Efficacy and safety of dolutegravir/lamivudine in virologically suppressed female participants: week 48 data from the pooled TANGO and SALSA studies.

OBJECTIVES: Women represent >50% of people with HIV globally but have historically been underrepresented in clinical trials. We evaluated the efficacy and safety of switching to dolutegravir/lamivudine (DTG/3TC) vs continuing their current antiretroviral regimen (CAR) by sex assigned at birth (female and male) in virologically suppressed adults with HIV-1 without prior virological failure in a pooled analysis of two randomized controlled trials. METHODS: This analysis included 48-week data from the phase 3 TANGO and SALSA studies. Primary and key secondary endpoints included proportions of participants with HIV-1 RNA ≥50 and <50 copies/mL at week 48, respectively. Safety was also assessed. RESULTS: Of 1234 participants, 250 (DTG/3TC, n = 133; CAR, n = 117) were female at birth. Week 48 proportions of participants with Snapshot HIV-1 RNA ≥50 copies/mL were similar regardless of sex at birth (DTG/3TC vs CAR: female, <1% [1/133] vs 2% [2/117]; male, <1% [1/482] vs <1% [3/502]). Proportions with HIV-1 RNA <50 copies/mL were high across sexes and treatment groups (DTG/3TC vs CAR: female, 91% [121/133] vs 89% [104/117]; male, 94% [455/482] vs 94% [471/502]). Immunological response with DTG/3TC was slightly higher in female participants. Incidences of adverse events leading to withdrawal and serious adverse events were low and comparable between treatment groups and across sexes. Weight gain was higher with DTG/3TC than with CAR among female participants aged ≥50 years (treatment difference 2.08 kg [95% confidence interval 0.40-3.75]). CONCLUSIONS: Results confirm the robustness of DTG/3TC as a switch option in virologically suppressed females with HIV-1, with outcomes similar to those in males.

Cost-utility analysis for advanced breast cancer therapy in Germany: results of the fulvestrant sequencing model.

Therapy decisions in advanced breast cancer (ABC) increasingly require assessment not only of treatment efficacy but also of cost-effectiveness. To this end, we performed a cost-utility analysis by comparing treatment sequences including/omitting fulvestrant in a hypothetical population of hormone receptor-positive (HR+) postmenopausal women with ABC. The analysis was performed from the German health care perspective. Using a first-order sequential Markov model, expected costs and utilities were calculated over a time horizon of 10 years for cohorts of patients with HR+ ABC, previously treated for at least 5 years using adjuvant endocrine therapies. Utilities were primarily quantified in terms of quality adjusted life years (QALY). "Base-case" estimates of state transition rates, resource utilization, and other model parameters were derived from published evidence and expert assessment. The impacts of uncertainties in all key model parameters were evaluated by sensitivity analysis. Costs and benefits were discounted at 3% annually. Including second-line fulvestrant in the treatment sequence led to greater estimated health gains (0.021 QALY) and cost savings of 564 euros ($745, 380 pounds) per patient, i.e. the fulvestrant-containing sequence was "dominant". The prediction of a cost savings was robust with respect to variations in all key parameters. The probability of acceptable cost-effectiveness for the fulvestrant sequence was 72% at a willingness to pay (WTP) of 30,000 euros/QALY ($39,621/QALY, 20,198 pounds/QALY); the probability was even higher at lower WTP and substantially exceeded 50% for any realistic WTP. In a representative population of women with HR+ advanced breast cancer, inclusion of fulvestrant in the treatment sequence provides a cost-effective alternative from the German health care perspective. A high probability of cost-effectiveness is maintained under variations in all key parameters. The results reflect a tendency for patients receiving fulvestrant at an early stage to maintain high quality of life for a longer interval.

Economic evaluation of fulvestrant as an extra step in the treatment sequence for ER-positive advanced breast cancer.

Drug therapies for advanced breast cancer in hormone-receptor-positive disease include both hormonal and chemotherapies. Current UK practice is to minimise toxicity by using sequential hormonal agents for as long as clinically appropriate. A Markov model was developed to investigate the cost effectiveness of different sequences of therapies, particularly exploring the effects of adding an additional hormonal agent, fulvestrant, to the treatment pathway. A systematic review was undertaken and a panel of seven UK oncologists validated assumptions used for treatment efficacy, treatment pathways and resources used. Fulvestrant was found to be a cost-effective treatment option when added to the treatment sequence as a second- or third-line hormonal therapy for advanced disease. For a cohort of 1000 patients, fulvestrant as a second-line hormone therapy provided an additional 47 life years and 41 quality-adjusted life years (QALYs), at an additional cost of pound 301 359. This equated to pound 6500 per life years gained and pound 7500 per QALY. When used as a third-line option, the fulvestrant arm was dominant providing an increase in health benefit of 27 QALYs for the whole cohort, at a mean overall cost reduction of pound 430 per patient. Sensitivity analyses showed these results to be robust, demonstrating that fulvestrant is an economically viable additional endocrine option in the United Kingdom for the treatment of hormone responsive advanced breast cancer.

