Lung cancer (non-small-cell, first line) - gefitinib: appraisal consultation document

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

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

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

  • Has all of the relevant evidence been taken into account?
  • Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
  • Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
  • Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of gender, race, disability, age, sexual orientation, religion or belief?

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

After consultation:

  • the Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees
  • at that meeting, the Committee will also consider comments made by people who are not consultees
  • after considering these comments, the Committee will prepare the final appraisal determination (FAD)
  • subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using gefitinib in the NHS in England and Wales.

For further details, see the guide to the technology appraisal process.

The key dates for this appraisal are:

Closing date for comments: 18 February 2010

Second Appraisal Committee meeting: 4 March 2010

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

1 Appraisal Committee’s preliminary recommendations

1.1 The Committee is minded not to recommend gefitinib as a treatment option for people with locally advanced or metastatic non-small-cell lung cancer (NSCLC).

1.2 The Committee recommends that NICE requests further clarification on the clinical and cost effectiveness of gefitinib from the manufacturer as described in sections 1.3 to 1.5. This information should be made available for the next Appraisal Committee meeting.

1.3 NICE requests an exploration of alternative probability distributions for the extrapolation of progression-free survival and overall survival beyond the timeframe of the Iressa Pan Asian Study (IPASS). This should include the following.

1.4 Independent survival curves (overall survival and progression-free survival) for both gefitinib and paclitaxel/carboplatin based on the IPASS data and exploration of different approaches to applying the hazard ratio to incorporate other comparators (for example, pemetrexed and other platinum-based regimens). The different approaches to applying the hazard ratio should consider using either gefitinib or paclitaxel/carboplatin as the baseline.

1.5 Examination of alternative probability distributions and consideration of model fit to early trial data and the shape of the curves at the tail of the distribution.

1.6 Observational or epidemiological evidence on long-term survival in patients with locally advanced or metastatic NSCLC and how this relates to the most plausible model fit.

1.7 The provision of individual patient-level data from IPASS to enable the Evidence Review Group (ERG) to validate key aspects of the submitted model, including the modelling of overall survival and progression-free survival, the choice of parameter values, and structural assumptions.

1.8 NICE requests an analysis to determine the robustness of the incremental cost-effectiveness ratio (ICER) to alternative survival distributions for progression-free and overall survival, based on the independent survival curves for gefitinib and paclitaxel/carboplatin from the IPASS data. The analysis should also provide evidence on alternative approaches to applying the hazard ratio to link to other comparators. These cost-effectiveness analyses should include amended costs for first-line chemotherapy to account for a lower level of dosing in female patients and varying the number of first-line chemotherapy cycles between four and six.

1.9 NICE also requests further analyses to explore the sensitivity of the ICER to:

1.10 varying the prevalence of EGFR-TK mutations between 5% and 17%, taking into account different scenarios costs, comorbidities and the probability of obtaining a specimen suitable for testing (including possible repeat biopsy and the possibility of not obtaining a useful result)

1.11 alternative assumptions about the volume, and hence cost, of the EGFR-TK mutation tests carried out.

2 The technology

2.1 Gefitinib (Iressa, AstraZeneca) is a selective inhibitor of epithelial growth factor receptor tyrosine kinase (EGFR-TK) inhibitor that blocks the signal pathways involved in cell proliferation. By blocking EGFR-TK, gefitinib helps to slow the growth and spread of the cancer. Gefitinib has UK marketing authorisation for the treatment of adult patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with activating mutations of EGFR-TK.

2.2 The summary of product characteristics (SPC) lists the following conditions that may be associated with gefitinib treatment: interstitial lung disease, hepatotoxicity and liver impairment. For full details of side effects and contraindications, see the SPC. The SPC also states that when assessing the EGFR-TK mutation status of a patient, it is important that a well-validated and robust methodology is chosen to avoid false-negative and false-positive determinations.

2.3 Gefitinib is administered orally as 250-mg film-coated tablets. The recommended dosage is 250 mg daily until disease progression or at the clinician’s discretion.

2.4 The manufacturer’s submission states that the price for a pack of 250-mg tablets (30 tablets per pack) is £2167.71. The manufacturer has agreed a patient access scheme with the Department of Health, in which gefitinib for first-line treatment of NSCLC will be available at a single fixed cost per patient irrespective of the duration of treatment. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.

3 The manufacturer’s submission

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

3.1 The manufacturer’s decision problem compared gefitinib with gemcitabine and carboplatin, paclitaxel and carboplatin, vinorelbine and cisplatin, and gemcitabine and cisplatin. The decision problem defined the population as patients with locally advanced or metastatic NSCLC who are previously untreated and test positive for an EGFR-TK mutation (EGFR-TK mutation-positive patients). Outcomes were defined as being overall survival, progression-free survival, objective tumour response rates, health-related quality of life and adverse events associated with treatment. In the economic evaluation the incremental cost per quality-adjusted life year (QALY) gained was presented. A lifetime horizon was used, and costs were considered from the NHS and personal social services (PSS) perspective.

3.2 The manufacturer’s submission presented clinical-effectiveness data from the Iressa Pan Asian Study (IPASS), which was a randomised controlled trial (RCT) set in East Asian countries. IPASS was a multicentre, open-label RCT in clinically selected patients older than 18 years who had the following characteristics: histologically or cytologically confirmed stage IIIb (locally advanced disease not amenable to local therapy such as pleural effusion) or stage IV (metastatic) NSCLC with adenocarcinoma histology (including bronchoalveolar carcinoma), had never smoked (fewer than 100 cigarettes per lifetime) or were light ex-smokers (stopped smoking at least 15 years previously and smoked no more than 10 pack-years), had no prior chemotherapy, biological or immunological therapy, and had a WHO performance status of 0–2.

3.3 IPASS included 1217 patients from 87 East Asian centres. Patients were randomised to receive 250 mg of gefitinib once daily or paclitaxel (200 mg/m2 body surface area) immediately followed by carboplatin (at a dose calculated to produce an area under the curve [AUC] of concentration versus time of 5.0–6.0 mg/ml/minute) in 3-weekly cycles. Treatment was continued until disease progression (according to Response Evaluation Criteria in Solid Tumours [RECIST], which use tumour measurement rather than investigator assessment), unacceptable adverse events, patient or clinician request to discontinue, severe non-adherence to the protocol, or until six chemotherapy cycles were reached. Following disease progression, all patients in the gefitinib arm were offered treatment with paclitaxel and carboplatin; if the patient declined or the combination was considered unsuitable, an approved therapy of the clinician’s  choice was used. Following disease progression on paclitaxel and carboplatin treatment, choice of treatment was at the clinician’s discretion.

3.4 The manufacturer’s submission focused on a subgroup of 261 EGFR-TK mutation-positive patients from the overall IPASS population. This subgroup accounted for 21% of the overall IPASS population. Baseline characteristics in the subgroup were similar between both treatment arms. Of these patients, 80.8% were women. Most patients (94.3%) had never smoked, 5.4% were light ex-smokers, and 0.4% were ex-smokers. On a scale of 0 (good) to 4 (poor), most patients (65.9%) had a WHO performance status of 1, 26.4% had a WHO performance status of 0, and 7.7% had a WHO performance status of 2. Most patients had histology indicating adenocarcinoma (94.6%); 5.4% had histology indicating bronchocarcinoma and none had unknown histology. At study entry most patients had metastatic disease (81.6%); 18.4% had stage IIIb locally advanced disease.

