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Health technology assessment

Pemetrexed as maintenance therapy for advanced, non-squamous, non-small cell lung cancer (NSCLC)

This health technology assessment (HTA) includes a systematic review of the efficacy and safety of pemetrexed given in addition to best supportive care for the maintenance treatment of patients with NSCLC.

This health technology assessment (HTA) includes a systematic review of the efficacy and safety of pemetrexed given in addition to best supportive care for the maintenance treatment of patients with NSCLC.


Key message

About 2 600 new cases of lung cancer are diagnosed each year in Norway, of which 80% are classified as non-small cell lung cancer (NSCLC).  Of these, about 75% have locally advanced or metastatic disease at the time of diagnosis.  Palliative chemotherapy is the standard treatment for patients in NSCLC stages IIIB-IV who cannot receive curative treatment and whose performance status is good (PS 0-2). The five-year survival rate for patients in these stages is low at about 1%.

Pemetrexed disodium (Alimta®) has marketing authorisation in Norway for the maintenance treatment of locally advanced or metastatic NSCLC other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy.

This health technology assessment (HTA) includes a systematic review of the efficacy and safety of pemetrexed given in addition to best supportive care for the maintenance treatment of patients with NSCLC. It also incorporates an economic evaluation of this intervention compared to a strategy of watchful waiting plus best supportive care.

  • One clinical trial was included in the systematic review, the quality and risk of bias of which was assessed to be moderate and low, respectively. The rate of adverse events associated with pemetrexed was low. 
  • In a sub-group analysis of the non-squamous patient population, the pemetrexed group showed an improved median overall survival compared to the placebo group of 5.2 months (15.5 months vs. 10.3 months, HR 0.70 CI 0.56 to 0.88).
  • The economic analysis was based on a Markov model with a time-horizon of six years. The analysis resulted in a cost per quality-adjusted life year and life year gained of approximately NOK 770 000 and NOK 425 000, respectively.
  • |Whether maintenance treatment with pemetrexed compared to watchful waiting is to be considered cost-effective depends on whether the threshold of NOK 500 000 is applied to QALYs gained, in which case it most likely is not, or life years gained,  in which case it most likely is. 
  • The results are associated with uncertainty as they are based on the efficacy data of a sub-population analysis from only one clinical trial.

Summary

Background

Lung cancer is one of the most common cancers in the world and is one of the leading causes of cancer mortality In Norway, the disease is the second most common cancer among men and the third among women. About 2 600 new cases of lung cancer are diagnosed each year in Norway of which approximately 80% of lung cancer cases are classified as non-small cell lung cancer (NSCLC).  Of these, about 75% have locally advanced or metastatic disease at the time of diagnosis. The main types of NSCLC are squamous cell carcinoma, adenocarcinoma and large cell carcinoma. Although NSCLCs are associated with cigarette smoking in about 90% of patients, adenocarcinomas may also be found in patients who have never smoked. Patients in early and localized stages of NSCLC can be cured by surgery, often in combination with chemotherapy and sometimes radiotherapy.  There are patients with local advanced NSCLC (stages IIIA and IIIB) who may receive curative treatment. Resection surgery may be appropriate for a few (stage IIIA) and curative radiotherapy for others (stage IIIB).  Poor lung function, large tumour volume, poor performance status and other factors serve to explain why many patients are not candidates for curative treatment. Such patients are offered palliative chemotherapy and/or palliative radiotherapy. Palliative chemotherapy is the standard treatment for patients in stages IIIB-IV who cannot receive curative treatment and whose performance status is good (PS 0-2). The five-year survival rate for these patients is low at about 1%.

Pemetrexed disodium (Alimta®) has marketing authorisation in Norway for the maintenance treatment of locally advanced or metastatic NSCLC other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. It is estimated that approximately 100-200 patients will be eligible for maintenance treatment with pemetrexed in Norway annually

Evaluation of clinical documentation

We performed a systematic search for literature in the following databases:

•         The Cochrane Library; CENTRAL, NHS EED

•         Centre for Reviews and Dissemination (CRD); NHS EED

•         Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1950 to present

•         EMBASE (Ovid) 1980 to present

Inclusion criteria

Population: Patients with non small cell lung cancer (NSCLC)

Comparator: Watchful waiting, standard care

Outcomes: Overall survival, progression free survival, disease control rate, adverse events and quality of life.

