Systematic review of efficacy and safety of pemetrexed in non-small-cell-lung cancer.

INTRODUCTION: Lung cancer accounts for 20 % of cancer deaths in Spain. The most frequent subtype (87 %) is non-small cell lung cancer (NSCLC). Pemetrexed is a recently marketed drug added to NSCLC therapeutic arsenal. It seems to have become one of the most used options for the treatment of this condition over the last 3 years. AIM OF THE REVIEW: To evaluate the efficacy and safety of pemetrexed in NSCLC, in the different therapy lines. Method A systematic search of published literature was conducted using the main databases (MEDLINE, EMBASE, the Cochrane Library and the Center for Reviews and Dissemination) and subsequently a search of referenced literature was performed. We included clinical trials, meta-analyses and systematic reviews. The evaluation of the quality of the articles was performed by pairs using specific assessment scales, Critical Appraisal Skills Program (CASP) adapted for CASP Spain. Then we extracted data on efficacy and safety according to the treatment line assessed. RESULTS: We identified 277 references. Finally, nine clinical trials and a meta-analysis complied with inclusion criteria. In first-line induction, treatment with pemetrexed associated with a platinum was similar in terms of efficacy to other alternative chemotherapy regimens, except in patients with non-squamous histology, in whom survival was higher in the experimental group. In maintenance treatment, greater efficacy was seen with pemetrexed in patients with non-squamous histology. In second-line treatment, there were no significant differences in terms of efficacy and safety for pemetrexed treatment versus other chemotherapy options. The most frequent adverse reactions were: hematological, gastrointestinal and neurological. All were significantly less frequent with pemetrexed versus other alternative therapies, except for liver toxicity. CONCLUSIONS: Due to the high degree of uncertainty as to its efficacy in certain subgroups of patients, including conflicting data; to its recent incorporation, and therefore lack of safety data in the medium and long term, and the high budgetary impact of its incorporation into health systems, it seems reasonable to optimize its use, identifying those patients who may benefit most.

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

INTRODUCTION: Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide. Although advanced NSCLC is still incurable, various anti-neoplastic agents have become available for the treatment of this disease. Pemetrexed , a multi-target folate antagonist, has improved the survival of non-squamous NSCLC patients. Currently, pemetrexed is approved for first-line treatment in combination with a platinum derivate, for second-line treatment as a single agent and, more recently, as maintenance treatment after first-line chemotherapy. AREAS COVERED: The authors analyzed the state of the art of pemetrexed through a review of the literature. Clinical trials and meta-analyses involving pemetrexed in NSCLC were evaluated. Pemetrexed improved survival of non-squamous NSCLC in first-line, maintenance, and second-line treatments; this benefit is limited to non-squamous histology. Because pemetrexed has become part of the standard of care, current clinical trials are designed to compare it to other investigational combinations. Limited data on resectable disease are available, and additional clinical trials are being conducted. EXPERT OPINION: Pemetrexed has shown effectiveness and a favorable toxicity profile. Histology-driven indications and the relationship of pemetrexed with thymidylate synthase expression suggest that a more precise definition of predictive biomarkers could be further investigated.

Cost-effectiveness of continuation maintenance pemetrexed after cisplatin and pemetrexed chemotherapy for advanced nonsquamous non-small-cell lung cancer: estimates from the perspective of the Chinese health care system.

BACKGROUND: Continuation maintenance treatment with pemetrexed is approved by current clinical guidelines as a category 2A recommendation after induction therapy with cisplatin and pemetrexed chemotherapy (CP strategy) for patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). However, the cost-effectiveness of the treatment remains unclear. OBJECTIVE: We completed a trial-based assessment, from the perspective of the Chinese health care system, of the cost-effectiveness of maintenance pemetrexed treatment after a CP strategy for patients with advanced nonsquamous NSCLC. METHODS: A Markov model was developed to estimate costs and benefits. It was based on a clinical trial that compared continuation maintenance pemetrexed therapy plus best supportive care (BSC) versus placebo plus BSC after a CP strategy for advanced nonsquamous NSCLC. Sensitivity analyses were conducted to assess the stability of the model. RESULTS: The model base case analysis suggested that continuation maintenance pemetrexed therapy after a CP strategy would increase benefits in a 1-, 2-, 5-, or 10-year time horizon, with incremental costs of $183,589.06, $126,353.16, $124,766.68, and $124,793.12 per quality-adjusted life-year gained, respectively. The most sensitive influential variable in the cost-effectiveness analysis was the utility of the progression-free survival state, followed by proportion of patients with postdiscontinuation therapy in both arms, proportion of BSC costs for PFS versus progressed survival state, and cost of pemetrexed. Probabilistic sensitivity analysis indicated that the cost-effective probability of adding continuation maintenance pemetrexed therapy to BSC was zero. One-way and probabilistic sensitivity analyses revealed that the Markov model was robust. CONCLUSIONS: Continuation maintenance of pemetrexed after a CP strategy for patients with advanced nonsquamous NSCLC is not cost-effective based on a recent clinical trial. Decreasing the price or adjusting the dosage of pemetrexed may be a better option for meeting the treatment demands of Chinese patients.