Clinical effectiveness of first-line chemoradiation for adult patients with locally advanced non-small cell lung cancer: a systematic review.

BACKGROUND: The National Institute for Health and Clinical Excellence has issued guidelines on the treatment of non-small cell lung cancer (NSCLC) and recommends that patients with stage IIIA-IIIB disease who are not amenable to surgery be treated with potentially curative chemoradiation (CTX-RT). This review was conducted as part of a larger systematic review of all first-line chemotherapy (CTX) and CTX-RT treatments for patients with locally advanced or metastatic NSCLC. However, it was considered that patients with potentially curable disease (e.g. stage IIIA) are different from those with advanced disease, who are suitable for palliative treatment only, and therefore the results should be reported separately. OBJECTIVE: To evaluate the clinical effectiveness of first-line CTX in addition to radiotherapy (RT) (CTX-RT vs CTX-RT) for adult patients with locally advanced NSCLC who are suitable for potentially curative treatment. DATA SOURCES: Three electronic databases (MEDLINE, EMBASE and The Cochrane Library) were searched from January 1990 to September 2010. REVIEW METHODS: Inclusion criteria comprised adult patients with locally advanced NSCLC, trials that compared any first-line CTX-RT therapy (induction, sequential, concurrent and consolidation) and outcomes of overall survival (OS) and/or progression-free survival (PFS). The results of clinical data extraction and quality assessment were summarised in tables and with narrative description. Direct meta-analyses using OS data were undertaken where possible: sequential CTX-RT compared with concurrent CTX-RT; sequential CTX-RT compared with concurrent/consolidation CTX-RT; and sequential CTX-RT compared with concurrent CTX-RT with or without consolidation. There were not sufficient data to perform meta-analysis on PFS. RESULTS: Of the 240 potentially relevant studies that were published post 2000, 19 met the inclusion criteria and compared CTX-RT with CTX-RT. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT appear to show an OS advantage for concurrent CTX-RT arms over sequential arms; this result is not statistically significant [hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.50 to 1.25)]. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent/consolidation CTX-RT appear to show a statistically significant OS advantage for concurrent/consolidation CTX-RT treatment over sequential treatment (HR 0.68; 95% CI 0.55 to 0.83). The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT with or without consolidation appear to show a statistically significant OS advantage for concurrent CTX-RT with or without consolidation over sequential treatment (HR 0.72; 95% CI 0.61 to 0.84). LIMITATIONS: This report provides a summary and critical appraisal of a comprehensive evidence base of CTX-RT trials; however, it is possible that additional trials have been reported since our last literature search. It is disappointing that the quality of the research in this area does not meet the accepted quality standards regarding trial design and reporting. CONCLUSIONS: This review identified that the research conducted in the area of CTX-RT was generally of poor quality and suffered from a lack of reporting of all important clinical findings, including OS. The 19 trials included in the systematic review were too disparate to form any conclusions as to the effectiveness of individual CTX agents or types of RT. The focus of primary research should be good methodological quality; appropriate allocation of concealment and randomisation, and comprehensive reporting of key outcomes, will enable meaningful synthesis and conclusions to be drawn. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Clinical effectiveness and cost-effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer: a systematic review and economic evaluation.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) has issued multiple guidance for the first-line management of patients with lung cancer and recommends different combinations of chemotherapy treatments. This review provides a synthesis of clinical effectiveness and cost-effectiveness evidence supporting current guidance. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of first-line chemotherapy currently licensed in Europe and recommended by NICE, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). DATA SOURCES: Three electronic databases (MEDLINE, EMBASE and The Cochrane Library) were searched from 2001 to August 2010. REVIEW METHODS: Trials that compared first-line chemotherapy currently licensed in Europe and recommended by NICE in chemotherapy-naive adult patients with locally advanced or metastatic NSCLC were included. Data on key outcomes including, but not limited to, overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were extracted. For the assessment of cost-effectiveness, outcomes included incremental cost per quality-adjusted life-year (QALY) gained. Analyses were performed for three NSCLC subpopulations: patients with predominantly squamous disease, patients with predominantly non-squamous disease and patients with epidermal growth factor receptor (EGFR) mutation-positive (M+) status. Meta-analysis and mixed-treatment comparison methodology were conducted where appropriate. RESULTS: Twenty-three trials involving > 11,000 patients in total met the inclusion criteria. The quality of the trials was poor. In the case of patients with squamous disease, there were no statistically significant differences in OS between treatment regimes. The mixed-treatment comparison demonstrated that, in patients with non-squamous disease, pemetrexed (Alimta®, Eli Lilly and Company; PEM) + platinum (PLAT) increases OS statistically significantly compared with gemcitabine (Gemzar®, Eli Lilly and Company; GEM) + PLAT [hazard ratio (HR) = 0.85; 95% confidence interval (CI) 0.74 to 0.98] and that paclitaxel (Abraxane®, Celgene Corporation; PAX) + PLAT increases OS statistically significantly compared with docetaxel (Taxotere®, Sanofi-aventis; DOC) + PLAT (HR = 0.79, 95% CI 0.66 to 0.93). None of the comparisons found any statistically significant differences in OS among patients with EGFR M+ status. Direct meta-analysis showed a statistically significant improvement in PFS with gefitinib (Iressa®, AstraZeneca; GEF) compared with DOC + PLAT and PAX + PLAT (HR = 0.49; 95% CI 0.33 to 0.73; and HR = 0.38; 95% CI 0.24 to 0.60, respectively). No papers related to UK decision-making were identified. A de novo economic model was developed. Using list prices (British National Formulary), cisplatin (CIS) doublets are preferable to carboplatin doublets, but this is reversed if electronic market information tool prices are used, in which case drug administration costs then become more important than drug acquisition costs. For patients with both squamous and non-squamous disease, moving from low to moderate willingness-to-pay thresholds, the preferred drugs are PAX → GEM → DOC. However, in patients with non-squamous disease, PEM + CIS resulted in increased OS and would be considered cost-effective up to £35,000 per QALY gained. For patients with EGFR M+, use of GEF compared with PAX or DOC yields very high incremental cost-effectiveness ratios. Vinorelbine (Navelbine®, Pierre Fabre Pharmaceutical Inc.) was not shown to be cost-effective in any comparison. LIMITATIONS: Poor trial quality and a lack of evidence for all drug comparisons complicated and limited the data analysis. Outcomes and adverse effects are not consistently combined across the trials. Few trials reported quality-of-life data despite their relevance to patients and clinicians. CONCLUSIONS: The results of this comprehensive review are unique to NSCLC and will assist clinicians to make decisions regarding the treatment of patients with advanced NSCLC. The design of future lung cancer trials needs to reflect the influence of factors such as histology, genetics and the new prognostic biomarkers that are currently being identified. In addition, trials will need to be adequately powered so as to be able to test for statistically significant clinical effectiveness differences within patient populations. New initiatives are in place to record detailed information on the precise chemotherapy (and targeted chemotherapy) regimens being used, together with data on age, cell type, stage of disease and performance status, allowing for very detailed observational audits of management and outcomes at a population level. It would be useful if these initiatives could be expanded to include the collection of health economics data. FUNDING: The National Institute for Health Research Health Technology Assessment.