3.5 The primary outcome examined in IPASS was progression-free survival, which was assessed from the date of randomisation to disease progression (determined by RECIST) or death from any cause. Secondary outcomes included overall survival, objective tumour response rate, health-related quality of life, symptomatic improvement, safety and tolerability. Estimates of overall survival in the overall population were based on an interim analysis after 450 deaths, with 37% data maturity and ongoing follow-up, with a final analysis due in the second quarter of 2010. Health-related quality of life was assessed by the Functional Assessment of Cancer Therapy–Lung (FACT–L) and the Trial Outcome Index (TOI), which is a sum of the physical and functional wellbeing, and lung cancer symptoms (LCS) domain scores of FACT–L.

3.6 Analysis of progression-free survival used a Cox proportional hazard model in the intention-to-treat population to assess the non-inferiority of gefitinib compared with paclitaxel and carboplatin, adjusting for baseline covariates.

3.7 In the overall study population, patients receiving gefitinib had statistically significantly longer progression-free survival compared with patients receiving paclitaxel and carboplatin. The hazard ratio (HR) for progression-free survival (gefitinib compared with paclitaxel and carboplatin) was 0.74 (95% confidence interval [CI] 0.65 to 0.85, p < 0.0001). The objective tumour response rate was statistically significantly higher for gefitinib compared with paclitaxel and carboplatin (43% versus 32.2%; odds ratio [OR] 1.59, 95% CI 1.25 to 2.01, p = 0.0001). The estimates of overall survival were similar for both groups in the overall study population (HR for gefitinib compared with paclitaxel and carboplatin 0.91, 95% CI 0.76 to 1.10).

3.8 In the subgroup of EGFR-TK mutation-positive patients (n = 261), progression-free survival in patients receiving gefitinib was statistically significantly longer than for patients receiving paclitaxel and carboplatin (HR 0.48, 95% CI 0.36 to 0.64, p < 0.0001). Median progression-free survival was 9.5 months for patients receiving gefitinib and 6.3 months for patients receiving paclitaxel and carboplatin. The objective tumour response rate was statistically significantly higher for patients receiving gefitinib compared with patients receiving paclitaxel and carboplatin (71.2% versus 47.3%; OR 2.75, 95% CI 1.65 to 4.60, p = 0.0001). There was no statistically significant difference in the estimates of overall survival for patients receiving gefitinib compared with patients receiving paclitaxel and carboplatin (HR 0.78, 95% CI 0.50 to 1.20).

3.9 In the subgroup of EGFR-TK mutation-negative patients (n = 176), progression-free survival in patients receiving gefitinib was statistically significantly shorter than for patients receiving paclitaxel and carboplatin (HR 2.85, 95% CI 2.05 to 3.98, p < 0.0001). Median progression-free survival was 1.5 months for patients receiving gefitinib and 5.5 months for patients receiving paclitaxel and carboplatin. The objective tumour response rate was statistically significantly lower with gefitinib than with paclitaxel and carboplatin (1.1% versus 23.5%; OR 0.04, 95% CI 0.01 to 0.27, p = 0.0013). There was no statistically significant difference in the estimates of overall survival for patients receiving gefitinib compared with those receiving paclitaxel and carboplatin (HR 1.38, 95% CI 0.92 to 2.09).

3.10 In the overall study population, statistically significantly more patients receiving gefitinib experienced a clinically relevant improvement in health-related quality of life and disease symptoms, assessed by the FACT–L and TOI, than patients receiving paclitaxel and carboplatin (FACT–L – OR 1.34, 95% CI 1.06 to 1.69, p = 0.0148; TOI – OR 1.78, 95% CI 1.40 to 2.26, p < 0.0001). Symptomatic improvement rates were measured using the lung cancer symptoms (LCS) domain of the FACT–L and were similar for patients receiving gefitinib and patients receiving paclitaxel and carboplatin.

3.11 Similarly in the subgroup of EGFR-TK mutation-positive patients, statistically significantly more patients receiving gefitinib experienced a clinically relevant improvement in health-related quality of life and disease symptoms than patients receiving paclitaxel and carboplatin (FACT–L – OR 3.01, 95% CI 1.79 to 5.07, p < 0.0001; TOI – OR 3.96, 95% CI 2.33 to 6.71, p < 0.0001; LCS – OR 2.70, 95% CI 1.58 to 4.62, p = 0.0003). Time to worsening of health-related quality of life and disease-related symptoms was longer for patients receiving gefitinib than for patients receiving paclitaxel and carboplatin (median range 11.3–16.6 months for gefitinib and 2.9–3.0 months for paclitaxel and carboplatin).

3.12 In the subgroup of EFGR-TK mutation-negative patients, statistically significantly more patients receiving paclitaxel and carboplatin had a clinically relevant improvement in health-related quality of life and disease-related symptoms than patients receiving gefitinib (FACT–L – OR 0.31, 95% CI 0.15 to 0.65, p = 0.0021; TOI – OR 0.35, 95% CI 0.16 to 0.79, p = 0 .00111; LCS – OR 0.28, 95% CI 0.14 to 0.55, p = 0.0002). Time to worsening of health-related quality of life and disease-related symptoms was similar or shorter for patients receiving gefitinib compared with patients receiving paclitaxel and carboplatin (median 1.4 months for gefitinib versus 1.4–4.2 months for paclitaxel and carboplatin).

3.13 The manufacturer’s submission did not provide an analysis of adverse events according to EGFR-TK mutation status. The manufacturer’s submission stated that gefitinib was associated with fewer grade 3 or 4 adverse events than paclitaxel and carboplatin (28.7% versus 61.0%).

3.14 The manufacturer identified two additional trials (First-SIGNAL [n = 42] and North East Japan Gefitinib Study Group [NEJGSG] trial [n = 198]) that compared gefitinib with chemotherapy for the treatment of chemotherapy-naïve patients with predominantly adenocarcinoma histology and EGFR-TK mutations. These studies were considered by the manufacturer for inclusion in a meta-analysis along with data from IPASS. However, the First-SIGNAL study was excluded by the manufacturer on the basis that it examined only a small number of EGFR-TK mutation-positive patients (n = 42) and because the comparator (gemcitabine and cisplatin) was different from IPASS. The NEJGSG trial, which compared gefitinib with paclitaxel and carboplatin, was considered by the manufacturer to be suitable for inclusion in the meta-analysis and used as supporting evidence for IPASS. In the NEJGSG trial, patients receiving gefitinib had a statistically significant longer progression-free survival than those receiving paclitaxel and carboplatin (HR 0.357, 95% CI 0.25 to 0.51, p < 0.001). The meta-analysis of progression-free survival from the IPASS and the NEJGSG trial demonstrated a statistically significant improvement in progression-free survival for EGFR-TK mutation-positive patients who received gefitinib compared with mutation-positive patients who received paclitaxel and carboplatin (fixed effects model: HR 0.43, 95% CI 0.34 to 0.53, p < 0.001).

