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

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 up to the end of 2009 UK clinical practice was to combine gemcitabine with a platinum drug, usually cisplatin or carboplatin, but that no particular regimen of combination chemotherapy was considered more effective than another. The regimen chosen for an individual patient depended on the ease of administration and the associated adverse effects. The Committee also heard that chemotherapy with carboplatin in combination with vinorelbine or paclitaxel is not used very often because of the adverse effects 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 concluded that pemetrexed plus cisplatin is the most appropriate principal comparator for the first-line treatment of non-squamous NSCLC.

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. 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. Furthermore, the Committee heard from the clinical specialists that targeting therapy at EGFR-TK mutation-positive patients represents an innovative approach to treatment in terms of increasing the response rate over what is normally seen in lung cancer treatment. The clinical specialists explained that, until recently, pathologists in the UK did not routinely carry out histological subtyping of NSCLC because treatment did not depend on the histological subtype. However, following NICE guidance (TA181) recommending pemetrexed and cisplatin as a treatment option for patients with confirmed adenocarcinoma or large-cell carcinoma, 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 the emergence of therapy targeted to EGFR-TK mutation status will lead to the introduction of testing in the NHS, and that the NHS has the capacity and expertise to undertake testing. The Committee was persuaded that the need for testing for the EGFR-TK mutation would not limit treatment and that it should be seen as analogous to testing for human epidermal growth factor receptor 2 (HER2), which has been successfully implemented in a short timeframe within 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 (IPASS) 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 did not smoke and who had adenocarcinoma histology. The Committee considered how this evidence would relate to the target population of EGFR-TK mutation-positive patients with locally advanced or metastatic NSCLC treated in England and Wales. It 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 would differ according to gender, ethnicity, histological subtype or smoking status.

4.5 The Committee considered the results from the IPASS study presented by the manufacturer. It noted that the primary outcome of progression-free survival in IPASS was assessed by unblinded investigators. 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 aware that the analysis of overall survival was an interim analysis of immature data based on 450 deaths (that is, 37% of patients having died) and that a final analysis from follow-up was due in the second quarter of 2010. The Committee noted that a longer progression-free survival may correlate with improved overall survival in NSCLC, but there was uncertainty around this. It also noted the ERG's concerns that crossover observed in IPASS may have influenced the length of overall survival observed. The Committee accepted the ERG's view that EGFR-TK mutation-positive patients who were randomised to receive gefitinib had a clinically relevant improvement in health-related quality of life and disease symptoms compared with patients randomised to receive paclitaxel and carboplatin. The Committee concluded that the evidence from IPASS demonstrated that gefitinib improved progression-free survival and health-related quality of life in EGFR-TK mutation-positive patients. By contrast, the Committee noted that for EGFR-TK mutation-negative patients gefitinib was associated with worse outcomes when compared with chemotherapy.

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 adverse effects profile compared with platinum-based chemotherapy.

4.7 The Committee noted the ERG's concerns that the manufacturer assumed a prevalence of EGFR-TK mutations of 16.6% in the UK population (representing patients with adenocarcinoma histology). The Committee heard from the clinical specialists that the prevalence of EGFR-TK mutations in patients with NSCLC may range from 5.0% to 17.0% depending on the subpopulation, and that in patients with adenocarcinoma histology the prevalence is more likely to be around 10%. This was also supported by consultees who advised that the prevalence of EGFR-TK mutations is between 10% and 15%. The Committee was therefore satisfied that the prevalence of the EGFR-TK mutation was likely to be between 10% and 15% in the target population.

4.8 The Committee noted the ERG's concerns about the accuracy and performance of the EGFR-TK mutation test and particularly the risk that patients may be wrongly identified as mutation positive and consequently receive a treatment (gefitinib) which has been shown in EGFR-TK mutation-negative patients to lead to worse outcomes than standard chemotherapy. However, the Committee heard from the clinical specialists that the EGFR-TK mutation test is qualitative rather than quantitative and shows either the presence or absence of an EGFR-TK mutation. The clinical specialists stated that it would be unlikely that patients would be wrongly identified as having a mutation when they did not have one. The Committee accepted that there was little reason to assume that patients would be incorrectly identified.

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 supported the clinical view of similar efficacy between these treatment options, with a marginal preference for gemcitabine-containing therapy. The Committee further noted that, following feedback from NICE as part of the initial clarification process, the manufacturer included pemetrexed and cisplatin in the mixed-treatment comparison. The results of the updated mixed-treatment comparison suggested that pemetrexed and cisplatin had a greater effect on overall survival (for patients with NSCLC of non-squamous type) than the other platinum combination therapies, that gefitinib showed similar effects in terms of overall survival to pemetrexed in combination with cisplatin, and that gefitinib showed longer progression-free survival than pemetrexed and cisplatin. The Committee accepted that there was uncertainty in these comparisons but concluded that it was likely that gefitinib was no less efficacious than pemetrexed and cisplatin, and that pemetrexed in combination with cisplatin was the relevant comparator for gefitinib.

