4 Evidence and interpretation
The appraisal committee considered evidence from a number of sources.
4.1 Clinical effectiveness
A single RCT of pemetrexed in MPM was identified. The EMPHACIS ('Evaluation of mesothelioma in a Phase III trial of pemetrexed with cisplatin') study compared pemetrexed plus cisplatin with cisplatin alone. This was a single-blind, international, multicentre trial in 448 patients. To be eligible, patients had to be 18 years or older, and were required to have a minimum life expectancy of 12 weeks, uni- or bi-dimensionally measurable disease, and a KPS of greater than or equal to 70. Patients who had had prior chemotherapy, those with a second primary malignancy or brain metastasis, and those unable to interrupt non-steroidal anti-inflammatory drugs were excluded.
Patients in the intervention arm (n=226) received pemetrexed at a dose of 500 mg/m2 followed 30 minutes later by cisplatin at a dose of 75 mg/m2. Patients in the control arm (n=222) received normal saline followed 30 minutes later by cisplatin at a dose of 75 mg/m2. In both arms, treatment was administered on the first day of each 21-day cycle. The median number of cycles given was 6 (range 1–12) in the pemetrexed plus cisplatin arm and 4 (range 1–9) in the cisplatin arm. Median length of follow-up was 10 months.
During the early stages of the trial, incidences of severe toxicity (including drug-related death, neutropenia, febrile neutropenia and diarrhoea) were high in the combination arm. Folic acid and vitamin B12 supplementation were therefore added to the trial protocol in both treatment arms to preserve blinding. With effect from the date of the protocol change, all patients received supplementation, resulting in three patient subgroups defined by supplementation status: never supplemented (n=70), partially supplemented (those who started treatment before the protocol change; n=47) and fully supplemented (those who started treatment after the protocol change; n=331). The primary analysis was performed on all patients who were randomised and treated (intention-to-treat [ITT] population). A subgroup analysis was performed on fully supplemented patients. Further post-hoc subgroup analyses were performed on fully supplemented patients with advanced disease (stage 3/4) because it was thought that most patients presenting to clinicians would fall into this category.
The primary endpoint of the EMPHACIS trial was survival. A statistically significant survival benefit was observed in patients randomised to pemetrexed plus cisplatin versus those receiving cisplatin alone. In the ITT population, median survival was 12.1 months (95% confidence interval [CI], 10.0 to 14.4) in the pemetrexed plus cisplatin arm versus 9.3 months (95% CI, 7.8 to 10.7) in the cisplatin arm (hazard ratio [HR] 0.77; 95% CI, 0.61 to 0.96; log rank test p=0.02). In fully supplemented patients, median survival was 13.3 months (95% CI, 11.4 to 14.9) in the combination arm versus 10 months (95% CI, 8.4 to 11.9) in the cisplatin arm (HR 0.75; 95% CI, 0.57 to 1.00; log-rank test p=0.051). In fully supplemented patients with advanced disease, median survival was 13.2 months (95% CI, 9.3 to 14.9) in the combination arm versus 8.4 months (95% CI, 6.8 to 10.2) in the cisplatin arm (HR 0.63; 95% CI, 0.46 to 0.86; log rank test p=0.003).
Secondary endpoints included 1-year survival, median time to progressive disease and tumour response rate. Pemetrexed plus cisplatin demonstrated statistically significant benefits versus cisplatin alone for all of these outcomes in the ITT population and in the subgroups. The results for these endpoints in the ITT population for the pemetrexed plus cisplatin group versus the cisplatin alone group, respectively, were as follows:
1-year survival: 50.3% versus 38.0% (p=0.012)
median time to progression: 5.7 months versus 3.9 months (p<0.001)
tumour response rate: 41.3% versus 16.7% (p<0.001).
Quality of life was evaluated using the Lung Cancer Symptom Scale–Meso instrument. Several aspects of quality of life were evaluated, including pain, dyspnoea, fatigue, anorexia and cough. Over 18 weeks, patients treated with pemetrexed plus cisplatin demonstrated statistically significant symptomatic improvements when compared with those who received cisplatin alone. For global quality of life in the ITT population, a least squares mean score of 56 out of 100 was reported for patients randomised to pemetrexed plus cisplatin versus a score of 53 out of 100 for patients in the cisplatin arm (p value for the difference between arms = 0.012). A similar result was observed in the fully supplemented population.