3.15 The manufacturer carried out a systematic review and mixed-treatment comparison of RCTs comparing chemotherapy in chemotherapy-naïve patients with NSCLC, with evidence on paclitaxel and carboplatin used as a baseline comparator for all analyses. The systematic review identified 29 trials, and 28 studies were selected for inclusion in the network that formed the basis for the mixed-treatment comparison. The manufacturer provided an updated mixed-treatment comparison in response to a request for clarification, which included treatment with pemetrexed and cisplatin as a comparator (n = 29). Data were extracted and analysed for clinical efficacy (progression-free survival, overall survival and objective tumour response) and tolerability (anaemia, diarrhoea, fatigue, febrile neutropenia, nausea and vomiting) for use in the economic evaluation. The manufacturer assumed that the relative effect of alternative chemotherapy compared with paclitaxel and carboplatin in an unselected population with NSCLC would be obtained and the relative estimates would be applied to a baseline event rate in EGFR-TK mutation-positive patients who received paclitaxel and carboplatin in IPASS. The manufacturer’s original mixed-treatment comparison, which did not include pemetrexed, did not identify an individual chemotherapy as offering both more substantial clinical benefit and more favourable tolerability than the other chemotherapies assessed.

3.16 The manufacturer used a Markov economic model to assess the cost effectiveness of gefitinib compared with chemotherapy in the first-line treatment of EGFR-TK mutation-positive patients with NSCLC. Patients entered the model with stable disease. The model then had four distinct health states: treatment response, stable disease, disease progression and death. The model had a cycle length of 21 days and a 5-year time horizon (assumed to be a lifetime horizon).

3.17 Effectiveness data were taken from a variety of sources. The hazard ratio for progression-free survival for EGFR-TK mutation-positive patients who were receiving gefitinib was derived from the meta-analysis conducted by the manufacturer (HR 0.43). The hazard ratio for overall survival for EGFR-TK mutation-positive patients who were receiving gefitinib was estimated from IPASS; estimates of hazard ratios for progression-free survival and overall survival for the chemotherapy regimens were derived from the manufacturer’s mixed-treatment comparison. The manufacturer chose a Weibull model for extrapolating costs and outcomes beyond the IPASS follow-up period. Covariates in the model included: mutation status, gender, performance status (0 or 1 versus > 1) and smoking history (never-smoker or ever-smoker).

3.18 The population in the manufacturer’s economic evaluation was based on the IPASS population, which comprised chemotherapy-naïve EGFR-TK mutation-positive patients who were eligible to receive chemotherapy. The comparator technologies were paclitaxel and carboplatin, gemcitabine and cisplatin, gemcitabine and carboplatin, and vinorelbine and cisplatin.

3.19 Utility estimates in the manufacturer’s model were adopted from a single UK study by Nafees et al. (2008) in which utility values were derived from a survey of 105 members of the general public who were asked to value health state descriptions of second-line chemotherapy for patients with NSCLC. This study did not provide utility estimates associated with the mode of delivery of treatment (oral versus intravenous), so the manufacturer used utility values previously applied  in NICE technology appraisal guidance 162 (‘Erlotinib for the treatment of relapsed non-small cell lung cancer’), which examined second-line chemotherapy for patients with NSCLC and included utilities related to oral and intravenous treatment.

3.20 Resource use in the model included: medication, delivery of chemotherapy, EGFR-TK mutation testing, patient monitoring, NHS transport service, management of grade 3 or 4 adverse events, best supportive care and active treatment after progression. Resource use was estimated from a range of secondary sources (such as references costs, British national formulary, previous NICE technology appraisal submissions and the ERG reports for NICE technology appraisal guidance 162).

3.21 The manufacturer’s model incorporated details of a patient access scheme. This will make gefitinib available to NSCLC patients registered under the scheme at a single fixed payment per NHS patient that covers the duration of their treatment, irrespective of treatment duration.  The scheme will be reviewed after 3 years in line with the Pharmaceutical Price Regulation Scheme.

3.22 In the manufacturer’s base case, the incremental cost-effectiveness ratios (ICERs) for the target population ranged from £19,402 per QALY gained (gefitinib compared with paclitaxel and carboplatin) to £35,992 per QALY gained (gefitinib compared with vinorelbine and cisplatin).

3.23 The manufacturer undertook a range of one-way sensitivity analyses and noted that the results of the cost-effectiveness analysis were sensitive to five key parameters: the overall survival for EGFR-TK mutation-positive patients receiving gefitinib; the overall survival for EGFR-TK mutation-positive patients receiving gemcitabine and carboplatin; the progression-free survival for EGFR-TK mutation-positive patients receiving gemcitabine and carboplatin; the progression-free survival for EGFR-TK mutation-positive patients receiving gefitinib; and the maximum number of chemotherapy cycles, which varied from four to eight.

3.24 The manufacturer also carried out a number of scenario analyses, although none led to any substantial change in the ICER. The manufacturer’s probabilistic sensitivity analysis showed that vinorelbine and cisplatin was the most cost-effective treatment for the first-line treatment of EGFR-TK mutation-positive patients up to a threshold of £35,100 per QALY gained. Beyond this threshold, gefitinib was the most cost-effective treatment option for the first-line treatment of EGFR-TK mutation-positive patients. At a threshold of £30,000 per QALY gained the probabilities of each treatment being the most cost effective in EGFR-TK mutation-positive patients were: vinorelbine and cisplatin (75%); gefitinib (18%); gemcitabine and carboplatin (4%); gemcitabine and cisplatin (3%); and paclitaxel and carboplatin (0%).

3.25 The ERG considered that the evidence of clinical effectiveness presented in the manufacturer’s submission was derived from a high quality trial that used robust randomisation techniques, was suitably powered to demonstrate the primary objectives of the trial for the overall population, and was carried out in a substantial number of patients. The ERG stated that the trial provided convincing evidence of efficacy and benefits to health-related quality of life for gefitinib.

3.26 The ERG highlighted several areas of concern about the clinical evidence submitted by the manufacturer. The ERG was concerned about the generalisability of the clinical results from IPASS to the UK population given the characteristics of the people in the trial (predominantly women, East Asians, non-smokers), the type of NSCLC (adenocarcinoma histology accounts for approximately 25% of the population with NSCLC in the UK), and the comparator used (chemotherapy with paclitaxel and carboplatin is used for first-line treatment of NSCLC in an estimated 5% of patients in the UK).

3.27 The ERG noted that the licensed indication for gefitiib was in locally advanced or metastatic NSCLC in patients with activating mutations of EGFR-TK, and questioned the feasibility of conducting EGFR-TK mutation testing within the NHS given that this is not routine. The ERG noted that making the service operational throughout England and Wales would require substantial investment in both time and resources.

3.28 The ERG highlighted that in IPASS the measurement of the primary outcome of progression-free survival may be unreliable because it was assessed without blinding. The ERG was also concerned that the hazard ratios for this outcome may have been inappropriately calculated using the Cox proportional hazards method. This was because this method is valid only if the hazard ratio for the two groups being compared remains constant over time, and the ERG believed that this criterion was not met in the manufacturer’s intention-to-treat analysis of IPASS. The ERG had major concerns about the immaturity of the overall survival data given that the interim analysis in the manufacturer’s submission was based on a small number of events (450/1217 deaths, 37% maturity) with follow-up ongoing. The ERG highlighted that confounding may have occurred in IPASS because of crossover of treatment after disease progression.Therefore any changes in overall survival may not be a result of the treatment to which patients were originally assigned.

