.3.19 4.3.20 4.3.17
How has the new cost-effectiveness evidence that has emerged since the original appraisals (TA162 and TA175) influenced the current (preliminary) recommendations?		The Committee concluded that if erlotinib and gefitinib are provided with their respective patient access schemes, the EGFR-TK mutation-positive population should have the option of treatment with erlotinib or gefitinib after prior chemotherapy because it would be unfair to disadvantage these patients because of a delayed diagnosis. It considered this population to be an extension of the first-line population for whom NICE has recommended erlotinib and gefitinib. The Committee noted that since the publication of NICE technology appraisal guidance 162, the results of the first published trial directly comparing erlotinib with docetaxel in patients whose tumours test negative for EGFR-TK mutations had become available (that is, the TAILOR trial). Additionally, the price of docetaxel reduced by approximately 90%, and the patient access scheme for erlotinib changed from the manufacturer providing erlotinib at an overall treatment cost (including administration, adverse events and monitoring costs) equal to that of docetaxel to a simple discount scheme. It was aware that direct evidence comparing erlotinib with docetaxel showed docetaxel to be clinically effective. It noted that the change in price of erlotinib was less relative to the change in price of docetaxel. The Committee stated that without new evidence and consistent with the recommendation in NICE technology appraisal guidance 162, erlotinib after prior chemotherapy did not represent a cost-effective use of NHS resources in people with non-small-lung cancer whose tumours test negative for the EGFR-TK mutation and for whom docetaxel is unsuitable, with the most plausible ICER likely to be over £50,000 per QALY gained compared with best supportive care and therefore it could not be recommended for this population. The Committee acknowledged that a patient’s EGFR-TK mutation status genuinely may be unobtainable in clinical practice because of inadequate tissue samples. The Committee considered that it would be unfair to disadvantage these people. It therefore concluded that erlotinib should be recommended as a treatment option in the EGFR-TK mutation-unknown population with clinical characteristics suggestive of EGFR-TK mutation-positive tumours and should be able to continue treatment until disease progression provided that their tumours have responded after 2 cycles.	4.3.18 4.3.19 4.3.20 4.3.21
Additional factors taken into account
Patient access schemes (PPRS)		The manufacturer of erlotinib has agreed a patient access scheme with the Department of Health. The level of discount is commercial in confidence.	3.3
End-of-life considerations		The Committee considered that the life expectancy of patients with non-small-cell lung cancer after prior chemotherapy was less than 24 months. The Committee was not convinced that the extension to life of patients to whom erlotinib could be offered was at least equal to an additional 3 months. Having established that erlotinib did not meet the extension-to-life criterion, the Committee decided that it was not necessary to make a decision about the population size criterion. It concluded, on this basis, that erlotinib did not fulfil the criteria for being a life-extending, end-of-life treatment.	4.3.24
Equalities considerations and social value judgements		Potential equality issues raised during the appraisal were outside the remit of NICE technology appraisal guidance.	-

 

5 Implementation

5.1 Section 7(6) of the National Institute for Health and Care Excellence (Constitution and Functions) and the Health and Social Care Information Centre (Functions) Regulations 2013 requires clinical commissioning groups, NHS England and, with respect to their public health functions, local authorities to comply with the recommendations in this appraisal within 3 months of its date of publication.

5.2 When NICE recommends a treatment ‘as an option’, the NHS must make sure it is available within the period set out in the paragraph above. This means that, if a patient has non-small-cell lung cancer that has progressed after prior chemotherapy and the doctor responsible for their care thinks that erlotinib or gefitinib is the right treatment, it should be available for use, in line with NICE’s recommendations.

5.3 The Department of Health and the manufacturer have agreed that erlotinib will be available to the NHS with a patient access scheme which makes erlotinib available with a discount. The size of the discount is commercial in confidence. It is the responsibility of the manufacturer to communicate details of the discount to the relevant NHS organisations. Any enquiries from NHS organisations about the patient access scheme should be directed to [NICE to add details at time of publication]

5.4 The Department of Health and the manufacturer have agreed that gefitinib will be available to the NHS with a patient access scheme which makes gefitinib available at a single fixed cost of £12,200 per patient irrespective of the duration of treatment. Any enquiries from NHS organisations about the patient access scheme should be directed to [NICE to add details at time of publication]

5.5 NICE has developed tools [link to www.nice.org.uk/guidance/TAXXX] to help organisations put this guidance into practice (listed below). [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

Details are correct at the time of consultation. Further information is available on the NICE website.

Published

• Epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation testing in adults with locally advanced or metastatic non-small-cell lung cancer. NICE diagnostics guidance 9 (2013).
• Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer. NICE technology appraisal guidance 258 (2012).
• Quality standard for lung cancer. NICE quality standard 17 (2012).
• Lung cancer. NICE clinical guideline 121 (2011).
• Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer. NICE technology appraisal guidance 192 (2010).
• Gefitinib for the second-line treatment of locally advanced or metastatic non-small-cell lung cancer. Terminated NICE technology appraisal guidance 175 (2009).
• Erlotinib for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 162 (2008).
• Pemetrexed for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 124 (2007).