Proposal for a novel methodology to screen and score cost versus survival for anticancer drugs in metastatic disease: could cost weigh in evaluation?

PURPOSE: Rising costs of anticancer drugs prompt concerns about their approval, use, and affordability. A methodology was developed to evaluate cost versus survival for anticancer drugs in metastatic breast cancer and non-small-cell lung cancer (NSCLC). METHODS: Costs of evaluated drugs were calculated by using average wholesale prices in US dollars. Ratios of cost to day of survival (cost/survival/d) were obtained by dividing costs of the entire treatment by reported median survival gain in days. A crude score of 100% was assigned to a cost/survival/d of less than $25, and 0% to a cost/survival/d of more than $750. A strategy was designed to correct for overall survival (OS) versus progression-free survival (PFS), adverse effects, and quality of life. RESULTS: In breast cancer, PFS scores of bevacizumab varied between 0% and 60%. In NSCLC, OS scores of bevacizumab improved from 0% to 50%, as a result of histology, lower prices, and extended therapy. Gefitinib and erlotinib PFS scores were 80% and 70%, respectively. Correction for longer survival with erlotinib resulted in similar scores. In maintenance therapy, the OS score for pemetrexed was 70% as compared with 25% for erlotinib. Generic drugs scored 70% to 90%. CONCLUSION: Cost/survival varied with the number of cycles. In breast cancer, bevacizumab scores failed to justify its use. In NSCLC, 10 cycles of bevacizumab scored 0%. Scores improved with extended treatment and lower prices. Scores for gefitinib and erlotinib would support their approval. Erlotinib was preferred because of longer PFS. Results tended to endorse maintenance pemetrexed but not erlotinib. Generic drugs demonstrated high scores. Cost/survival could weigh in drug evaluation.

Cost-effectiveness of maintenance pemetrexed in patients with advanced nonsquamous-cell lung cancer from the perspective of the Swiss health care system.

OBJECTIVES: A recent randomized study showed switch maintenance with pemetrexed after nonpemetrexed-containing first-line chemotherapy in patients with advanced nonsmall-cell lung cancer to prolong overall survival by 2.8 months. We examined the cost-effectiveness of pemetrexed in this indication, from the perspective of the Swiss health care system, and assessed the influence of the costs of best supportive care (BSC) on overall cost-effectiveness. METHODS: A Markov model was constructed based on the pemetrexed maintenance study, and the incremental cost-effectiveness ratio (ICER) of adding pemetrexed until disease progression was calculated as cost per quality-adjusted life-year gained. Uncertainties concerning the costs of BSC on the ICER were addressed. RESULTS: The base case ICER for maintenance therapy with pemetrexed plus BSC compared to BSC alone was €106,202 per quality-adjusted life-year gained. Varying the costs for BSC had a marked effect. Assuming a reduction of the costs for BSC by 25% in the pemetrexed arm resulted in an ICER of €47,531 per quality-adjusted life-year, which is below predefined criteria for cost effectiveness in Switzerland. CONCLUSIONS: Switch maintenance with pemetrexed in patients with advanced nonsquamous-cell lung cancer after standard first-line chemotherapy is not cost-effective. Uncertainties on the resource use and costs for BSC have a large influence on the cost-effectiveness calculation and should be reported in more detail.

Cost effectiveness of personalized therapy for first-line treatment of stage IV and recurrent incurable adenocarcinoma of the lung.