Two reviewers independently identified studies for inclusion and assessed the quality of the documentation. We identified 395 titles in the search for literature. Of, these, 13 titles were found to be potentially relevant and full text copies were reviewed. Finally, only one study was found that met the pre-specified inclusion criteria. The included study was a phase III multicentre, double-blinded randomized controlled trial (JMEN study) published by Ciuleanu et al . 2009. The study investigated the clinical usefulness of maintenance treatment with pemetrexed compared to best supportive care for locally advanced or metastatic NSCLC.  We assessed the risk of bias in the study as low. Median progression-free survival was significantly longer with pemetrexed (4.3 months) compared with placebo (2.6 months), HR 0.50 (CI 0.42 to 0.61, P <0.0001). Safety data demonstrated that patients in the pemetrexed group had statistically significantly higher rates of grade 3 and 4 toxicity. Both fatigue and neutropenia were higher in the pemetrexed group, and more patients in the pemetrexed group received transfusions and erythropoiesis stimulating agents. No pemetrexed-related deaths occurred. Generally, pemetrexed was well tolerated.

In a subgroup analysis of the 326 patients with non-squamous NSCLC  who received pemetrexed and the 156 patients with non-squamous NSCLC who received placebo, the median progression-free survival was significantly longer with pemetrexed (4.7 months) compared with placebo (2.6 months), HR 0.47 (CI 0.37-0.6). The pemetrexed group showed an improved median overall survival compared to the placebo group of 5.2 months (15.5 months vs. 10.3 months, HR 0.70 (CI 0.56 to 0.88). The safety profile of pemetrexed recorded within histological subgroups was consistent with the safety profile noted for the overall study population. The quality-assessment tool GRADE was used to assess the quality of the evidence for each outcome, which was determined to be of a moderate quality (with the exception of the adverse events data), meaning that we have moderate confidence in the results.

Economic Evaluation

We performed a cost-utility analysis (CUA) in which relevant costs and effects were expressed in Norwegian kroner (NOK) in 2011-prices and quality-adjusted life years gained (QALYs) respectively. Effects were also calculated in the form of life years gained (LYG). The analysis was carried out from a health care provider perspective and both costs and effects were discounted at an annual discount rate of 4% according to Norwegian guidelines. We designed a model of the Markov type, with a six-year time horizon and a cycle length of three weeks. Efficacy data in the form of time-to-event data for overall and progression-free survival for patients with non-squamous NSCLC were provided by Eli Lilly, the proprietor company. Costs were estimated on the basis of Norwegian sources.

In the absence of an explicit threshold value for cost-effective interventions in Norway, we used NOK 500 000 per QALY gained as a threshold value since it has been suggested by the Norwegian Directorate of Health as a possible temporary estimate

The results indicate that pemetrexed + BSC is associated with an incremental cost of approximately 190 000 NOK , 0.25 QALYs gained and 0.44 life years gained compared to BSC alone for an average patient. The ICER for a QALY gained was thus approximately NOK 770 000 which is clearly above the NOK 500 000 threshold mentioned above. There is no recommended threshold level with regard to cost per life year gained in the health sector in Norway. If the NOK 500 000 were to apply, the ICER for a life year gained of approximately 425 000 would be within the acceptable range. Sensitivity analyses showed that even though there is a great deal of uncertainty regarding health related quality of life data and the cost of best supportive care, these variables had only a marginal impact on the results. The results were most sensitive to variation in efficacy in terms of overall survival and in the cost of pemetrexed.

Conclusion

Maintenance treatment with pemetrexed and best supportive care seems to be well tolerated, and leads to an increase in median overall and progression-free survival compared to a regimen of BSC alone, especially in non-squamous NSCLC. Compared to a strategy of watchful waiting and best supportive care, the intervention involves a cost per quality-adjusted life year gained and life year gained of approximately NOK 770 000 and NOK 425 000, respectively. Whether the maintenance treatment with pemetrexed compared to watchful waiting is to be considered cost-effective depends on whether the threshold of NOK 500 000 is applied to QALYs  gained, in which case it most likely is not, or life years gained  in which case it most likely is. 

The results are associated with uncertainty as they are based on the efficacy data of a sub-population analysis from only one clinical trial.

About this publication

  • Year: 2012
  • By: The Knowledge Centre for the Health Services
  • Authors Movik E, Juvet LK, Hamidi V, Sæterdal, I, Harboe, I, Klemp M.
  • ISSN (digital): 1890-1298
  • ISBN (digital): 978-82-8121-466-8