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Pemetrexed approved for the first-line treatment of non-small-cell lung cancer: summary of the NICE appraisal
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Special Report: Policy Pemetrexed approved for the first-line treatment of non-small-cell lung cancer: summary of the NICE appraisal The National Institute for Health and Clinical Excellence (NICE) has appraised the clinical and costeffectiveness of pemetrexed within its licensed indication for the treatment of first-line non-small-cell lung cancer (NSCLC). The final appraisal determination was published on August 6, 2009, recommending pemetrexed in combination with cisplatin 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 to be adenocarcinoma or large-cell carcinoma.1 In 2007, NICE published guidance on pemetrexed for the secondline treatment of locally advanced or metastatic NSCLC, and for this indication did not recommend use of the drug.2 Pemetrexed for the first-line treatment of NSCLC was appraised under the Single Technology Appraisal process.3 The manufacturer (Eli Lilly and Co Ltd, UK) submitted a systematic review of data on clinical effectiveness of the drug and an economic model to estimate the cost-effectiveness compared with current practice; both were reviewed and assessed by an independent academic group, in this case the Liverpool Reviews and Implementation Group.4 Other stakeholders, including patient and professional organisations, also submitted statements to the Appraisal Committee. The guidance was developed over two Committee meetings. At the first meeting, the Committee decided not to recommend pemetrexed and recommended that NICE request further clarification on the cost-effectiveness analysis from the manufacturer.5 At the second meeting, the Committee considered
all comments received during the public consultation and the additional analysis and evidence submitted by the manufacturer—including an independent review of this additional information. At this second meeting, the Appraisal Committee recommended pemetrexed as an option for the first-line treatment of patients with adenocarcinoma and large-cell carcinoma.6 The key evidence for the clinical effectiveness was based on one phase 3, non-inferiority, randomised controlled trial (JMBD trial), comparing pemetrexed plus cisplatin (n=862) with gemcitabine plus cisplatin (n=863).7 Patients with either squamous or non-squamous NSCLC were included and subgroups were stratified by histology type: adenocarcinoma, large-cell carcinoma, and “not otherwise specified”. Patients received up to six cycles of chemotherapy and were followed up for 2·5 years. For patients who had non-squamous NSCLC, median overall survival with pemetrexed plus cisplatin was 11 months, versus 10·1 months with gemcitabine plus cisplatin (HR 0·84, 95% CI 0·74–0·96, p=0·011). In a subgroup analysis, median overall survival in patients with adenocarcinoma and large-cell carcinoma was 11·8 months with pemetrexed plus cisplatin versus 10·4 months with gemcitabine plus cisplatin (HR 0·81, 0·70–0·94, p=0·005). Median progression-free survival was not significantly different between treatment groups for all randomised patients and for patients who had non-squamous NSCLC. The manufacturer did an indirect comparison of pemetrexed plus cisplatin with gemcitabine plus carboplatin and with docetaxel plus cisplatin, via two phase 2, open-label,
www.thelancet.com/oncology Vol 10 November 2009
randomised trials: Zatloukal and colleagues8 compared gemcitabine plus cisplatin (n=87) with gemcitabine plus carboplatin (n=89), and Schiller and colleagues9 compared gemcitabine plus cisplatin (n=301) with docetaxel plus cisplatin (n=304). The overall survival in patients with adenocarcinoma and largecell carcinoma for pemetrexed plus cisplatin was 11·8 months (95% CI 10·4–13·2), 9·5 months (8·1–13·4) for gemcitabine plus carboplatin, and 9·8 months (8·6–11·5) for docetaxel plus cisplatin. Progression free-survival was 5·3 months for pemetrexed plus cisplatin compared with 3·8 months for gemcitabine plus carboplatin and 4·1 months for docetaxel plus cisplatin. The Committee noted that pemetrexed plus cisplatin was associated with fewer adverse events than alternative therapies and this was highly valued by patients. The Committee further concluded that the results from the JMBD trial were robust and generalisable to UK clinical practice. The independent academic group commented that the indirect comparison presented by the manufacturer was not methodologically robust and excluded comparators such as vinorelbine. However, clinical experts present at the Committee meeting stated that docetaxel and vinorelbine are not widely used in the UK because of their adverse-event profile and that gemcitabine plus cisplatin are the most commonly used combination therapy. The Committee therefore concluded that pemetrexed plus cisplatin is clinically effective and associated with lower toxicity than gemcitabine plus cisplatin in patients with histology of adenocarcinoma or large-cell carcinoma.