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.

4.11 The Committee noted that the manufacturer's base-case analyses incorporated a patient access scheme. It 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 the updated scheme submitted by the manufacturer following consultation (whereby the NHS will not be invoiced until the supply of the third monthly pack of gefitinib) was probably relatively simple to administer in the NHS and that it involved less uncertainty than the original scheme. The Committee understood that the NHS would not be charged for gefitinib if patients needed two or fewer months of treatment.

4.12 The Committee discussed the incorporation of benefits to health-related quality of life and utility in the manufacturer's economic model. The Committee noted that the values of health-related quality of life derived from gefitinib's adverse event profile were included in the economic model. The Committee accepted that measurements of quality of life specific for patients with lung cancer rather than the EQ–5D were included in IPASS, because the EQ–5D is not widely used in Asia. The Committee was aware that the manufacturer used utility estimates from a study examining second-line chemotherapy for patients with NSCLC, which had included the mode of delivery of treatment (oral versus intravenous); these estimates were also used in 'Erlotinib for the treatment of relapsed non-small cell lung cancer' (NICE technology appraisal guidance 162). Acknowledging that patients receiving second-line treatment may have had more severe disease and slightly worse utility than patients receiving gefitinib for first-line therapy, the Committee 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 it heard from the clinical specialists and patient experts was an important benefit for patients, and noted that this may not have been fully captured in the manufacturer's economic model. The Committee concluded that these quality-of-life benefits were an important aspect of treatment with gefitinib and that taking these into account would reduce the ICERs for gefitinib.

4.13 The Committee noted that the ICERs for gefitinib estimated in the manufacturer's original base case were between £19,400 and £36,000 per QALY gained depending on the comparator chosen, and it was aware that the ICERs depended on the manufacturer having extrapolated progression-free survival and overall survival by fitting a Weibull probability distribution. The Committee considered the four alternative probability distributions presented in the manufacturer's additional analyses following its request for further clarification in the appraisal consultation document. The Committee accepted that for progression-free survival the fitted distributions for both the stratified and unstratified models appeared similar and that the manufacturer's selection of the unstratified Weibull model was appropriate because it appeared to provide the best fit to the progression-free survival data and because it met the proportional hazards assumption (that is, a constant ratio of the hazards between the two treatments across all points in time). The Committee noted that for overall survival the tails of the stratified Weibull and log-logistic models crossed after day 930. The Committee considered the final overall survival data from the NEJGSG study, submitted in confidence by the manufacturer, and accepted the manufacturer's explanation that there was no plausible clinical reason for crossing of the survival curves. The Committee was persuaded that, for both progression-free survival and overall survival, the unstratified Weibull distribution was appropriate for extrapolating the data beyond the duration of the IPASS because it appeared to fit the data better than other distributions and was consistent with long-term historical survival data in similar populations. The Committee considered the ERG's critique of the manufacturer's economic modelling. It was aware of the ERG's concern that there was an anomaly in the manufacturer's updated economic model relating to Kaplan–Meier estimates of survival in IPASS. However, the Committee accepted that the anomaly reflected a typographical error and did not affect the manufacturer's cost-effectiveness calculations.

4.14 In addition, the Committee was aware of concerns raised by the ERG that the costs of chemotherapy in the manufacturer's original model may not have been appropriate. The Committee heard from the ERG that EGFR-TK mutation-positive patients may differ from the general population with NSCLC and that the manufacturer's model did not take into account this variability. For example, a higher proportion of patients who test positive for the EGFR-TK mutation are women who, on average, have a smaller body surface area and a lower dosage of standard chemotherapy. The Committee acknowledged that this would reduce the cost of the comparator chemotherapy and increase the ICER of gefitinib. The Committee was also aware of the ERG's concerns that the maximum number of cycles of chemotherapy (six) assumed in the manufacturer's original model may not be appropriate. However, it accepted the views of the clinical specialists that, because of the availability of better anti-emetics and improved tolerability, there is an upward trend in the number of cycles given and that patients increasingly receive up to six cycles if their disease responds well, with five cycles being the average.