3.29 The ERG highlighted that the manufacturer’s meta-analysis could have appropriately included the First-SIGNAL trial because the comparator used in the First-SIGNAL trial (gemcitabine and cisplatin) was not substantially different in terms of clinical benefit and tolerability from the comparator used in IPASS. The ERG noted that an indirect comparison or mixed-treatment comparison including all three studies (IPASS, NEJGSG and First-SIGNAL) would have been more appropriate. The ERG emphasised a number of weaknesses in the manufacturer’s mixed-treatment comparison, such as the extraction of unreported outcome statistics for some studies from two published meta-analyses. However, different methods were used to estimate unreported hazard ratios and therefore there may have been selection bias regarding the studies included in the mixed-treatment comparison. The ERG was also concerned that the mixed-treatment comparison assumed that EGFR-TK mutation status did not affect treatment outcomes in patients receiving chemotherapy. 

3.30 The ERG noted that assessment of gefitinib is more complex than a simple comparison of two treatment options as presented in the manufacturer’s submission, because it involves both a specific diagnostic test to identify the presence of EGFR-TK mutations and the consequent choice of treatment following the test result (gefitinib or chemotherapy). The accuracy (that is, analytical validity) of the ARMS test for identifying EGFR-TK mutations is very high, but the power of the test result to predict a good response to treatment with gefitinib (that is, clinical validity) is lower. The ERG suggested that the average benefit for patients receiving gefitinib in IPASS involved a trade-off between those who would get a good outcome (people who were ‘true positives’, that is EGFR-TK mutation-positive patients who correctly tested positive for the mutation) and those who would get no benefit at all (people who were ‘false positives’, that is EGFR-TK mutation-negative patients who tested positive for the mutation). The ERG also noted that performance characteristics of the diagnostic test should have been incorporated within the model.

3.31 The ERG also  expressed concern that the prevalence of EGFR-TK mutations would determine the volume and cost of EGFR-TK tests, and that this would contribute to the incremental cost of adopting a ‘test and treat’ policy. The ERG noted that varying the prevalence of EGFR-TK mutations from that stated in the manufacturer’s submission (16.6% producing an ICER of £20,010 per QALY gained based on a 6-year time horizon) to between 5% and 25% produced ICERs ranging from £32,685 to £18,174 per QALY gained. The ERG highlighted that the results from the manufacturer’s economic model for EGFR-TK mutation-positive patients who were receiving gefitinib was dependent on the prevalence of EGFR-TK mutations (that is, the proportion of EGFR-TK mutation-positive patients within the tested population). The results of the economic model were also dependent on the combination of a specific test (ARMS) and gefitinib treatment, and might not be valid if tests other than ARMS were used.

3.32 The ERG believed that the time horizon in the manufacturer’s model should have been 6 years instead of 5 years because this would have been the closest approximation to a lifetime for patients with locally advanced or metastatic NSCLC. The ERG also highlighted that the chemotherapy costs in the model were not accurate. The ERG made adjustments to the costs of first-line chemotherapy comparators, which had a modest impact on cost effectiveness. However, the reduction in dose level of comparator chemotherapy because of the higher proportion of female patients in the population of EGFR-TK mutation-positive patients compared with the general lung cancer population, combined with lower BNF prices for generic paclitaxel, led to an increase in the ICER of gefitinib compared with paclitaxel and carboplatin from £20,010 per QALY gained (based on the 6-year time horizon) to £38,063 per QALY gained.

3.33 The ERG was concerned that IPASS allowed a maximum of six chemotherapy cycles whereas in their view the patients in the UK receive four cycles with up to a maximum of six allowed. This adjustment to the model by the ERG increased the ICER to more than £32,000 per QALYgained when gefitinib was compared with gemcitabine and carboplatin or paclitaxel and carboplatin, and to £44,000 per QALY gained when gefitinib was compared with vinorelbine and cisplatin or gemcitabine and cisplatin. Futhermore, the ERG noted that the economic model assumed that all patients received prescribed medication up to a maximum of six cycles and that this overestimated the mean number of cycles of chemotherapy administered per patient. When corrected, the ICER for gefitinib increased from £20,010 to £25,427 per QALY gained compared with paclitaxel and carboplatin, which was broadly representative of all chemotherapy regimens.

3.34 The ERG expressed concern about the manufactuer’s method of extrapolating survival data beyond the period of IPASS. This involved two-parameter Weibull formulation for modelling both progression-free survival and overall survival. The ERG digitised the Kaplan–Meier curves for EGFR-TK mutation-positive patients in IPASS and used these to calculate the cumulative hazard for each outcome. The ERG highlighted that in a Weibull survival model the cumulative hazard of an event increases exponentially over time, but the results from IPASS did not support this formulation and revealed poor correspondence between the parametric model and the source data, particularly at the beginning and end of the trial. The ERG stated that a simple match to the data could have been obtained by fitting a linear regression line to the two phases to obtain a ‘spline’ model (that is, two exponential models which are spliced together at a time when the risk profile of patients changes). The ERG stated that this method reflected the IPASS data accurately across the whole period of the study and is more accurate than the Weibull models, which overestimate progression-free survival for both treatment arms. The reanalysis by the ERG reduced estimates of progression-free survival and increased estimates of overall survival, but in all cases reduced the incremental gain attributable to gefitinib by approximately 1 month. This suggested a reduction in modelled outcome gains of approximately 25% from those reported in the manufacturer’s submission.

3.35 The ERG noted that the manufacturer’s economic analysis used differential hazard ratios for the four chemotherapy regimens derived from the mixed-treatment comparison. However the ERG felt that the four chemotherapy regimens were of clinically equivalent efficacy.. Furthermore, the mixed-treatment comparison was dependent upon the assumption of proportional hazards, and data from IPASS indicated that this may not be a valid assumption because the hazard ratios within IPASS varied over time. Because the hazard ratios for gefitinib compared with paclitaxel and carboplatin are the primary drivers of patients’ outcomes in the model, and are fed into all comparisons via the results of the mixed-treatment comparison, the ERG expressed concern about all the cost-effectiveness estimates generated by the manufacturer’s model.

3.36 The ERG identified several technical errors in the manufacturer’s model and carried out amendments and corrections to address these issues. The ERG also incorporated docetaxel and cisplatin, and pemetrexed and cisplatin (using results for pemetrexed and cisplatin from the manufacturer’s updated mixed-treatment comparison) into the economic analysis.

3.37 The ERG’s revised base-case analysis indicated that ICERs ranged from £59,016 to £72,908 per QALY gained depending on the comparator used. The ERG highlighted that it appeared from this analysis that gefitinib was dominated by pemetrexed and cisplatin (that is, gefitinib was both more expensive and less effective).

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

4 Consideration of the evidence

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of gefitinib for locally advanced or metastatic NSCLC, having considered evidence on the nature of locally advanced or metastatic NSCLC and the value placed on the benefits of gefitnib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

Management of locally advanced or metastatic NSCLC in UK clinical practice

4.1 The Committee discussed the clinical need of patients with locally advanced or metastatic NSCLC. It heard from the clinical specialists that the main aim of treatment is to extend progression-free and overall survival with the fewest adverse events and with the best quality of life possible for the remaining months of life.