PURPOSE: Patients with epidermal growth factor receptor (EGFR) mutation-positive stage IV adenocarcinoma have improved survival with tyrosine kinase inhibitor (TKI) treatments, but the cost effectiveness of personalized first-line therapy using EGFR mutation testing is unknown. METHODS: We created a decision analytic model comparing the costs and effects of platinum combination chemotherapy with personalized therapy in which patients with EGFR mutation-positive tumors were treated with erlotinib. We used two testing strategies: testing only those with tissue available and performing a repeat biopsy if tissue was not available versus three nontargeted chemotherapy regimens (ie, carboplatin and paclitaxel; carboplatin and pemetrexed; and carboplatin, pemetrexed, and bevacizumab). RESULTS: Compared with a carboplatin plus paclitaxel regimen, targeted therapy based on testing available tissue yielded an incremental cost-effectiveness ratio (ICER) of $110,644 per quality-adjusted life year (QALY), and the rebiopsy strategy yielded an ICER of $122,219 per QALY. Probabilistic sensitivity analysis revealed substantial uncertainty around these point estimates. With a willingness to pay of $100,000 per QALY, the testing strategy was cost effective 58% of the time, and the rebiopsy strategy was cost effective 54% of the time. Personalized therapy with an EGFR TKI was more favorable when the nontargeted chemotherapy regimen was more expensive. Compared with carboplatin, pemetrexed, and bevacizumab, ICERs were $25,547 per QALY for the testing strategy and $44,036 per QALY for the rebiopsy strategy. CONCLUSION: Although specific clinical circumstances should guide therapy, our cost-effectiveness analysis supports the strategy of testing for EGFR mutations in patients with stage IV or recurrent adenocarcinoma of the lung, rebiopsying patients if insufficient tissue is available for testing, and treating patients with EGFR mutations with erlotinib as first-line therapy.

Costs and clinical outcomes among patients with second-line non-small cell lung cancer in the outpatient community setting.

INTRODUCTION: A comparison of clinical and economic outcomes among patients receiving second-line monotherapy with erlotinib, docetaxel, and pemetrexed for non-small cell lung cancer was conducted using a large network of outpatient community clinics. METHODS: We identified 610 patients with advanced non-small cell lung cancer who received 2L treatment from July 1, 2006, to June 30, 2008, and were followed up through July 1, 2009, to evaluate progression-free survival (PFS), overall survival (OS), costs, and health resource utilization. Cox proportional hazards regression were used to compare PFS and OS across treatment cohorts. Economic outcomes were calculated per patient per month (PPPM) during a 12-month follow-up period. RESULTS: There were 73 patients who received erlotinib, 87 received docetaxel, and 450 received pemetrexed. The median age was 67 years, and 55% were men. No significant differences in stage, baseline performance status, hemoglobin level, or body mass index were observed by treatment. The median OS was 132 days for docetaxel, 132 days for pemetrexed, and 155 days for erlotinib (p = 0.39). Adjusting for age, gender, stage, performance status, and hemoglobin level, there was no significant association between treatment type and OS (p = 0.36) or PFS (p = 0.26). Relative to pemetrexed, total adjusted costs PPPM was $1579 lower for docetaxel and $1584 lower for erlotinib (p < 0.05). Outpatient visits, laboratory procedures, and acute care visits were also less frequent with erlotinib relative to pemetrexed (-2.6 PPPM, p < 0.05). CONCLUSIONS: We observed no significant differences in OS and PFS between patients receiving erlotinib, docetaxel, and pemetrexed. Nevertheless, erlotinib and docetaxel were associated with a statistically significant lower costs and resource use relative to pemetrexed.

Cost-effectiveness of epidermal growth factor receptor mutation testing and first-line treatment with gefitinib for patients with advanced adenocarcinoma of the lung.