Published Online September 23, 2009 DOI:10.1016/S14702045(09)70289-X
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The manufacturer submitted an economic analysis using a Markov model comparing pemetrexed plus cisplatin, gemcitabine plus carboplatin, and docetaxel plus cisplatin on the basis of a 6-year time horizon. In the model, patients received the fourth treatment cycle of pemetrexed plus cisplatin only if their disease responded after three cycles of treatment. The independent academic group noted that the economic model did not replicate the clinical results of the JMBD trial, especially for overall survival, progressionfree survival, and response rates (the primary clinical endpoints of the JMBD trial), and considering additional technical issues, concluded that the model might miscalculate the cost-effectiveness. At the end of the first meeting, the Committee therefore decided not to recommend pemetrexed and requested that the manufacturer carry out an additional analyses to improve the model’s external validity. The manufacturer subsequently provided a modified version of the original Markov model and two additional models: a trial-based economic analysis and an economic model that was submitted to the Pharmaceutical Benefits Advisory Committee in Australia. The Committee noted that the trial-based analysis diverged from the JMBD trial by reducing the maximum number of cycles to four, and considered such a diversion inappropriate. Furthermore,
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the revised Markov model still did not replicate the results from the JMBD trial. The independent academic group noted some remaining computational problems with the analyses. The independent academic group did explanatory analyses based on the manufacturer’s revised model and included patient data, also provided by the manufacturer, to estimate survival. The Committee considered these analyses sufficiently robust to reach conclusions regarding the costeffectiveness of pemetrexed. The Committee considered a scenario where the treatment cycles were reduced to four, and the potential for reduced effectiveness of this schedule was taken into account. Under these circumstances, costeffectiveness analyses yielded incremental cost-effectiveness ratios between £17 000 and £25 000 per quality-adjusted life year gained for pemetrexed plus cisplatin compared with gemcitabine plus cisplatin, in patients with adenocarcinoma or large-cell carcinoma. Therefore, the Committee concluded that pemetrexed plus cisplatin was a costeffective use of NHS resources for the first-line treatment of patients with adenocarcinoma or large-cell NSCLC, and could be recommended as a treatment option for this group of patients.
National Institute for Health and Clinical Excellence, MidCity Place, London, UK The authors declared no conflicts of interest. 1
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NICE. Pemetrexed for the first-line treatment of non-small cell lung cancer. Final Appraisal Determination. August, 2009. http://www. nice.org.uk/nicemedia/pdf FADPemetrexed LungCancer.pdf (accessed Sept 21, 2009). NICE Technology Appraisal TA142. Guidance on pemetrexed for the treatment of non-small cell lung cancer. August, 2007. http://www. nice.org.uk/nicemedia/pdf/TA124Guidance. pdf (accessed Sept 21, 2009). NICE. Guide to the single technology appraisal (STA) process. September 2006. http://www. nice.org.uk/media/8DE/74/STA_Process_ Guide.pdf (accessed Sept 21, 2009). NICE ERG report: Pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). February, 2009. http://www.nice.org.uk/nicemedia/pdf/ LungCancerPemetrexedERGAddendum.pdf (accessed Sept 21, 2009). NICE. Pemetrexed for the first-line treatment of non-small cell lung cancer. Appraisal Consultation Document. April, 2009. http:// www.nice.org.uk/guidance/index.jsp?action=a rticle&o=43745 (accessed Sept 21, 2009). NICE. STA Submission, Eli Lilly and Company Limited, December, 2008. http://www.nice. org.uk/guidance/index.jsp?action=download& o=43762 (accessed Sept 21, 2009). Scagliotti GV, Parikh P, von Pawel J, et al. A randomized phase 3 trial comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced-stage non-small cell lung cancer. J Clin Oncol 2008; 26: 3543–51. Zatloukal P, Petruzelka L, Zemanova M, et al. Gemcitabine plus cisplatin vs gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase 3 randomized trial. Lung Cancer 2003; 41: 321–31. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–98.
