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

N Fleeman, A Bagust, C McLeod, J Greenhalgh, A Boland, Y Dundar, R Dickson, C Tudur Smith, H Davis, J Green, M Pearson
Health Technology Assessment: HTA 2010, 14 Suppl 1: 47-53
This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in accordance with the licensed indication, based upon the evidence submission from Eli Lilly Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The majority of the efficacy evidence described in the manufacturer's submission is derived from a phase III open-label randomised controlled trial (RCT) known as the JMDB trial. The trial achieved its primary objective to demonstrate non-inferiority of pemetrexed/cisplatin to gemcitabine/cisplatin for overall survival in all patients with NSCLC. Because no other studies were found comparing pemetrexed/cisplatin with any other relevant comparator, additional efficacy evidence was presented from two phase III RCTs comparing gemcitabine/cisplatin with gemcitabine/carboplatin and docetaxel/cisplatin. The manufacturer's submission reported from its indirect comparisons' analysis that median overall survival and progression-free survival and tumour response rates were more favourable for pemetrexed/cisplatin than for any other comparator. The manufacturer did not identify any published cost-effectiveness analyses of pemetrexed for the first-line treatment of patients with NSCLC. Therefore economic evidence was derived solely from a de novo economic model developed by the manufacturer. A Markov model was developed to evaluate the cost-effectiveness of pemetrexed/cisplatin compared to gemcitabine/cisplatin, docetaxel/cisplatin and gemcitabine/carboplatin. The clinical data used in the economic evaluation were primarily generated from the JMDB trial, with additional data from the two further trials used in the indirect comparisons analysis. The ERG identified a series of problems with this economic model. As a result, three different versions of the model were submitted to NICE and considered by the ERG. The ICERs estimated by this final version of the model ranged from 8056 pounds to 33,065 pounds per QALY, depending on the comparator, the population and the application of a continuation rule. The ERG considered that the model required extensive modification and redesign, and should be subjected to thorough validation against the JMDB trial results. A full quality audit was also required as it was likely that further model inconsistencies may be present that had not yet been identified. The manufacturer subsequently included evidence in the form of three cost effectiveness analyses (two models and an 'in-trial' analysis), stating that a thorough validation process had been followed according to the NICE request. The very short time available to the ERG to consider the new evidence precluded a comprehensive assessment. Instead, the ERG chose to present a simple exploratory analysis combining its own survival projections with key cost estimates obtained from the JMDB trial individual patient data. Compared to gemcitabine, this resulted in ICERs ranging from 17,162 pounds to 30,142 pounds per QALY, depending on the patient population, the maximum number of cycles of chemotherapy and whether a cycle based efficacy adjustment was applied or not. The guidance issued by NICE in September 2009 states that pemetrexed in combination with cisplatin is recommended as an option for the first-line treatment of patients with locally advanced or metastatic NSCLC only if the histology of the tumour has been confirmed as adenocarcinoma or large-cell carcinoma.

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