Severe to life-threatening or disabling adverse events were statistically significantly more frequent in patients receiving pemetrexed plus cisplatin than in those receiving cisplatin alone. The most commonly reported of these in patients receiving pemetrexed plus cisplatin were: neutropenia (27.9%), leukopenia (17.7%), nausea (14.6%) and vomiting (13.3%). Supplementation with folic acid and vitamin B12 resulted in a consistent reduction in the severity and incidence of adverse events (except for dehydration) in the pemetrexed plus cisplatin arm. The most common severe adverse events in fully supplemented patients randomised to pemetrexed plus cisplatin were: neutropenia (23.2%), leukopenia (14.9%), nausea (11.9%) and vomiting (10.7%).
Supplementary documentation on pemetrexed provided by the manufacturer indicated that, in the ITT population, 42% (94 of 226) of patients randomised to pemetrexed plus cisplatin responded to treatment. Of those who experienced a response, 87% (82 of 94) did so within four cycles.
Summary of the evidence on clinical effectiveness
The results of the EMPHACIS trial suggest that pemetrexed plus cisplatin confers a survival benefit of approximately 3 months compared with cisplatin alone. The combination treatment also appears to demonstrate advantages in terms of 1-year survival, median time to progressive disease, tumour response rate and quality of life. Pemetrexed plus cisplatin appears to offer greater survival benefits than cisplatin alone in patients with advanced disease.
4.2 Cost effectiveness
Estimates of cost effectiveness were provided by the manufacturer and by the Assessment Group. A review of the published literature identified a single cost-effectiveness study. This was a conference presentation/abstract that was a forerunner of the manufacturer's submission.
Two cost-effectiveness models were submitted by the manufacturer. Model 1 compared pemetrexed plus cisplatin with cisplatin alone. Model 2 compared pemetrexed plus cisplatin with standard care (as defined by the manufacturer on the basis of a market research survey). Both models had a 29-month time horizon (reflecting the trial follow-up period) and took a health service perspective. Both considered outcomes in terms of life years gained and quality-adjusted life years (QALYs). No discounting was applied to costs, because they were all incurred within 1 year. Outcomes were discounted at 3.5%.
Model 1 was based on individual patient data from the EMPHACIS trial. The model considered four subgroups: fully supplemented patients; fully supplemented patients with advanced disease; fully supplemented patients with good performance status (WHO performance status of 0 or 1); and fully supplemented patients with advanced disease and good performance status. Data for resource use were taken from the trial and unit costs were taken from Department of Health reference costs or official drug price lists (BNF,MIMS 2005). Mean survival was estimated from the trial data using Kaplan-Meier curves. Utility scores were taken from an ongoing observational study in patients with non-small-cell lung cancer (NSCLC) who completed the EQ‑5D health-related quality of life questionnaire before chemotherapy. The base-case utility scores in both economic models were similar for both arms (0.68 for the pemetrexed plus cisplatin arm and 0.69 for the cisplatin alone arm) and did not take account of loss of quality of life in people with MPM as their disease progresses. A range of one-way and two-way sensitivity analyses was performed. No probabilistic sensitivity analysis was performed.
The incremental cost-effectiveness ratio (ICER) was £68,598 per QALY gained in the fully supplemented population. The ICER was more favourable in fully supplemented patients with advanced disease (£53,314 per QALY gained), fully supplemented patients with good performance status (£48,099 per QALY gained), and fully supplemented patients with advanced disease and good performance status (£47,567 per QALY gained).
Model 2 indirectly compared pemetrexed plus cisplatin with MVP, vinorelbine (with or without platinum) and ASC. Costs and outcomes for pemetrexed plus cisplatin were taken from the fully supplemented population in model 1. For the comparators, resource use data were gathered from market research surveys of oncologists, commissioned by the manufacturer. Zero cost was assumed for ASC, because it was reasoned that participants in chemotherapy trials would have received a similar level of ASC to patients receiving ASC alone. Median survival estimates were taken from a review of the published literature. Mean values for use in the cost-effectiveness analysis were derived by calculating a weighted average of reported medians and assuming the same mean to median ratio as that observed in the cisplatin only arm of the EMPHACIS trial. The same utility values were used as in model 1, with the utility for cisplatin (0.69) being applied to all comparators in model 2. A range of one-way and two-way sensitivity analyses was performed. The incremental cost per QALY gained for pemetrexed plus cisplatin was calculated to be £21,731 versus MVP, £28,391 versus vinorelbine with or without platinum and £32,066 versus ASC.
When the Assessment Group corrected the survival estimate for MVP for performance status, an ICER of £47,972 per QALY gained was obtained for pemetrexed plus cisplatin versus MVP. Using more favourable survival estimates and taking the number of cycles of chemotherapy from the literature rather than the manufacturer's market research survey, the ICERs versus MVP and vinorelbine were both above £60,000 per QALY gained. Using survival estimates for ASC taken from a meta-analysis designed to consider prognostic factors in MPM resulted in an ICER of £48,779 per QALY gained for pemetrexed plus cisplatin versus ASC.