BACKGROUND: Epidermal growth factor receptor (EGFR) testing and first-line therapy with gefitinib for patients with activating mutations is quickly becoming the standard option for the treatment of advanced lung adenocarcinoma. Yet, to date, little is known about the cost-effectiveness of this approach. METHODS: A decision-analytic model was developed to determine the cost-effectiveness of EGFR testing and first-line treatment with gefitinib for those patients who harbor activating mutations versus standard care, which includes first-line treatment with chemotherapy followed by gefitinib as second-line treatment. The model uses clinical and outcomes data from randomized clinical trials and societal costs from Singapore cancer centers. Health effects were expressed as quality-adjusted life-years. All costs and cost-effectiveness ratios were expressed in 2010 Singapore dollars. Sensitivity and different scenarios analyses were conducted. RESULTS: EGFR testing and first-line treatment with gefitinib is a dominant strategy (with lower costs and greater effectiveness) compared with standard care. Because the primary savings result from not providing gefitinib to those who are not likely to benefit, this finding holds regardless of the prevalence of activating mutations. In a secondary analysis, first-line treatment with gefitinib was also dominant when compared with first-line chemotherapy in patients with activating EGFR mutations. CONCLUSIONS: This strategy can be considered a new standard of care and should be of great interest for health care payers and decision makers in an era in which our greatest challenge is to balance hard-won and incremental, yet small, improvements in patient outcomes with exponentially rising costs.

A cross-market cost comparison of erlotinib versus pemetrexed for first-line maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer.

Erlotinib and pemetrexed were approved by the European Medicines Agency for first-line maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) to prolong overall survival after first-line therapy. An adjusted, matched, indirect comparison of erlotinib and pemetrexed suggested that survival benefits were not statistically significantly different between treatments. We conducted a cost-comparison analysis of erlotinib versus pemetrexed in first-line maintenance treatment of locally advanced or metastatic, non-squamous NSCLC in France, Germany, Italy and Spain, performed from the perspective of national health-care decision-makers or purchasers. The analysis was limited to direct costs and comprised drug-acquisition costs, administration costs and costs of treating adverse events (AEs). A one-way sensitivity analysis on administration, acquisition and AE costs was also performed. Total monthly per-patient treatment costs for erlotinib in France, Germany, Italy and Spain were €2140, €2732, €1518 and €2048, respectively, and for pemetrexed €3453, €5534, €2921 and €3164, respectively. AE cost was greater for pemetrexed in all countries, as was administration cost. As an oral treatment, erlotinib is not associated with any administration costs, except in Germany, where the cost is lower than for pemetrexed. The sensitivity analysis showed acquisition costs to be the main driver of total monthly per-patient costs. Erlotinib appears to be a cost-saving treatment alternative to pemetrexed, producing comparable survival benefits, based on an indirect comparison, at a lower cost.

Budget impact analysis of pemetrexed introduction: case study from a teaching hospital perspective, Thailand.

OBJECTIVE: Thailand does not currently require Budget Impact Analysis (BIA) assessment. The present study aimed to estimate the annual drug cost and the incremental impact on the hospital pharmaceutical budget of the introduction of pemetrexed to a Thai teaching hospital. MATERIAL AND METHOD: The budget impact model was conducted in accordance with the Guidelines for preparing submissions to the Pharmaceutical Benefits Advisory Committee (PBAC). The model variables consisted of number of patients, growth rate of lung cancer, uptake rate of pemetrexed over time, unit prices of drugs, and the length and cost of treatment. Sensitivity analysis was performed to determine changes in budgetary impact due to variation of parameters or assumptions in the model. RESULTS: The introduction of pemetrexed was estimated to cause considerable costs for the teaching hospital. In the base-case analysis, the incremental costs were estimated at 8,553,984 Baht in the first year increasing to 12, 118, 144 Baht, 17,820,800 Baht and 17,820,800 Baht in the following years. The 4-year net budgetary impact was 20,154,480 Baht or approximately 127,560 Baht per patient. Sensitivity analyses found that number of treatment cycles andproportion of patients assumed to be treated with pemetrexed were the two most important influencing factors in the model. CONCLUSION: New costly innovative interventions should be evaluated using the BIA model to determine whether they are affordable. The Thai government should consider requiring the BIA study as one of the requirements for drug submission to assist in the determination of listing and subsidizing decision for medicines.

Budget impact of erlotinib for maintenance therapy in advanced non-small cell lung cancer.