4.2 The Committee heard from clinical specialists that current UK clinical practice is to combine gemcitabine with a platinum drug, usually cisplatin or carboplatin, but that no particular combination chemotherapy regimen is considered more effective than another. The regimen chosen for an individual patient depends on the ease of administration and the associated adverse events. The Committee also heard that chemotherapy with carboplatin in combination with vinorelbine or paclitaxel is not used very often because of the adverse events associated with these agents. The clinical specialists also highlighted that following NICE guidance recommending pemetrexed and cisplatin for the first-line treatment of locally advanced or metastatic NSCLC (TA181),  this therapy is becoming more widely used and is likely to become the standard treatment for patients with non-squamous NSCLC. The Committee accepted that current standard practice in England and Wales is platinum combination therapy, but that pemetrexed and cisplatin is increasingly used. The Committee agreed that treatment which is administered orally, such as gefitinib, offers an advantage because it can be taken at home, and would allow patients to carry on with normal daily activities.

4.3 The Committee was aware that the licensed indication for gefitinib is treatment of locally advanced or metastatic NSCLC in patients with activating mutations of EGFR-TK. The Committee accepted that the manufacturer’s decision problem focused on EGFR-TK mutation-positive patients and therefore the subsequent discussion focused on this population only. The Committee heard from the clinical specialists that gefitinib is the first oral therapy for the first-line treatment of locally advanced or metastatic NSCLC, and that gefitinib’s biological mechanism of action results in targeted therapy with fewer adverse events and improvements in health-related quality of life for EGFR-TK mutation-positive patients. However, outcomes were worse for EGFR-TK mutation-negative patients. Furthermore, the Committee heard from the clinical specialists that targeting therapy at EGFR-TK mutation-positive patients represents a leap forward in terms of increasing the response rate over what is normally seen in lung cancer treatment. The clinical specialists explained that until recently, histological subtyping of NSCLC was not carried out routinely in UK clinical practice because treatment did not depend on the histological subtype of the tumour. However, following NICE guidance (TA181) recommending pemetrexed and cisplatin as a treatment option for patients with NSCLC, it is now rapidly becoming standard practice to determine the histological subtype of NSCLC. The Committee heard from the clinical specialists that EGFR-TK mutation testing is not routinely carried out in UK clinical practice at present because it has not been needed to date. However, the clinical specialists expressed the view that this was not a limiting factor and that implementation of EGFR-TK mutation testing should be seen as analogous to HER2 testing which has been successfully implemented in a short timeframe within the NHS. The Committee was persuaded that although both subtyping and mutation testing may currently not be widely available, the emergence of targeted therapy will lead to the introduction of such testing in the NHS.

Clinical effectiveness

4.4 The Committee considered that the clinical effectiveness evidence presented in the manufacturer’s submission was derived from a large, high quality trial that used robust randomisation techniques, and was suitably powered to demonstrate the primary objectives of the trial for the overall population. However, it noted that evidence from IPASS related mainly to East-Asian women who were non-smokers and had adenocarcinoma histology, and that the licensed indication for gefitinib was in a subgroup of EGFR-TK mutation-positive patients.

4.5 The Committee considered the clinical effectiveness data presented by the manufacturer. It noted that the primary outcome of progression-free survival in IPASS was assessed by unblinded investigator assessment. Evidence from this study showed that in EGFR-TK mutation-positive patients, gefitinib increased the median progression free survival by 3.2 months compared with paclitaxel and carboplatin. The Committee was mindful that the analysis of overall survival was an interim analysis of immature data based on 450 deaths (that is, 37% of patients having died) with ongoing follow-up and a final analysis due in the second quarter of 2010. The Committee noted that progression-free survival may correlate with improved overall survival in NSCLC because of the distribution of local and metastatic disease, but there was uncertainty around this. It also noted the ERG’s concerns that crossover observed in IPASS may have confounded the length of overall survival observed. The Committee accepted the ERG’s view that EGFR-TK mutation-positive patients who received gefitnib had a clinically relevant improvement in health-related quality of life and disease symptoms compared with patients receiving paclitaxel and carboplatin. The Committee accepted the evidence from IPASS that demonstrated that gefitinib improved progression-free survival and health-related quality of life in EGFR-TK mutation-positive patients, but noted that these outcomes were worse than for comparator chemotherapy for EGFR-TK mutation-negative patients.

4.6 The Committee discussed the adverse events experienced by patients receiving treatment for locally advanced or metastatic NSCLC and noted that in IPASS treatment with gefitinib was associated with fewer grade 3 or 4 adverse events than chemotherapy with paclitaxel and carboplatin. The clinical specialists confirmed that gefitinib had been shown to be well tolerated in clinical practice and that this is an important aspect of treatment with this drug. The Committee concluded that gefitinib was associated with an improved safety profile compared with platinum-based chemotherapy.

4.7 The Committee noted that the clinical effectiveness evidence from IPASS related to patients from East Asia who were predominantly female, were non-smokers and had adenocarcinoma histology. It considered how this evidence related to the target population of EGFR-TK mutation-positive patients with locally advanced or metastatic NSCLC treated in England and Wales. The Committee accepted advice from the clinical specialists that the efficacy of gefitinib depended on EGFR-TK mutation status and that there was no reason to assume that efficacy was related to sex, ethnicity, histological subtype or smoking status.

4.8 The Committee noted the ERG’s concerns that the manufacturer assumed the prevalence of EGFR-TK positive mutations in the UK population to be 16.6% (representing patients with adenocarcinoma histology). The Committee heard from the clinical specialists that the prevalence of EGFR-TK positive mutations in patients with NSCLC may range from 5% to 17% depending upon the subpopulation, and that in patients with adenocarcinoma histology the prevalence is more likely to be around 10%. The Committee agreed that there was considerable uncertainty regarding the prevalence of EGFR-TK mutations and that this may have been overestimated in the manufacturer’s submission. The Committee noted the ERG’s concerns about the accuracy and performance of the EGFR-TK mutation test and particularly that patients may be wrongly identified as mutation positive and consequently receive a treatment (gefitinib) which has been shown to lead to worse outcomes than standard chemotherapy in EGFR-TK mutation-negative patients. However, the Committee heard from the clinical specialists that the EGFR-TK mutation test is qualitative rather than quantitative showing either the presence or absence of an EGFR-TK mutation. The clinical specialists stated that there are four or five EGFR-TK mutations that can be identified in NSCLC and it would be unlikely that patients would be wrongly identified as mutation positive. The Committee accepted that there was no reason to assume that patients would be incorrectly identified as mutation positive.

4.9 The Committee discussed the mixed-treatment comparison carried out by the manufacturer which included standard combination therapy with a platinum drug and paclitaxel, docetaxel, gemcitabine or vinorelbine. The Committee noted that this analysis confirmed the clinical view of equivalence between these treatment options with a marginal preference for gemcitabine-containing combination therapy. The Committee further noted that, following feedback from NICE as part of the clarification process, the manufacturer subsequently included pemetrexed and cisplatin in the mixed-treatment comparison. The results of the updated mixed-treatment comparison demonstrated that pemetrexed and cisplatin is more efficacious (for patients with NSCLC of non-squamous type) than the other platinum combination therapies, that gefitinib and pemetrexed/cisplatin showed similar effects in terms of overall survival, but that gefitinib showed longer progression-free survival than pemetrexed and cisplatin. The Committee concluded that there was uncertainty in these comparisons but that it was likely that gefinitib was no less efficacious than pemetrexed and cisplatin.