The Assessment Group also carried out its own economic analysis of pemetrexed plus cisplatin compared with cisplatin alone. The four subgroups considered in the manufacturer's model 1 were analysed. Mean costs were derived from the individual patient data in model 1. Costs were not discounted. To derive mean effectiveness estimates, Weibull distributions were fitted to the Kaplan-Meier survival curves from the EMPHACIS trial, in order to model the survival distribution of patients at the end of the follow-up period. Mean survival was estimated using the weighted least squares method and a discount rate of 3.5% was applied. In both arms, the Assessment Group used mean utility values of 0.51–0.54 for each subgroup. These values were calculated using an initial utility of 0.65, falling to 0.40 during a 100-day terminal period to account for lower quality of life in people with MPM towards the end of their life.
The Assessment Group's analysis resulted in an ICER of £60,600 per QALY gained in the fully supplemented population. The results were more favourable in fully supplemented patients with advanced disease (£49,100 per QALY gained), fully supplemented patients with good performance status (£50,400 per QALY gained) and fully supplemented patients with advanced disease and good performance status (£37,700 per QALY gained). The Assessment Group also calculated the cost effectiveness of pemetrexed plus cisplatin versus cisplatin alone in fully supplemented patients with advanced disease and good performance status under the assumption that a smaller 100-mg vial of pemetrexed becomes available. In this case the ICER was £34,500 per QALY gained.
In a later document, the manufacturer suggested that the ICERs for pemetrexed plus cisplatin might be lower if treatment was stopped in patients who did not experience a tumour response after their fourth cycle. It was suggested that this would lower overall costs without reducing aggregate health benefit, because only those who respond to treatment would experience survival gains. No clinical evidence or economic analysis to support this proposal was submitted.
Summary of the evidence on cost effectiveness
The economic analyses carried out by the manufacturer and the Assessment Group, using model 1, both indicated an incremental cost per QALY gained of greater than £60,000 when pemetrexed plus cisplatin was compared with cisplatin alone in the fully supplemented population. Pemetrexed plus cisplatin, when compared with cisplatin alone, appears to have lower ICERs in patients with advanced disease and/or good performance status. The manufacturer's economic analyses (based on indirect comparisons) using model 2 indicated more favourable ICERs for pemetrexed plus cisplatin when compared with MVP, vinorelbine and ASC. However, the assumptions underpinning model 2 are subject to high levels of uncertainty. When the assumptions were modified to reflect performance-status-adjusted survival, and resource use based on published data, the ICERs from model 2 were in line with those of pemetrexed plus cisplatin versus cisplatin alone.
4.3 Consideration of the evidence
The committee reviewed the data available on the clinical and cost effectiveness of pemetrexed for the treatment of MPM, having considered evidence on the nature of the condition and the value placed on the benefits of pemetrexed by patient representatives and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.
The committee heard from clinical specialists and patient experts that pemetrexed plus cisplatin is valued as a potential treatment option in a disease area where it has demonstrated survival and quality of life advantages in an RCT and where there is incomplete evidence on the efficacy of alternative treatments.
The committee discussed the relevant comparator for pemetrexed plus cisplatin in the context of the NHS. Clinical specialists advised that cisplatin monotherapy would not normally be used to treat MPM in clinical practice in England and Wales because of a lack of evidence of its effectiveness and its relatively unfavourable adverse-effect profile. The committee heard that there is no standard care pathway for MPM; although some patients receive chemotherapy treatment, notably with MVP or vinorelbine, many patients receive ASC only. However, the committee was also aware that there have been no published RCTs of MVP or vinorelbine in MPM, either versus ASC or against each other. The committee noted that the results of a meta-analysis investigating prognostic factors for MPM suggest that survival with ASC without chemotherapy may be no worse than with chemotherapy. The committee agreed that a direct RCT comparison of the efficacy of pemetrexed plus cisplatin versus other chemotherapy treatments and ASC would be an informative addition to the evidence base.
The committee discussed whether pemetrexed should be recommended over treatments for MPM used most frequently in the UK, and therefore considered the indirect comparisons submitted by the manufacturer. It discussed the plausibility of the result that pemetrexed plus cisplatin had lower ICERs when compared with MVP, vinorelbine and ASC than when it was compared with cisplatin alone. The committee noted the high degree of uncertainty surrounding the assumptions underpinning the model and observed that the survival estimates had been taken from relatively small, non-comparative and observational studies. It also noted that the study populations were unlikely to be comparable with the population of the EMPHACIS trial, particularly in terms of performance status, a key independent predictor of survival in MPM patients.
