Pemetrexed for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer

Article history

The research reported in this article of the journal supplement was commissioned and funded by the HTA programme on behalf of NICE as project number 08/207/01. The assessment report began editorial review in November 2009 and was accepted for publication in February 2010. See the HTA programme website for further project information (www.hta.ac.uk). This summary of the ERG report was compiled after the Appraisal Committee’s review. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Declared competing interests of authors

none

Copyright statement

© 2010 Queen’s Printer and Controller of HMSO. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (http://www.publicationethics.org/). This journal may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2009 Queen’s Printer and Controller of HMSO

Description of the underlying health problem

Lung cancer is the second most common cancer diagnosed in the UK, with over 33,000 new cases diagnosed in England and Wales in 2006, and the leading cause of cancer death. 2 Lung cancer is the second most common cancer in men after prostate cancer, and the third most common cancer in women after breast and bowel cancer.

Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers diagnosed. The main subtypes of NSCLC are squamous cell carcinoma (33%), adenocarcinoma (25%), large cell carcinoma (4%), and NSCLC ‘not-otherwise specified’ (NOS; 36%). 3 A further 1% are ‘carcinoma in situ’ and 1% are broncho-alveolar cell carcinoma. While cigarette smoking has been linked to all four types of lung cancer, the incidence of adenocarcinoma has been steadily increasing worldwide, and modifications to cigarette design are thought to be responsible for this shift in pathologic diagnosis pattern. 4

Survival in patients with lung cancer is poor. It was responsible for approximately 29,600 deaths in England and Wales in 2007. 2 For patients with stage IIIB, only 7–9% may live for 5 years and for patients with stage IV (metastatic) cancer, only about 2–13% survive for 5 years. 2

One reason for this poor prognosis is the late identification of the disease. Lung cancer is asymptomatic in the early stages and advanced disease is not amenable to curative treatment. Another reason, which explains the UK’s relatively poor performance in comparison with other developed countries, is low active anti-cancer treatment rates. The National Lung Cancer Audit states that only 23.2% of NSCLC patients in England and Wales received first-line CTX in 2006. 5

Maintenance treatment is a new treatment paradigm and is proposed as an alternative for the ‘watch and wait’ phase of the current treatment pathway, for patients with complete or partial response/stable disease after four cycles of first-line treatment.

The goal of maintenance treatment is to maintain the clinical benefit achieved with first-line CTX. Maintenance treatment is continued until disease progression.

Scope of the evidence review group report

Pemetrexed is licensed in Europe as monotherapy for the maintenance treatment of patients with NSCLC, other than predominantly squamous cell histology. First-line treatment should be a platinum doublet with gemcitabine, paclitaxel or docetaxel. 6

The ERG report presents the results of the evaluation of the manufacturer (Eli Lilly) evidence submission regarding the use of pemetrexed as a maintenance therapy in the patient group outlined above. The report includes an assessment of both the clinical effectiveness and cost-effectiveness evidence submitted by the manufacturer. The manufacturer submission (MS) described the use of pemetrexed + best supportive care (BSC) with BSC + placebo.

The primary clinical outcome measure was progression-free survival (PFS). Secondary outcomes included overall survival (OS), time to worsening of symptoms, objective tumour response rate, adverse events and changes in lung cancer symptom scale.

Cost-effectiveness was measured in terms of incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY).

Data for two populations were presented: patients with non-squamous NSCLC histology and patients with adenocarcinoma histology.

Summary of submitted clinical evidence

The evidence described in the MS is derived from a double-blind, placebo-controlled randomised controlled trial (RCT), the JMEN trial. 8 The trial compared the use of pemetrexed + BSC as maintenance therapy, with placebo + BSC in patients with NSCLC (n = 663) who had received four cycles of platinum-based CTX and whose disease had not progressed. The MS focused on the clinical outcomes of the subgroup of patients with non-squamous histology (n = 481), which is the population for which pemetrexed is licensed in this indication; the MS also focused on a subgroup of the licensed population, patients with adenocarcinoma.

