4 Consideration of the evidence
4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pemetrexed for the treatment of NSCLC, having considered evidence on the nature of the condition and the value placed on the benefits of pemetrexed by people with NSCLC, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources
4.2 The Committee considered the evidence on the clinical effectiveness of pemetrexed for the treatment of NSCLC. It considered the data presented by the manufacturer that compared pemetrexed with docetaxel, and concluded that overall survival with pemetrexed was not significantly greater than with docetaxel, and that the results of non-inferiority testing did not formally exclude the possibility of a marginal loss of efficacy of pemetrexed when compared with docetaxel.
4.3 The Committee heard from the clinical specialists and patient experts that pemetrexed was a potential treatment for relapsed patients with NSCLC, for whom there are few treatment options. The Committee also heard that some patients may prefer pemetrexed to docetaxel because of its different side-effect profile, particularly the lower rate of alopecia. However, the clinical specialists considered that patients undergoing second-line chemotherapy treatment usually valued other effects of treatment more highly, in particular increased life expectancy and overall quality of life. The Committee acknowledged that hair loss can be distressing, but concluded that a higher rate of alopecia would not normally preclude consideration of a particular chemotherapy regimen. It concluded that the reduction in rates of alopecia was not sufficient reason to recommend pemetrexed as an alternative to docetaxel.
4.4 The Committee considered the manufacturer's assessment of the cost effectiveness of pemetrexed compared with docetaxel. It discussed both the base-case analysis based on an unadjusted indirect comparison of pooled absolute survival estimates from several trials, and a sensitivity analysis based on an adjusted indirect comparison of pooled rates from several trials. It considered both indirect comparisons inappropriate given the inconsistency of the findings in relation to the direct randomised comparison between pemetrexed and docetaxel in the JMEI trial. The Committee noted that both the base-case analysis (which estimated a mean survival of 11.0 months for pemetrexed and 8.8 months for docetaxel) and the adjusted indirect comparison (mean survival of 14.4 months for pemetrexed and 12.4 months for docetaxel) both contradicted the results of the RCT, which showed that the mean survival was 8.56 months for pemetrexed and 8.74 months for docetaxel. The Committee concluded that the survival estimates included in the manufacturer's economic analysis were inappropriate.
4.5 The Committee considered the ERG's review of the economic analysis. The Committee noted that if an assumption of equivalent survival for docetaxel and pemetrexed was used in the economic analysis, the resulting ICER for pemetrexed compared with docetaxel would be over £450,000 per additional QALY gained.
4.6 The Committee also considered the estimates of cost included in the manufacturer's economic analysis, particularly those relating to the number of cycles of treatment and the inclusion of non-treatment costs (including BSC). The Committee concluded that the estimate of clinical effectiveness and of the number of treatment cycles should be based on the same source – that is, the registration trial in which a mean of 4.4 cycles was used. It noted that even if, in clinical practice, the number of cycles used is lower than this, the clinical effectiveness of shorter regimens (for example, the three cycles of treatment which were included in the manufacturer's analysis) was unknown. The Committee also considered the appropriateness of the estimates of patient average BSA. The Committee acknowledged that BSA would vary between patients and concluded that the mean BSA could be lower than the ERG estimate, particularly in patients with relapsed NSCLC. The Committee considered the manufacturer's estimate to be appropriate, but concluded that this factor would not substantially change the ICER. The Committee noted that if the ERG's revised estimates of costs were included, the ICER for pemetrexed compared with docetaxel would be greater than £1 million per additional QALY gained.
4.7 The Committee considered whether the cost of G-CSF or the treatment of neutropenia had been adequately taken into account by the manufacturer. The Committee noted that the cost of G-CSF was not explicitly included in the ERG review of the manufacturer's economic evaluation. However, the ERG highlighted that the costs of some G-CSF usage would be included in its cost estimates which were based on NHS reference costs. The Committee acknowledged there was uncertainty about the extent of G-CSF usage in clinical practice in the UK, and considered that if G-CSF was used to the extent suggested by the experts, inclusion of this factor would not lead to a substantial improvement in the cost effectiveness of pemetrexed compared with docetaxel.
4.8 The Committee also considered the use of pemetrexed in people who had previously received docetaxel or for whom docetaxel therapy was unsuitable. The Committee heard from the clinical specialists that some patients experience mild allergic reactions to docetaxel (such as rash or nausea). In these circumstances it is usual to treat the reaction rather than discontinue treatment. The Committee also heard that some patients experience a severe neuropathic reaction to first-line platinum-based chemotherapy or an anaphylactic reaction (such as bronchospasm or hypotension) to docetaxel, and that initiation or continuation of docetaxel second-line therapy might therefore be unsuitable for them. However the Committee noted that these types of toxicity and allergic reactions are rare.
4.9 The Committee heard that the RCT of pemetrexed did not include patients who could not receive docetaxel and it was therefore concerned that the clinical effectiveness of pemetrexed had not been established in this context. Nevertheless, the Committee considered the calculations on the cost effectiveness of pemetrexed compared with BSC. It noted that the manufacturer's analysis assumed that mean survival for patients receiving pemetrexed was 11.0 months but considered that the mean survival from the RCT of pemetrexed (8.56 months) was more credible.
4.10 The Committee noted that if the ERG's revised estimates of costs were used in the analysis, the ICER would be over £40,000 per additional QALY gained. It also noted that if the ERG's revised estimates of effectiveness were also included the ICER would be nearly £60,000 per additional QALY gained.
4.11 The Committee also considered the appropriateness of the cost estimates of BSC or non-treatment-related costs required in the two treatment arms. It noted that the manufacturer's cost estimates assumed that those receiving pemetrexed would only require treatment for adverse effects of treatment and not for disease-related symptoms (supportive care). The ERG suggested that the costs of treating disease-related symptoms would be the same for both treatment arms. The Committee proposed that those treated with pemetrexed would receive some underlying supportive care, but that this was plausibly at a lower rate than for patients not receiving active treatment .The Committee considered that if the cost of underlying supportive care for people receiving active treatment was 50% of that for people who were not, and using the ERG's other cost and survival assumptions (including the manufacturer's pooled estimate of mean overall survival for BSC of 7.2 months), the incremental cost would be approximately £8,000, resulting in an ICER of over £50,000 per additional QALY gained.
4.12 The Committee concluded that pemetrexed would not be a cost-effective use of NHS resources when compared with either docetaxel or BSC. After considering all the evidence available, the Committee concluded that pemetrexed could not be recommended for the treatment of locally advanced or metastatic NSCLC.