4.15 The Committee considered the manufacturer's additional analyses following its request for further clarification in the appraisal consultation document. These additional analyses incorporated amended costs for first-line chemotherapy and a sensitivity analysis varying the number of first-line chemotherapy cycles between four and six. The Committee accepted the ERG's view that four of the requested amendments to the modelling (a mid-cycle correction, corrected costs for first- and second-line chemotherapy, and adjusted costs to take account of patient drug exposure) had not been implemented correctly in the manufacturer's revised analysis. It further accepted that the ERG's additional analysis to adjust for this resulted in ICERs for gefitinib ranging from £30,400 per QALY gained compared with six cycles of gemcitabine and carboplatin to £40,000 per QALY gained compared with four cycles of gemcitabine and carboplatin (see section 3.39).

4.16 The Committee discussed the impact of the prevalence of the EGFR-TK mutation (10% to 15% for patients with NSCLC of adenocarcinoma histology, see section 4.7) on the cost effectiveness of gefitinib. The Committee was aware that the cost of testing was linked to the prevalence of EGFR-TK mutations and the volume of tests and heard from the clinical specialists and consultees that the cost was likely to be in the region of £150. The Committee noted that, following its request for further clarification in the appraisal consultation document, the manufacturer had provided two-way sensitivity analyses, varying both the prevalence of EGFR-TK mutations and the costs of EGFR testing. The Committee further noted that applying the ERG's corrections to the manufacturer's additional analyses (see section 3.40), and assuming a cost for EGFR-TK mutation testing of £157.50 and six cycles of chemotherapy, resulted in ICERs ranging from £31,800 per QALY gained (with a 10% prevalence of EGFR-TK mutation) to £27,500 per QALY gained (with a 17% prevalence of EGFR-TK mutation) for gefitinib compared with gemcitabine plus carboplatin. The Committee concluded that varying the prevalence of EGFR-TK mutations between 10% and 15% did not dramatically alter the ICERs for gefitinib.

4.17 The Committee discussed additional analyses performed by the ERG which expanded the manufacturer's economic model to include docetaxel plus cisplatin, and pemetrexed plus 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 than gefitinib) using the manufacturer's assumptions, but not when using the spline modelling and other assumptions used by the ERG. The Committee understood that this was because of different approaches used by the manufacturer and the ERG to modelling survival for the different comparators.

4.18 The Committee noted that, following its request for further clarification in the appraisal consultation document, the manufacturer had provided additional analyses comparing gefitinib with pemetrexed plus cisplatin using either paclitaxel plus carboplatin or gefitinib as the baseline (that is, the baseline rates of survival to which the hazard ratios were applied). The Committee noted that taking into account the ERG's corrections to the manufacturer's additional analyses (see section 3.41) and using paclitaxel plus carboplatin as the baseline resulted in ICERs of £23,600 per QALY gained for a maximum of six cycles (mean 5.4 cycles) and £64,500 per QALY gained for a maximum of five cycles (mean 4.6 cycles). When using gefitinib as the baseline, gefitinib dominated pemetrexed plus cisplatin (that is, pemetrexed plus cisplatin was both more expensive and less effective than gefitinib) regardless of whether the model assumed a maximum or five or six cycles. The Committee considered that it was not possible to make a judgement about the most appropriate method for applying the hazard ratios and noted the differences in the ICERs depending on the method used. Taking into account this uncertainty, together with advice received on the variation in the number of chemotherapy cycles received by patients (see section 4.14), and the probable underestimation in the modelling of quality-of-life benefits associated with gefitinib (see section 4.12) the Committee agreed that the results of the ERG's additional analyses comparing gefitinib with pemetrexed plus cisplatin suggested, on balance, that gefitinib would be a cost-effective use of NHS resources. The Committee concluded that at the fixed price agreed under the patient access scheme, gefitinib should be recommended for the first-line treatment of locally advanced or metastatic NSCLC in EGFR-TK mutation-positive patients.

4.19 The Committee considered whether its recommendations were associated with any potiental issues related to equality. The Committee was aware that selecting patients with a higher probability of being positive when testing for EGFR-TK mutations (on the basis of their gender or ethnicity) could reduce the cost to the NHS, but that this could raise issues related to equality. The Committee heard from the clinical specialists that although EGFR-TK mutation-positive patients were more likely to have certain characteristics (that is, to be Asian women who have never smoked and have tumours with adenocarcinoma histology), 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 eligible patients irrespective of gender, ethnicity, and smoking status to ensure that all eligible patients who could benefit would be identified.

4.20 The Committee had initially considered whether it should follow the 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. However, the Committee agreed that, following the additional information submitted by the manufacturer, this consideration was no longer necessary given that the most plausible ICERs, as outlined in section 4.18, fell below the threshold normally considered to be a cost-effective use of NHS resources.

Summary of Appraisal Committee's key conclusions