Panagiota Vrouchou, Prashanth Kandaswamy, Elisabeth George, David Barnett
www.thelancet.com/oncology Vol 10 November 2009
Special Report: Policy Pemetrexed approved for the first-line treatment of non-small-cell lung cancer: summary of the NICE appraisal The National Institute for Health and Clinical Excellence (NICE) has appraised the clinical and costeffectiveness of pemetrexed within its licensed indication for the treatment of first-line non-small-cell lung cancer (NSCLC). The final appraisal determination was published on August 6, 2009, recommending pemetrexed in combination with cisplatin 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 to be adenocarcinoma or large-cell carcinoma.1 In 2007, NICE published guidance on pemetrexed for the secondline treatment of locally advanced or metastatic NSCLC, and for this indication did not recommend use of the drug.2 Pemetrexed for the first-line treatment of NSCLC was appraised under the Single Technology Appraisal process.3 The manufacturer (Eli Lilly and Co Ltd, UK) submitted a systematic review of data on clinical effectiveness of the drug and an economic model to estimate the cost-effectiveness compared with current practice; both were reviewed and assessed by an independent academic group, in this case the Liverpool Reviews and Implementation Group.4 Other stakeholders, including patient and professional organisations, also submitted statements to the Appraisal Committee. The guidance was developed over two Committee meetings. At the first meeting, the Committee decided not to recommend pemetrexed and recommended that NICE request further clarification on the cost-effectiveness analysis from the manufacturer.5 At the second meeting, the Committee considered
all comments received during the public consultation and the additional analysis and evidence submitted by the manufacturer—including an independent review of this additional information. At this second meeting, the Appraisal Committee recommended pemetrexed as an option for the first-line treatment of patients with adenocarcinoma and large-cell carcinoma.6 The key evidence for the clinical effectiveness was based on one phase 3, non-inferiority, randomised controlled trial (JMBD trial), comparing pemetrexed plus cisplatin (n=862) with gemcitabine plus cisplatin (n=863).7 Patients with either squamous or non-squamous NSCLC were included and subgroups were stratified by histology type: adenocarcinoma, large-cell carcinoma, and “not otherwise specified”. Patients received up to six cycles of chemotherapy and were followed up for 2·5 years. For patients who had non-squamous NSCLC, median overall survival with pemetrexed plus cisplatin was 11 months, versus 10·1 months with gemcitabine plus cisplatin (HR 0·84, 95% CI 0·74–0·96, p=0·011). In a subgroup analysis, median overall survival in patients with adenocarcinoma and large-cell carcinoma was 11·8 months with pemetrexed plus cisplatin versus 10·4 months with gemcitabine plus cisplatin (HR 0·81, 0·70–0·94, p=0·005). Median progression-free survival was not significantly different between treatment groups for all randomised patients and for patients who had non-squamous NSCLC. The manufacturer did an indirect comparison of pemetrexed plus cisplatin with gemcitabine plus carboplatin and with docetaxel plus cisplatin, via two phase 2, open-label,
www.thelancet.com/oncology Vol 10 November 2009
randomised trials: Zatloukal and colleagues8 compared gemcitabine plus cisplatin (n=87) with gemcitabine plus carboplatin (n=89), and Schiller and colleagues9 compared gemcitabine plus cisplatin (n=301) with docetaxel plus cisplatin (n=304). The overall survival in patients with adenocarcinoma and largecell carcinoma for pemetrexed plus cisplatin was 11·8 months (95% CI 10·4–13·2), 9·5 months (8·1–13·4) for gemcitabine plus carboplatin, and 9·8 months (8·6–11·5) for docetaxel plus cisplatin. Progression free-survival was 5·3 months for pemetrexed plus cisplatin compared with 3·8 months for gemcitabine plus carboplatin and 4·1 months for docetaxel plus cisplatin. The Committee noted that pemetrexed plus cisplatin was associated with fewer adverse events than alternative therapies and this was highly valued by patients. The Committee further concluded that the results from the JMBD trial were robust and generalisable to UK clinical practice. The independent academic group commented that the indirect comparison presented by the manufacturer was not methodologically robust and excluded comparators such as vinorelbine. However, clinical experts present at the Committee meeting stated that docetaxel and vinorelbine are not widely used in the UK because of their adverse-event profile and that gemcitabine plus cisplatin are the most commonly used combination therapy. The Committee therefore concluded that pemetrexed plus cisplatin is clinically effective and associated with lower toxicity than gemcitabine plus cisplatin in patients with histology of adenocarcinoma or large-cell carcinoma.