Under development

• Afatinib for the treatment of EGFR-TK mutation-positive non‑small-cell lung cancer. NICE technology appraisal guidance. Earliest anticipated date of publication June 2014.

NICE pathways

• NICE has produced a pathway on non-small-cell lung cancer.

 

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 3 years after final publication. 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.

Andrew Stevens
Chair, Appraisal Committee
January 2014

8 Appraisal Committee members and NICE project team

8.1 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 4 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.

Professor Andrew Stevens
Chair of Appraisal Committee C, Professor of Public Health, University of Birmingham

Professor Eugene Milne
Vice Chair of Appraisal Committee C, Director for Adult and Older Adult Health and Wellbeing, Public Health England

Professor Kathryn Abel
Director of Centre for Women’s Mental Health, University of Manchester

Dr David Black
Medical Director, NHS South Yorkshire and Bassetlaw

David Chandler
Lay member

Gail Coster
Advanced Practice Sonographer, Mid Yorkshire Hospitals NHS Trust

Professor Peter Crome
Honorary Professor, Department of Primary Care and Population Health, University College London

Professor Rachel A Elliott
Lord Trent Professor of Medicines and Health, University of Nottingham

Dr Greg Fell
Consultant in Public Health, Bradford Metropolitan Borough Council

Dr Alan Haycox
Reader in Health Economics, University of Liverpool Management School

Dr Janice Kohler
Senior Lecturer and Consultant in Paediatric Oncology, Southampton University Hospital Trust

Emily Lam
Lay member

Dr Nigel Langford
Consultant in Clinical Pharmacology and Therapeutics and Acute Physician, Leicester Royal Infirmary

Dr Allyson Lipp
Principal Lecturer, University of South Wales

Dr Claire McKenna
Research Fellow in Health Economics, University of York

Professor Gary McVeigh
Professor of Cardiovascular Medicine, Queens University Belfast and Consultant Physician, Belfast City Hospital

Dr Grant Maclaine
Formerly – Director, Health Economics and Outcomes Research, BD, Oxford

Dr Andrea Manca
Health Economist and Senior Research Fellow, University of York 

Henry Marsh
Consultant Neurosurgeon, St George's Hospital, London

Dr Suzanne Martin
Reader in Health Sciences

Professor Stephen O’Brien
Professor of Haematology, Newcastle University

Dr Anna O’Neill
Deputy Head of Nursing and Healthcare School / Senior Clinical University Teacher, University of Glasgow

Alan Rigby
Academic Reader, University of Hull

Professor Peter Selby
Consultant Physician, Central Manchester University Hospitals NHS Foundation Trust

Professor Matt Stevenson
Technical Director, School of Health and Related Research, University of Sheffield

Dr Paul Tappenden
Reader in Health Economic Modelling, School of Health and Related Research, University of Sheffield

Professor Robert Walton
Clinical Professor of Primary Medical Care, Barts and The London School of Medicine and Dentistry

Dr Judith Wardle
Lay member

8.2 NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Martyn Burke
Technical Lead

Fay McCracken
Technical Adviser

Nicole Fisher
Project Manager

9 Sources of evidence considered by the Committee

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

• Greenhalgh J, Bagust A, Boland A et al. Erlotinib and gefitinib for treating non-small-cell lung cancer that has progressed following prior chemotherapy (review of NICE technology appraisals 162 and 175), October 2013.

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:

• AstraZeneca
• Roche Products

II. Professional/specialist and patient/carer groups:

• British Thoracic Society
• National Lung Cancer Forum for Nurses
• Roy Castle Lung Cancer Foundation
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians

III. Other consultees:

• None

IV. Commentator organisations (without the right of appeal):

• British Thoracic Oncology Group
• Health Improvement Scotland
• National Collaborating Centre for Cancer

C. The following individuals were selected from clinical specialist and patient expert nominations from the 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 erlotinib and gefitinib by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Paul Bishop, Consultant Histopathologist, nominated by the Royal College of Pathologists – clinical specialist
• Dr Yvonne Summers, Consultant Medical Oncologist, nominated by the Royal College of Physicians – clinical specialist
• Dr Jesme Fox, Medical Director, nominated by the Roy Castle Lung Cancer Foundation – 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.

• AstraZeneca
• Roche Products

E. Other sources of evidence considered by the Committee that were not included or considered in the manufacturer's submission or Assessment Group’s submission:

• Morgan A, Sutton A and Wailoo A (2007). The risks and costs of febrile neutropenia in patients with non-small-cell lung cancer treated with docetaxel. NICE Decision Support Unit.