Pemetrexed for the treatment of non-small-cell lung cancer

Evidence-based recommendations on pemetrexed for treating non-small-cell lung cancer in adults.

# Guidance
Pemetrexed is not recommended for the treatment of locally advanced or metastatic non-small-cell lung cancer.
People currently receiving pemetrexed should have the option to continue therapy until they and their clinicians consider it appropriate to stop.# The technology
Pemetrexed (Alimta, Eli Lilly and Company) is an antifolate agent that works by disrupting folate-dependent metabolic processes essential for cancer cell replication and survival. It is licensed as a monotherapy for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) after prior chemotherapy. For further information see the summary of product characteristics (SPC).
Pemetrexed is associated with suppression of bone marrow function, nausea and vomiting, fatigue and a range of other side effects. For full details of side effects and contraindications, see the SPC.
The recommended dose of pemetrexed is 500mg/m2 body surface area (BSA). It is administered by intravenous infusion over 10 minutes on the first day of each 21-day cycle.
The acquisition cost of pemetrexed is 800 for a 500-mg vial (excluding VAT; 'British national formulary' , 52nd edition). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of pemetrexed and a review of this submission by the Evidence Review Group (ERG; appendix B). The Institute and the ERG sought clarification on aspects of the manufacturer submission.
The manufacturer approached the decision problem by comparing pemetrexed with docetaxel and with best supportive care (BSC). The population under consideration had locally advanced or metastatic NSCLC and had relapsed after previous chemotherapy. The primary outcome measure outlined in the decision problem was overall survival. Secondary outcome measures included time to documented progression of disease, progression-free survival, duration of tumour response, quality of life and the incidence of adverse events.
The manufacturer's submission presented evidence on the clinical effectiveness of pemetrexed from one open-label randomised controlled trial (RCT) that compared pemetrexed with docetaxel (the JMEI trial). Final analysis showed no significant difference in median overall survival; 8.3 months with pemetrexed versus 7.9 months with docetaxel (p = 0.93 for ITT superiority). The hazard ratio  was 0.99 (95% confidence interval , 0.82 to 1.20) with a non-inferiority p-value of 0.226 for testing HR of <1.11. This means that the non-inferiority criteria were not met using the fixed margin method. Prior to un-blinding of the trial data, another (secondary) non-inferiority criterion was defined in the analysis plan, whereby non-inferiority was defined by HR < 1.21. This 'percentage efficacy method' was used to determine whether pemetrexed retained at least 50% of the assumed efficacy of docetaxel over BSC, using docetaxel efficacy data from an RCT of docetaxel compared with BSC (HR 0.56; 95% CI, 0.35 to 0.88). The estimate of the percentage of survival benefit (docetaxel over BSC) retained by pemetrexed was 102% (95% CI, 52% to 157%) with a non-inferiority p-value of 0.047 for testing 50% retention.
Regarding adverse effects reported in the RCT, compared with docetaxel, pemetrexed was associated with fewer grade 3 and 4 haematological toxicities; less neutropenia (p < 0.001), febrile neutropenia (p < 0.001) and neutropenia with infection (p = 0.004). There were fewer hospitalisations for neutropenic fever (n= 4 for pemetrexed and n = 35 for docetaxel) (p < 0.001) and reduced use of granulocyte colony-stimulating factor (G-CSF; n = 7 for pemetrexed versus n = 53 for docetaxel p < 0.001) in the pemetrexed group. No differences between the groups were found for anaemia (or number of patients receiving red blood cell transfusions or erythropoietin) or thrombocytopenia. There were also no differences for 10 of the 12 non-haematological toxicities reported, but the docetaxel group had more alopecia (p < 0.001) and a higher percentage of the pemetrexed group had raised levels of alanine transferase, an indicator of impaired liver function (p = 0.028). No statistically significant differences were reported for rate of hospitalisations for any other drug-related adverse event.
The RCT reported no differences between treatments in disease-specific quality of life, measured using the Lung Cancer Symptom Scale, which includes six symptoms (anorexia, fatigue, cough, dyspnoea, haemoptysis and pain).