OBJECTIVE: Assess the budgetary impact of adding erlotinib for maintenance therapy (MTx) in advanced non-small cell lung cancer (NSCLC) from a US health plan perspective. METHODS: A budget impact model was developed to analyze the costs (drug, administration, adverse events) associated with adding erlotinib MTx to a hypothetical 500,000 member US health plan. Treatment durations and dosing were derived from randomized controlled trials, FDA labeling, and National Comprehensive Cancer Network guidelines. Treatment patterns and assumptions were based on market research data, the SEER registry, and published literature. Cost data were obtained from Centers for Medicare and Medicaid Services payment rates and a drug pricing database. Sensitivity analyses were conducted to assess uncertainty. RESULTS: Overall health plan expenditures increased by $0.010 per member per month (PMPM). The main driver of additional cost was the erlotinib drug cost (∼$66,000) with the administration ($464) and side-effect ($47) costs being relatively modest. One-way sensitivity analyses showed that the results were most sensitive to the proportion of members receiving MTx; however, the PMPM did not exceed $0.013. CONCLUSIONS: The overall budget impact to a health plan of expanding the use of erlotinib from the 2nd/3rd-line advanced NSCLC setting to include the maintenance setting was relatively small. This was primarily due to the proportion of patients who would receive erlotinib MTx, the low cost of side-effects and minimal cost of drug administration. Additional research may be warranted to estimate the relative clinical and economic impacts of erlotinib MTx versus alternative MTx treatments.

Cost-effectiveness of second-line chemotherapy for non-small cell lung cancer: an economic, randomized, prospective, multicenter phase III trial comparing docetaxel and pemetrexed: the GFPC 05-06 study.

BACKGROUND: There are few data on the cost-effectiveness of second-line chemotherapies for non-small cell lung cancer (NSCLC). The objective of this phase III, randomized, multicenter, prospective study was to compare the cost-effectiveness of docetaxel and pemetrexed, two widely used drugs. METHODS: We compared, from a payer's perspective, the directs costs and effectiveness of docetaxel (75 mg/m, arm A) and pemetrexed (500 mg/m, arm B) administered every 3 weeks to NSCLC patients who had progressed after first-line platinum-based chemotherapy. Monthly health utilities (based on disease states: responding, stable or progressive, and grade 3/4 toxicities) were derived from the literature. Costs were prospectively assessed. RESULTS: One hundred fifty patients were enrolled between February 2006 and June 2008. The patients in the docetaxel and pemetrexed arms had similar clinical characteristics and treatment efficacy (respective objective response rates 10.7% and 12%; median progression-free survival times 2.8 and 2.5 months; median survival times 8.0 and 6.4 months, respectively). Grade 3/4 toxicities were significantly less frequent with pemetrexed (52.0% versus 33.3%, p = 0.02). Docetaxel was associated with lower treatment-period costs (€9709 ± €6272 versus €13,436 ± €6508, p < 0.001). Docetaxel had a more favorable cost-utility ratio than pemetrexed. When compared with best supportive care, the cost-utility was €32,652/quality-adjusted life year for docetaxel and €40,980/quality-adjusted life year for pemetrexed. CONCLUSION: Second-line treatment for NSCLC is more cost-effective with docetaxel than with pemetrexed. Both strategies have acceptable cost-effectiveness ratios compared with commonly used and reimbursed regimens for advanced NSCLC.

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

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of pemetrexed for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in accordance with the licensed indication, based upon the evidence submission from the manufacturer (Eli Lilly) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. 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. Data for two populations were presented: patients with non-squamous NSCLC histology and patients with adenocarcinoma histology. The clinical evidence was derived from a double-blind, placebo-controlled randomised controlled trial (RCT), the JMEN trial. The trial compared the use of pemetrexed + best supportive care (BSC ) as maintenance therapy, with placebo + BSC in patients with NSCLC (n = 663) who had received four cycles of platinum-based chemotherapy (CTX) and whose disease had not progressed. In the licensed population (patients with non-squamous histology), 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 vs 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 incremental cost-effectiveness ratios (ICERs) estimated by the manufacturer's model were 33,732 pounds per quality adjusted life-year (QALY) for the licensed nonsquamous population, and 39,364 pounds per QALY for the adenocarcinoma subgroup. Both of these ICERs were above the standard NICE willingness-to-pay range (20,000 pounds-30,000 pounds per QALY). The manufacturer also presented a case for pemetrexed to be considered as an end of life treatment. The ERG identified a number of problems in the economic model presented by the manufacturer; after correction, the base case ICER was re-estimated as 51,192 pounds per QALY gained and likely to exceed NICE's willingness-to-pay thresholds. Following a revised economic analysis submitted by the manufacturer, the AC accepted that an ICER of 47,000 pounds per QALY gained was most plausible. The AC also considered that maintenance treatment with pemetrexed fulfilled the end of life criteria.The guidance issued by NICE, on 20 June 20 2010, in TA190 as a result of the STA states that: People who have received pemetrexed in combination with cisplatin as first-line chemotherapy cannot receive pemetrexed maintenance treatment. 1.1 Pemetrexed is recommended as an option for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology if disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel.