The committee also noted that resource-use estimates for MVP and vinorelbine (based on the number of cycles of chemotherapy derived from the manufacturer's market research surveys) were higher than those reported in the studies from which the effectiveness estimates were taken, and considered the possibility that comparator costs may have been overestimated. The committee saw that when the model assumptions were amended to incorporate more favourable survival estimates and resource use taken from the literature, ICERs were significantly higher. On balance, the committee concluded that it could not base its decision on the indirect comparison model.
The committee heard from clinical specialists that cisplatin could be considered a valid chemotherapeutic agent even though it is not favoured in the UK. The committee discussed what could be inferred when the comparative evidence was limited to pemetrexed and cisplatin. It concluded that the survival benefit demonstrated by pemetrexed plus cisplatin in the EMPHACIS trial was likely to be robust because cisplatin was likely to be at least as effective as placebo or ASC, although, in terms of quality of life, cisplatin is likely to have adverse effects. The committee also noted that cisplatin was likely to have higher costs than placebo or ASC and that this would affect the results of cost-effectiveness analysis. The committee discussed the ICERs of pemetrexed plus cisplatin versus cisplatin alone produced by the manufacturer and the Assessment Group, and observed that the range of ICERs was higher than is normally considered acceptable.
The committee considered whether it was appropriate to accept economic results expressed in incremental costs per life year gained. The committee noted that the 'Guide to the methods of technology appraisal' advises that the reference case measure of health benefits is the QALY, and that 'where health gain is expressed in terms of life years gained, the range of most plausible ICERs that are acceptable will be substantially lower...' (18.104.22.168). The committee did not consider it plausible that a patient with MPM on chemotherapy would have a full quality of life and this was confirmed by the experts present at the meeting. Furthermore, the committee heard from clinical specialists that utility values derived from studies in NSCLC are a fair approximation of the utility values for people with MPM, and noted that sensitivity analyses indicated the ICERs from the manufacturer's economic model were not strongly influenced by the utility values. The committee agreed that there are no reasons for it to change its preference for QALYs.
The committee discussed the subgroup of patients with both advanced disease and good performance status, in view of the relatively favourable ICERs of pemetrexed plus cisplatin versus cisplatin alone (£37,000 per QALY gained, or £34,500 per QALY gained assuming a 100-mg pemetrexed vial becomes available) that were calculated for this subgroup. The committee was aware that most people with unresectable disease would be considered to have advanced disease and that this subgroup of patients comprised the majority of people with MPM seen in UK clinical practice. The committee accepted that it was plausible that people with good performance status were likely to show a better response to treatment than those with poor performance status.
The committee noted that not all patients respond to treatment with pemetrexed plus cisplatin and saw that, in the EMPHACIS trial, 87% of those who responded had done so within four cycles. Furthermore, the committee noted from the consultation that it would be unusual for a UK oncologist to continue treatment beyond four cycles if there was disease progression or no response to treatment. The committee therefore accepted that the mean number of cycles in clinical practice was likely to be less than the mean of six cycles reported in the EMPHACIS trial, and this would result in lower estimates of pemetrexed drug costs.
The committee discussed the possibility that differences in symptom relief (including pain and dyspnoea) and quality of life between pemetrexed plus cisplatin and cisplatin alone may not have been captured fully by the economic model because the utilities for both treatment and comparator had been estimated based on data from people with NSCLC. The committee noted that there was some evidence from the EMPHACIS trial showing that pemetrexed plus cisplatin was associated with statistically significant symptomatic improvements (especially with pain relief) compared with cisplatin alone. The committee agreed that the economic analyses may have underestimated the overall quality of life benefits of pemetrexed in people with MPM.
Having considered the likelihood of lower numbers of treatment cycles in clinical practice, the potential availability of a 100-mg pemetrexed vial and the likelihood of greater quality of life benefits than assumed by the cost-effectiveness analyses, the committee agreed that the ICER for pemetrexed plus cisplatin in the fully supplemented subgroup with advanced disease and good performance status was likely to fall within acceptable levels.
The committee also noted that MPM is a rare and aggressive malignancy caused by occupational exposure to asbestos and was mindful that this disease has a very poor prognosis.
The committee concluded that pemetrexed in combination with cisplatin should be recommended as an option for the treatment of MPM only in people who are considered to have advanced disease and who have a WHO performance status of 0 or 1, in whom surgical resection is not considered appropriate.