Cost effectiveness

4.10 The Committee considered the manufacturer’s economic model, and the critique and exploratory sensitivity analyses performed by the ERG. It noted that the manufacturer used a Markov economic model to evaluate the cost effectiveness of gefitinib compared with four different double chemotherapy combinations. The clinical data used were derived from a variety of sources, and although the evaluation was primarily trial-based the manufacturer had carried out modelling to extrapolate the health effects beyond the duration of the IPASS. The Committee noted that the manufacturer’s base-case analyses also incorporated a patient access scheme. The Committee was mindful of the ERG’s concerns around a number of aspects of the economic model, such as choice of time horizon and comparator, costs of first-line chemotherapy, number of chemotherapy treatment cycles, survival modelling, and validity of the results of the mixed-treatment comparison. The Committee was also aware that the ERG had identified a number of technical errors in the manufacturer’s model.

4.11 The Committee noted that the ICERs for gefitinib estimated in the manufacturer’s base case were between £19,402 and £35,992 per QALY gained depending on the comparator chosen. It was mindful that the ICERs presented in the manufacturer’s base case depended on the extrapolation of progression-free survival and overall survival by fitting a Weibull probability distribution. The Committee heard from the manufacturer that a Weibull distribution was chosen to extrapolate survival data beyond the duration of the IPASS trial because there was a good match between the model and the empirical data from the trial. Therefore alternative distributions were not explored. The Committee noted the ERG’s concern that there was poor correspondence between the parametric model and the source data, particularly at the beginning and end of IPASS, and that the ERG’s exploratory analyses using a spline model provided an acceptable fit to the data for progression-free survival. The Committee agreed that there was considerable uncertainty around both the manufacturer’s and ERG’s methods of extrapolating overall survival data and that observational or epidemiological evidence on long-term survival in locally advanced or metastatic NSCLC would be required to determine the most plausible model fit. The Committee agreed that clarification should be sought from the manufacturer including a request for independent survival extrapolations (for overall survival and progression-free survival) for both gefitinib and paclitaxel/carboplatin based on the IPASS data. It also agreed that there should be exploration of different approaches to applying the hazard ratio. It requested that for the comparison of gefitinib with gemcitabine/carboplatin and gemcitabine/cisplatin the following alternative approaches should be used: (a) assuming the same progression-free survival and overall survival as established for paclitaxel/carboplatin through the independent survival curve fitting from IPASS using gemcitabine related costs and adverse events; and (b) applying the hazard ratio from the mixed-treatment comparison for the gemcitabine regimens to the independent survival curves for paclitaxel/carboplatin from IPASS, and using gemcitabine related costs and adverse events. The Committee also agreed that alternative probability distributions should be examined and model fit to early trial data and the shape of the curves at the tail of the distribution should be considered. Furthermore, the Committee requested observational or epidemiological evidence on long-term survival in locally advanced or metastatic NSCLC and clarification of how this relates to the most plausible model fit. The Committee agreed that individual patient-level data from IPASS should be requested from the manufacturer to enable the ERG to validate key aspects of the submitted model, including the modelling of overall survival and progression-free survival, the choice of parameter values, and structural assumptions.

4.12 The Committee noted the wide variation between the ICERs generated by the manufacturer and the ERG, with the ERG generating ICERs ranging from £59,000 to £73,000 per QALY gained. The Committee heard from the clinical specialists that some of the amendments made by the ERG, such as omission of the granulocyte colony-stimulating factor (GCSF) prophylaxis, were not consistent with clinical practice in the NHS. The Committee was however mindful of the concerns raised by the ERG that the costs of chemotherapy in the manufacturer’s model may not be appropriate. The Committee heard from the ERG that EGFR-TK mutation-positive patients may differ from the general population with NSCLC and that this variability was not accounted for in the manufacturer’s model. For example, a higher proportion of EGFR-TK mutation-positive patients are women and would therefore have a lower level of standard chemotherapy because of a smaller body surface area. The Committee agreed that a lower level of dosing for standard chemotherapy may be required and that this would reduce the cost of the comparator chemotherapy and increase the ICER of gefitinib. The Committee was aware that the maximum number of cycles (six) of chemotherapy used in the manufacturer’s model may not be appropriate. The Committee heard from the clinical specialists that in UK clinical practice patients routinely receive four cycles of chemotherapy and up to six cycles if their disease responds well. On the basis of these limitations in the manufacturer’s model, the Committee agreed that it did not have sufficient information to assess the most plausible ICER for gefitinib compared with standard platinum combination therapy, but that the ICER is likely to be above the current estimates from the manufacturer. The Committee concluded that clarification should be sought from the manufacturer including a request for revised costs for first-line chemotherapy and a sensitivity analysis varying the number of first-line chemotherapy cycles between four and six.

4.13 The Committee discussed the additional analyses carried out by the ERG which included expansion of the manufacturer’s economic model to include docetaxel and cisplatin, and pemetrexed and cisplatin. The Committee noted that pemetrexed and cisplatin treatment was dominated by gefitinib (that is, pemetrexed and cisplatin treatment was more expensive and less effective) using the manufacturer’s assumptions. However, when the spline modelling and other assumptions used by the ERG were applied to this comparison, gefitinib was dominated by pemetrexed and cisplatin (gefitinib was more expensive and less effective). The Committee noted that the ERG’s model generated more QALYs gained for pemetrexed and cisplatin than for gefitinib and that this appeared to be counterintuitive. This was because the hazard ratio for progression-free survival for pemetrexed and cisplatin compared with platinum-based chemotherapy from the mixed-treatment comparison was less favourable than the hazard ratio for gefitinb compared with platinum-based chemotherapy. Furthermore, gefitinib is associated with fewer adverse events than pemetrexed and cisplatin. The Committee heard that this discrepancy may be a result of different approaches to modelling survival for the different comparators. The manufacturer's model used a single approach whereby all comparators were modelled by applying a hazard ratio with respect to one treatment with paclitaxel and carboplatin, which led to all treatments being modelled consistently. The ERG's analysis used two approaches: in the first, paclitaxel/carboplatin and gefitinib were modelled independently using separate 'spline' models. In the second, the remaining comparators were modelled by applying a hazard ratio to the 'spline' model for paclitaxel and carboplatin. The Committee considered that the ERG’s two different approaches to modelling overall survival and progression-free survival were not consistent and produced counterintuitive results. The Committee therefore agreed that it did not have sufficient information to assess the most plausible ICER for gefitinib compared with pemetexed and cisplatin and concluded that clarification should be sought from the manufacturer, including an economic analysis of gefintib compared with pemetrexed and cisplatin. The Committee also agreed that exploration of different approaches to applying the hazard ratio should be carried out for the comparison of gefitinib with pemetrexed/cisplatin as follows: (a) applying the hazard ratio from the mixed-treatment comparison for pemetrexed/cisplatin to the independent survival curves for paclitaxel/carboplatin from IPASS, and using pemetrexed-related costs and adverse events; and (b) applying an indirectly derived hazard ratio for pemetrexed/cisplatin compared with gefitinib to the independent survival curves for gefitinib from IPASS, and using pemetrexed-related costs and adverse events.

4.14 The Committee discussed the impact of the prevalence of the EGFR-TK mutation on the cost effectiveness of gefitinib. It noted the prevalence of EGFR-TK mutations assumed by the manufacturer (16.6%, including all patients who had sufficient tissue for testing) and the clinical specialists’ testimony that this figure is more likely to be in the region of 10% for patients with NSCLC of adenocarcinoma subtype in England and Wales. The Committee agreed that clarification should be sought from the manufacturer, including further analyses to explore the sensitivity of the ICER to the prevalence of EGFR-TK mutations (varying the assumption from 5% to 17%). The Committee requested that the manufacturer also take into account different costs, comorbidities and the probability of obtaining a specimen suitable for testing (including possible repeat biopsy to obtain a sample) and the probability of obtaining no useful result for tested specimens.