Published Online September 23, 2009 DOI:10.1016/S14702045(09)70289-X
1031
News
The manufacturer submitted an economic analysis using a Markov model comparing pemetrexed plus cisplatin, gemcitabine plus carboplatin, and docetaxel plus cisplatin on the basis of a 6-year time horizon. In the model, patients received the fourth treatment cycle of pemetrexed plus cisplatin only if their disease responded after three cycles of treatment. The independent academic group noted that the economic model did not replicate the clinical results of the JMBD trial, especially for overall survival, progressionfree survival, and response rates (the primary clinical endpoints of the JMBD trial), and considering additional technical issues, concluded that the model might miscalculate the cost-effectiveness. At the end of the first meeting, the Committee therefore decided not to recommend pemetrexed and requested that the manufacturer carry out an additional analyses to improve the model’s external validity. The manufacturer subsequently provided a modified version of the original Markov model and two additional models: a trial-based economic analysis and an economic model that was submitted to the Pharmaceutical Benefits Advisory Committee in Australia. The Committee noted that the trial-based analysis diverged from the JMBD trial by reducing the maximum number of cycles to four, and considered such a diversion inappropriate. Furthermore,
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the revised Markov model still did not replicate the results from the JMBD trial. The independent academic group noted some remaining computational problems with the analyses. The independent academic group did explanatory analyses based on the manufacturer’s revised model and included patient data, also provided by the manufacturer, to estimate survival. The Committee considered these analyses sufficiently robust to reach conclusions regarding the costeffectiveness of pemetrexed. The Committee considered a scenario where the treatment cycles were reduced to four, and the potential for reduced effectiveness of this schedule was taken into account. Under these circumstances, costeffectiveness analyses yielded incremental cost-effectiveness ratios between £17 000 and £25 000 per quality-adjusted life year gained for pemetrexed plus cisplatin compared with gemcitabine plus cisplatin, in patients with adenocarcinoma or large-cell carcinoma. Therefore, the Committee concluded that pemetrexed plus cisplatin was a costeffective use of NHS resources for the first-line treatment of patients with adenocarcinoma or large-cell NSCLC, and could be recommended as a treatment option for this group of patients.
National Institute for Health and Clinical Excellence, MidCity Place, London, UK The authors declared no conflicts of interest. 1
2
3
4
5
6
7
8
9
NICE. Pemetrexed for the first-line treatment of non-small cell lung cancer. Final Appraisal Determination. August, 2009. http://www. nice.org.uk/nicemedia/pdf FADPemetrexed LungCancer.pdf (accessed Sept 21, 2009). NICE Technology Appraisal TA142. Guidance on pemetrexed for the treatment of non-small cell lung cancer. August, 2007. http://www. nice.org.uk/nicemedia/pdf/TA124Guidance. pdf (accessed Sept 21, 2009). NICE. Guide to the single technology appraisal (STA) process. September 2006. http://www. nice.org.uk/media/8DE/74/STA_Process_ Guide.pdf (accessed Sept 21, 2009). NICE ERG report: Pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). February, 2009. http://www.nice.org.uk/nicemedia/pdf/ LungCancerPemetrexedERGAddendum.pdf (accessed Sept 21, 2009). NICE. Pemetrexed for the first-line treatment of non-small cell lung cancer. Appraisal Consultation Document. April, 2009. http:// www.nice.org.uk/guidance/index.jsp?action=a rticle&o=43745 (accessed Sept 21, 2009). NICE. STA Submission, Eli Lilly and Company Limited, December, 2008. http://www.nice. org.uk/guidance/index.jsp?action=download& o=43762 (accessed Sept 21, 2009). Scagliotti GV, Parikh P, von Pawel J, et al. A randomized phase 3 trial comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced-stage non-small cell lung cancer. J Clin Oncol 2008; 26: 3543–51. Zatloukal P, Petruzelka L, Zemanova M, et al. Gemcitabine plus cisplatin vs gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase 3 randomized trial. Lung Cancer 2003; 41: 321–31. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–98.
Panagiota Vrouchou, Prashanth Kandaswamy, Elisabeth George, David Barnett
www.thelancet.com/oncology Vol 10 November 2009