The results for the licensed non-squamous population are summarised in Table 1. In the licensed population the trial demonstrated greater median PFS for patients treated with pemetrexed than for patients in the placebo arm [4.5 vs 2.6 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.36 to 0.55, p < 0.00001]. Median OS was also greater for the pemetrexed-treated patients (15.5 versus 10.3 months; HR 0.70; 95% CI 0.56 to 0.88, p = 0.002). In addition, tumour response and disease control rates were statistically significantly greater for patients who received pemetrexed. Patient survival rates at 1 year and 2 years were higher in the pemetrexed arm. The health-related quality of life (HRQoL) data presented were limited owing to high levels of censoring/missing data. Safety data demonstrated that patients treated with pemetrexed had statistically significantly higher rates of grade 3 or 4 neutropenia, and experienced higher rates of transfusions and hospitalisation due to drug toxicity.

Summary of submitted cost-effectiveness evidence

The manufacturer did not identify any published cost-effectiveness analyses of pemetrexed for the maintenance treatment of patients with NSCLC, and therefore developed a de novo economic model to support their economic case. The model compares pemetrexed + BSC with ‘watch and wait’ + BSC. The clinical data used in the economic model were primarily generated from the JMEN trial. 8 Although the model was trial-based, there was also a modelling component to allow the extrapolation of health effects beyond the 29 month trial period up to 6 years. The manufacturer’s economic evaluation adopts a lifetime horizon (taken as 6 years) for the consideration of costs and benefits, and the perspective is that of the UK NHS and Personal Social Services.

The ICERs estimated by the manufacturer’s model are £33,732 per QALY for the licensed non-squamous population, and £39,364 per QALY for the adenocarcinoma subgroup. Both of these ICERs are above the standard NICE willingness-to-pay range (£20,000–£30,000 per QALY).

The manufacturer also presented a case for pemetrexed to be considered as an end-of-life treatment.

Commentary on the robustness of submitted evidence

The manufacturer cited evidence from a well-designed trial (JMEN)8 of the clinical benefit of pemetrexed + BSC as maintenance treatment compared with placebo + BSC. The trial recruited a substantial number of patients in a difficult disease area. It is noteworthy that patients and assessors in the JMEN8 trial were blinded to treatment group allocation and that investigators’ outcome assessments were independently verified.

The ERG noted that there was only one relevant RCT (JMEN)8 that compared pemetrexed + BSC as maintenance treatment with placebo + BSC. Despite designing the trial to include a comprehensive analysis of HRQoL, very limited data was collected and reported in the MS. This means it was very difficult to determine how patients’ HRQoL would be affected by pemetrexed in a maintenance setting.

The primary end point of the key trial was changed by the manufacturer from OS to PFS during the course of the trial. No information was provided that fully justified the change of clinical end point.

The statistical analysis plan described by the manufacturer also included a test for treatment by histology interaction and corresponding subgroup analyses. The results for the subgroup of patients with non-squamous histology provided the clinical evidence in the MS. However, the trial randomisation process did not include stratification by histology status. Moreover, the restriction of the licensed population to only the non-squamous subgroup effectively reduced the statistical power of the trial, with consequences of increased uncertainty in the cost-effectiveness analysis.

The projection of survival from the end of the trial period, the costing of CTX treatment and the utility values used in the manufacturer’s model were not ideal and underestimate the size of the ICER.

The manufacturer implemented a capping rule in its economic model to limit the maximum number of cycles of maintenance treatment that patients could receive. However, the cycle capping rule affected only costs; it did not take account of any reduction in outcomes caused by capping the maximum number of cycles at 17 rather than allowing the JMEN trial8 maximum of 55. Again, this capping rule underestimated the size of the ICER.

Making all of the necessary ERG corrections/adjustments to the manufacturer’s model, the ERG’s base-case ICER for the non-squamous population was estimated at £51,192 per QALY (Table 2).

‘End-of-life’ criteria

Analysis of the JMEN trial8 individual patient data and revised projection modelling confirmed that the mean life extension from use of pemetrexed as maintenance therapy was likely to exceed 3 months. However, the number of patients who would be eligible to receive pemetrexed is uncertain. The manufacturer’s estimates (used to present its end of life case) were based on amalgamation of information from different sources with differing definitions. The methods of calculation are not well reported and a number of assumptions were made which may not be valid.

Several factors serve to limit the generalisability of the trial to UK clinical practice, and the ERG could not be confident that the clinical results presented in the MS give a true reflection of the benefits that could be expected with pemetrexed for the maintenance treatment of patients with non-squamous NSCLC in UK clinical practice. Furthermore, in the economic analysis there were a number of problems identified with the model (in addition to the JMEN trial8 data) which indicate that the ICER (re-estimated as £51,192 per QALY gained) could well exceed NICE’s willingness-to-pay thresholds.

Disclaimers

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health.