4.15 The Committee discussed the likely volume of tests for EGFR-TK mutation status that would be carried out and the associated cost of testing. It noted that the number of tests assumed in the manufacturer’s submission was quite conservative and that alternative assumptions had not been explored by the manufacturer or the ERG. It also noted that the cost of testing was linked to the prevalence of EGFR-TK mutations and that the cost of the test could vary according to the volume of tests. The Committee agreed that clarification should be sought from the manufacturer to include further analyses exploring the sensitivity of the ICER to alternative assumptions about the number of EGFR-TK mutation tests and the associated costs.

4.16 The Committee discussed the incorporation of benefits to health-related quality of life and utility values in the manufacturer’s economic model. The Committee noted that the health-related quality of life benefits derived from gefitinib’s adverse event profile were included in the economic model. It accepted that quality of life measurements specific for patients with lung cancer were included in IPASS rather than the EQ5D, because IPASS was a pan-Asian study and the EQ5D is not widely used in Asia. The Committee was aware that the manufacturer also used utility estimates from a study examining second-line chemotherapy for patients with NSCLC in which the mode of delivery of treatment (oral versus intravenous) was included, and that these had been used in ‘Erlotinib for the treatment of relapsed non-small cell lung cancer’ (NICE technology appraisal guidance 162). The Committee noted that there may have been small differences in utility estimates because patients receiving second-line treatment may have had more severe disease than patients receiving gefitinib for first-line therapy, but agreed that the methods used by the manufacturer were appropriate in the absence of other data. The Committee agreed that treatment with gefitinib may reduce the amount of time spent in hospital towards the end of life, which may be an important benefit for patients, and noted that this may not have been fully captured. However, the Committee concluded that the main benefits, and factors affecting the cost effectiveness, were increases in progression-free survival and overall survival rather than these quality of life benefits.

4.17 The Committee noted that the patient access scheme involved a fixed cost being charged for each patient treated with gefitinib regardless of the length of treatment. The Committee agreed that such a scheme was probably relatively simple to administer in the NHS. However, the Committee was concerned that although such a scheme may be beneficial across the whole NHS, there could be some areas where patients receive short courses of treatment and the cost of gefitinib under such circumstances would be greater with the scheme than without it.

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

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

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

4.19 The Committee agreed that because the marketing authorisation specifies use in EGFR-TK mutation-positive patients, gefitinib can be considered to be licensed for a small patient population. The Committee also agreed that currently the life expectancy of people with locally advanced or metastatic NSCLC would normally be less than 24 months. The Committee discussed the survival benefits provided by gefitinib and noted that only data on progression-free survival (not overall survival) were available. These data indicated an extension to progression-free survival of around 3 months based on a comparison of gefitinib with paclitaxel and carboplatin. The Committee agreed that, compared with other combination therapies currently available in the NHS, namely pemetrexed and cisplatin, it has not been shown that gefitinib provides an additional survival benefit of 3 months. The Committee therefore concluded that it could not apply the supplementary advice to treatment with gefitinib.

4.20 The Committee considered issues related to equality. The Committee recognised that the oral administration of gefitinib may be of benefit to patients with mobility issues. However, the Committee noted that no specific analysis was presented to demonstrate the the impact of this on the cost effectiveness of gefitinib. The Committee was also aware that preselecting patients for testing of EGFR-TK mutations on the basis of sex or ethnicity could reduce the cost to the NHS, compared with testing of all patients, but that this could raise equalities issues. The Committee heard from the clinical specialists that although EGFR-TK mutation-positive patients were more likely to have certain characteristics (that is, Asian women with adenocarcinoma histology who are never-smokers), they would not feel comfortable limiting testing to these patients. The Committee accepted the views of the clinical specialists that testing should be carried out on all patients irrespective of sex, ethnicity, and smoking status to ensure that all patients who could benefit would be identified.

4.21 In summary, the Appraisal Committee could not assess whether gefitinib is a cost-effective treatment option because it did not have sufficient information to assess the most plausible ICER for gefitinib compared with standard platinum combination therapy or with pemetrexed and cisplatin. Therefore the Appraisal Committee is minded not to recommend gefitinb for the treatment of locally advanced or metastatic NSCLC. It is recommending that clarification should be sought from the manufacturerer, including analyses that use alternative survival extrapolations and application of hazard ratios, amended first-line chemotherapy costs and chemotherapy cycles, alternative prevalence rates of EGFR-TK mutations and alternative assumptions about the cost of the EGFR-TK mutation tests.

Summary of Appraisal Committee’s key conclusions

TAXXX (STA)

 

Appraisal title: Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer

 

FAD section

 

Key conclusion

 

The Appraisal Committee is minded not to recommend gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer because the evidence for additional benefits over current standard care was insufficient.

The manufacturer has been requested to provide additional data. 

4.21

 

Current practice

 

Clinical need of patients

 

The main aim of treatment is to extend progression-free and overall survival with the fewest adverse events and with the best quality of life possible for the remaining months of life.

 

4.1

 

Availability of alternative treatments

 

Current standard practice in England and Wales is platinum combination therapy with no particular combination chemotherapy regimen considered more effective than another. Pemetrexed is increasingly used for the treatment of non-squamous NSCLC.

 

4.2

 

The technology

 

Proposed benefits of the technology from the manufacturer, clinician and patient perspective

 

The oral method of administration of gefitinib offers an advantage for patients because it can be taken at home, and would allow patients to carry on with normal daily activities.

 

4.2

 

How innovative is the technology

 

Targeting therapy at mutation status positive patients increases the response rate over what is normally seen in lung cancer treatment.

The marketing authorisation requires the implementation of a specific mutation test prior to gefitinib treatment. Although mutation testing is not currently available widely, the Appraisal Committee considered that the emergence of targeted therapy such as gefitinib is likely to lead to the introduction of such testing in the NHS.

4.3

4.3

Adverse events

 

Gefitinib is associated with an improved safety profile compared with platinum-based chemotherapy, an important feature for patients and their carers.

 

4.6

 

Evidence for clinical effectiveness

 

Quality of the evidence

 

The clinical effectiveness evidence was derived from a large, high quality trial that used robust randomisation techniques, and was suitably powered to demonstrate the primary objectives of the trial for the overall population.

 

 

4.4

Availability and nature of evidence

 

The clinical evidence for gefitinib related mainly to East-Asian women, who were non-smokers and had adenocarcinoma histology, and the licensed indication for gefitinib was in a subgroup of patients who were EGFR-TK mutation positive.

The trial provided convincing evidence that, compared with standard platinum combination therapy, gefitinib improves progression-free survival and health-related quality of life in EGFR-TK mutation-positive patients, and that these outcomes were worse for EGFR-TK mutation-negative patients.

Although there is uncertainty in the comparison with pemetrexed/cisplatin treatment, the Appraisal Committee agreed that it was likely that gefinitib is no less efficacious than pemetrexed/cisplatin.

4.4

4.4

4.5

4.9

Relevance to general  clinical practice in the NHS

 

The efficacy of gefitinib depends on the mutation status of each patient and mutation-positive patients are likely to respond to gefitinib irrespective of sex, ethnicity, histological subtype or smoking status.