Cost-effectiveness analysis of bevacizumab versus pemetrexed for advanced non-squamous NSCLC in Italy.

INTRODUCTION: The new targeted agent bevacizumab in combination with cisplatin and gemcitabine (BCG), and a third-generation chemotherapy pemetrexed in combination with cisplatin (PC), are approved as first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: An indirect comparison between BCG and PC showed that the bevacizumab triplet achieved a favourable hazard ratio in terms of progression-free survival among patients with advanced NSCLC. This analysis aimed to compare the detailed costs and benefits of these treatments for advanced non-squamous NSCLC in Italy. RESULTS: The monthly cost of single-agent bevacizumab, including administration and supportive care costs, and costs for adverse events as a single agent was 4,007 euro/patient less than pemetrexed over the patient's lifetime. BCG also achieved a mean gain of 0.12 life-years compared with PC over this period. The incremental cost-effectiveness ratio of BCG relative to PC was calculated to be 34,919 euro per additional life-year gained suggesting that BCG is cost-effective compared with PC as first-line treatment for advanced NSCLC in Italy. CONCLUSIONS: In conclusion, bevacizumab-based therapy can be considered as a cost-effective option when compared to chemotherapy treatments such as pemetrexed for the treatment for advanced non-squamous NSCLC.

Costs of bevacizumab and pemetrexed for advanced non-squamous NSCLC in Italy and Germany.

The new targeted agent bevacizumab in combination with cisplatin and gemcitabine, and a third-generation chemotherapy pemetrexed in combination with cisplatin, have been approved as first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSCLC). An indirect comparison between bevacizumab plus cisplatin and gemcitabine and pemetrexed plus cisplatin showed that bevacizumab (plus cisplatin and gemcitabine) achieved a favourable hazard ratio in terms of progression-free survival among patients with advanced NSCLC. This analysis aimed to compare the monthly cost of these treatments for advanced non-squamous NSCLC in Italy and Germany. The comparison used country specific cost data and adopted the payer perspective in Italy and Germany. The monthly cost of bevacizumab, including administration cost, as a single agent was 1,509 euro and 2,564 euro less than pemetrexed in Italy and Germany, respectively. The monthly treatment cost of bevacizumab plus cisplatin and gemcitabine was 1,001 euro and 446 euro less than pemetrexed plus gemcitabine in Italy and Germany, respectively. Results indicate that clinical benefits with bevacizumab plus cisplatin and gemcitabine therapy are achieved at a lower monthly cost than pemetrexed plus gemcitabine doublet therapy. Therefore, from a budget perspective, bevacizumab should be considered as a preferred targeted treatment of choice for advanced non-squamous NSCLC.

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

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.

Cost-effectiveness analysis of pemetrexed versus docetaxel in the second-line treatment of non-small cell lung cancer in Spain: results for the non-squamous histology population.

BACKGROUND: The objective of this study was to conduct a cost-effectiveness evaluation of pemetrexed compared to docetaxel in the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) for patients with predominantly non-squamous histology in the Spanish healthcare setting. METHODS: A Markov model was designed consisting of stable, responsive, progressive disease and death states. Patients could also experience adverse events as long as they received chemotherapy. Clinical inputs were based on an analysis of a phase III clinical trial that identified a statistically significant improvement in overall survival for non-squamous patients treated with pemetrexed compared with docetaxel. Costs were collected from the Spanish healthcare perspective. RESULTS: Outcomes of the model included total costs, total quality-adjusted life years (QALYs), total life years gained (LYG) and total progression-free survival (PFS). Mean survival was 1.03 years for the pemetrexed arm and 0.89 years in the docetaxel arm; QALYs were 0.52 compared to 0.42. Per-patient lifetime costs were 34677 euros and 32343 euros, respectively. Incremental cost-effectiveness ratios were 23967 euros per QALY gained and 17225 euros per LYG. CONCLUSIONS: Pemetrexed as a second-line treatment option for patients with a predominantly non-squamous histology in NSCLC is a cost-effective alternative to docetaxel according to the 30000 euros /QALY threshold commonly accepted in Spain.