The manufacturer's submission presented an economic analysis based on a Markov model with a 3-year time horizon. The estimates of efficacy used in the economic model were based on an unadjusted indirect comparison of absolute overall survival in which weighted estimates of absolute survival were pooled from single arms of different trials in published literature. The median absolute overall survival was estimated to be 8.3 months for pemetrexed (95% CI, 6.9 to 9.7) based on the results of the JMEI trial, 7.0 months for docetaxel (95% CI, 5.6 to 9.9) based on the pooled results of seven trials, and 4.9 months for BSC (95% CI, 4.2 to 5.5) based on the pooled results of three trials. When these absolute overall survival parameters were put into the economic model, the predicted mean life years gained were estimated to be  11.0 months for pemetrexed, 8.8 months for docetaxel and 7.2 months for BSC. The manufacturer's base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of 18,672 per additional quality-adjusted life year (QALY) gained for pemetrexed compared with docetaxel and an ICER of 16,458 per additional QALY gained for pemetrexed compared with BSC.
An adjusted indirect comparison, conducted as a sensitivity analysis, pooled median overall survival from single arms of the trials to estimate hazard rates for each treatment group. The adjusted indirect comparison estimated the life years gained to be 14.4 months for pemetrexed and 12.4 months for docetaxel. This analysis found that the mean ICER of pemetrexed compared with docetaxel was 31,612 per additional QALY gained and the mean ICER of pemetrexed compared with BSC was 10,298 per additional QALY gained.
The ERG reviewed the evidence submitted for clinical and cost effectiveness. The ERG judged that the open-label RCT had not proved formally the equivalent efficacy of pemetrexed compared to docetaxel, and had not demonstrated that pemetrexed was more efficacious than docetaxel. The ERG's viewpoint on the manufacturer's use of an indirect comparison to generate estimates of efficacy for its model, was that that indirect comparison is only acceptable when direct comparison evidence is not available. The ERG noted that the manufacturer's indirect comparison estimate of mean survival with docetaxel was less than the survival estimate obtained from the head-to-head trial (7.14 compared with 8.74 months, respectively). The ERG considered that the use of an unadjusted indirect comparison for the base-case was not ideal because it was based on pooling of median absolute survival estimates from individual arms of the trials rather than a consideration of the relative treatment effects. The ERG also noted that the estimates of drug acquisition costs used needed adjustment; in particular, the number of chemotherapy cycles should have reflected the number of cycles reported in the head-to-head trial.
The ERG considered the effect on the ICER of assuming equivalent overall survival for pemetrexed and docetaxel, in place of the manufacturer's assumption of greater survival. In this situation, the ERG estimated that the ICER for pemetrexed versus docetaxel would increase to approximately 458,000 per additional QALY gained. It also noted that if the revised estimates of drug acquisition/administration costs, costs of treating adverse events, and non-treatment-related and palliative care costs were included in the analysis, the ICER for pemetrexed versus docetaxel could be up to 1.8 million per additional QALY gained.
The ERG evaluated the manufacturer's economic analysis of pemetrexed versus BSC. Based on the manufacturer's estimates of survival and QALYs for the BSC group, but using a survival effect of pemetrexed equivalent to docetaxel, and revised cost estimates, the ERG estimated an ICER of approximately 60,000 per additional QALY gained.# Consideration of the evidence
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

# Pemetrexed compared with docetaxel
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.
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.
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.
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.
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.
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.

# Pemetrexed compared with best supportive care
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.
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.
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.
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.

# Summary
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.# Related NICE guidance
Lung cancer: the diagnosis and treatment of lung cancer. NICE clinical guideline 24 (2005). 
Erlotinib for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 162 (2008)
Pemetrexed disodium for the treatment of malignant pleural mesothelioma. NICE technology appraisal guidance 162 (2008).# Review of guidance
The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.
A review proposal for the guidance on this technology was proposed in July 2011.
Andrew DillonChief ExecutiveAugust 2007# Changes after publication
March 2014: minor maintenance
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
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 National Institute for Health and Clinical Excellence 2007. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.