 

4.7

 

Uncertainties generated by the evidence

 

There is considerable uncertainty about the prevalence of EGFR-TK mutations in NSCLC patients in England and Wales, but there is no reason to assume that patients would be incorrectly identified as mutation positive.

 

4.8

 

Evidence for cost effectiveness

 

Availability and nature of evidence

 

The manufacturer used out a Markov economic model to evaluate the cost effectiveness of gefitinib compared with four different double chemotherapy combinations; using clinical data  derived from a variety of sources, and including modelling to extrapolate the health effects beyond the duration of the clinical trial. The ERG undertook exploratory sensitivity analyses and included two additional comparators. 

 

4.10

 

Uncertainties around and plausibility of assumptions and inputs in the economic model

 

There is considerable uncertainty around both the manufacturer’s and the ERG’s methods of extrapolating overall survival data and observational or epidemiological evidence on long-term survival in locally advanced or metastatic NSCLC is required to determine the most plausible model fit.

There was uncertainty about the first-line chemotherapy costs and the number of cycles of first-line chemotherapy in the model.

There was uncertainty around the sensitivity of the ICER to the prevalence of EGFR-TK mutations of between 5% and 17% and to the probability of obtaining a specimen unsuitable for testing.

There was uncertainty around the sensitivity of the ICER to alternative assumptions regarding the number of EGFR-TK mutation tests and the associated cost.

4.11

4.13

4.12

4.14

4.15

Incorporation of health-related quality of life benefits and utility values

 

The benefits derived from gefitinib’s favourable adverse event profile were included in the economic model.

Treatment with gefitinib may reduce the amount of time spent in hospital towards the end of life, which is likely to be important for patients’ quality of life and for their carers. Although this may not have been fully captured in the utility values used in the economic model, the main benefits and factors affecting the cost effectiveness were increases in progression-free survival and overall survival rather than these quality of life benefits.

4.16

4.16

Most likely cost-effectiveness estimate (given as an ICER)

 

The Appraisal Committee could not assess whether gefitinib is a cost effective treatment option because it did not have sufficient information to assess the most plausible ICER for gefitinib compared with standard platinum combination therapy, but it considered that the ICER is likely to be higher than the estimates provided by the manufacturer. 

The Appraisal Committee was not provided with sufficient information to assess the most plausible ICER for the comparison with pemetrexed.

4.21

 

Additional factors taken into account

 

Patient access scheme

 

The Appraisal Committee was advised that the patient access scheme is likely to be relatively simple to administer in the NHS. However, there were concerns that while such a scheme may be beneficial across the NHS generally, there may be some parts of the NHS where patients receive short courses of treatment. The cost of gefitinib under these circumstances would be greater with the scheme than without it.

 

4.17

 

End-of-life considerations

 

Because of the restriction to mutation-positive patients, gefitinib can be considered to be licensed for a small patient population and life expectancy of people with locally advanced or metastatic NSCLC would normally be less than 24 months with current NHS management. Gefitinib may provide an extension to life compared with paclitaxel and carboplatin, but there is uncertainty around this because the estimate is based on progression-free survival data. Compared with other combination therapies currently available in the NHS, (pemetrexed and cisplatin), it has not been demonstrated that gefitinib provides an additional survival benefit of 3 months or more. The supplementary advice on end-of-life treatments was therefore not considered to be applicable to treatment with gefitinib.

 

4.19

 

Equalities considerations, Social value judgements

 

The oral administration of gefitinib may be of benefit to patients who have mobility issues. However, no specific analysis was available to demonstrate the impact of this on the cost effectiveness of gefitinib.

Testing for EGFR mutations should be carried out on all patients irrespective of sex, ethnicity, and smoking status to ensure that all patients who could benefit would be identified.

4.20

 

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

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

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

6 Related NICE guidance

Published

  • Pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer. NICE technology appraisal guidance No. 181, 2009.  Available from www.nice.org.uk/TA181.
  • Bevacizumab for the treatment of non-small-cell lung cancer (terminated appraisal). NICE technology appraisal guidance  No.148, 2008. Available from www.nice.org.uk/TA148.
  • The diagnosis and treatment of lung cancer.. NICE clinical guideline No.24, February 2005. Available from www.nice.org.uk/CG24.

Under development

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

  • Cetuximab for the treatment of advanced non-small cell lung cancer..NICE technology appraisal guidance. Earliest anticipated date of publication to be confirmed.

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in April 2013. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Amanda Adler
Chair, Appraisal Committee
January 2010


Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and a 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

Dr Amanda Adler (Chair)
Consultant Physician, Addbrooke's Hospital, Cambridge

Professor Keith Abrams
Professor of Medical Statistics, University of Leicester

Dr Michael Boscoe
Consultant Cardiothoracic Anaesthetist, Royal Brompton and Harefield NHS Foundation Trust

Dr Mark Chakravarty
External Relations Director – Pharmaceuticals & Personal Health, Oral Care Europe

Dr Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Ms Sally Gooch
Independent Nursing and Healthcare Consultant

Mr Terence Lewis
Lay member

Dr Ruairidh Milne
Director of Strategy and Development and Director for Public Health Research at the NIHR Evaluation, Trials and Studies Coordinating Centre, University of Southampton

Dr Rubin Minhas
General Practitioner and Clinical Director, BMJ Evidence Centre

Mr Stephen Palmer
Senior Research Fellow, Centre for Health Economics, University of York

Dr Sanjeev Patel
Consultant Physician and Senior Lecturer in Rheumatology, St Helier University Hospital, Carshalton

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr Ann Richardson
Lay member

Dr Florian Alexander Ruths
Consultant Psychiatrist and Cognitive Therapist, Maudsley Hospital, London

Mr Roderick Smith
Finance Director, West Kent Primary Care Trust

Mr Cliff Snelling
Lay member

Professor Ken Stein (Vice Chair)
Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens
Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham

Ms Nathalie Verin
Health Economics Manager, Boston Scientific UK and Ireland

C NICE project team

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

Fay McCracken
Technical Lead

Bhash Naidoo and Zoe Charles
Technical Advisers

Jeremy Powell
Project Manager

Appendix B: Sources of evidence considered by the Committee

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

  • Brown T, Boland A, Bagust A, et al. Gefitinib for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), November 2009

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

I Manufacturer/sponsor:

  • AstraZeneca

II Professional/specialist and patient/carer groups:

  • British Thoracic Society (Lung Cancer and Mesothelioma Working Party)
  • Cancer Research UK
  • Macmillan Cancer Support
  • National Lung Cancer Forum for Nurses
  • Royal College of Nursing
  • Royal College of Pathologists
  • Royal College of Physicians, Medical Oncology Joint Special Committee
  • Roy Castle Lung Cancer Foundation
  • UK Oncology Nursing Society

III Other consultees:

  • Deparment of Health
  • Kirklees Primary Care Trust
  • Welsh Assembly Government

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

  • British Thoracic Oncology Group
  • Commissioning Support Appraisals Service
  • Department of Health, Social Services and Public Safety for Northern Ireland
  • Eli Lilly
  • Medac
  • NHS Quality Improvement Scotland
  • Pierre Fabre
  • Sanofi Aventis

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

  • Professor Mike Lind, Consultant Medical Oncologist, Castle Hill Hospital, nominated by the Royal College of Physicians – clinical specialist

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

  • AstraZeneca

This page was last updated: 30 March 2010