A systematic review of the clinical effectiveness and cost-effectiveness of Pharmalgen® for the treatment of bee and wasp venom allergy.

BACKGROUND: Each year in the UK, there are between two and nine deaths from anaphylaxis caused by bee and wasp venom. Anaphylactic reactions can occur rapidly following a sting and can progress to a life-threatening condition within minutes. To avoid further reactions in people with a history of anaphylaxis to bee and wasp venom, the use of desensitisation, through a process known as venom immunotherapy (VIT), has been investigated and is in use in the UK. VIT consists of subcutaneous injections of increasing amounts of purified bee and/or wasp venom extract. Pharmalgen® products (ALK Abelló) have had UK marketing authorisation for VIT (as well as diagnosis) of allergy to bee venom (using Pharmalgen Bee Venom) and wasp venom (using Pharmalgen Wasp Venom) since March 1995. OBJECTIVE: This review assessed the clinical effectiveness and cost-effectiveness of Pharmalgen in providing immunotherapy to individuals with a history of type 1 [immunoglobulin E (IgE)-mediated] systemic allergic reaction to bee and wasp venom. DATA SOURCES: A comprehensive search strategy using a combination of index terms (e.g. Pharmalgen) and free-text words (e.g. allerg$) was developed and used to interrogate the following electronic databases: EMBASE, MEDLINE, The Cochrane Library. REVIEW METHODS: Papers were included if they studied venom immunotherapy using Pharmalgen (PhVIT) in patients who had previously experienced a systemic reaction to a bee and/or a wasp sting. Comparators were any alternative treatment options available in the NHS without VIT. Included outcomes were systemic reactions, local reactions, mortality, anxiety related to the possibility of future allergic reactions, health-related quality of life (QoL) and adverse reactions (ARs) to treatment. Cost-effectiveness outcomes included cost per quality-adjusted life-years (QALYs) gained. Because of the small number of published randomised controlled trials (RCTs), no meta-analyses were conducted. A de novo economic model was developed to assess the cost-effectiveness of PhVIT plus high-dose antihistamine (HDA) plus adrenaline auto-injector (AAI) plus avoidance advice in relation to two comparators. RESULTS: A total of 1065 citations were identified, of which 266 full-text papers were obtained. No studies were identified that compared PhVIT with any of the outlined comparators. When these criteria were widened to include different protocols and types of PhVIT administration, four RCTs and five quasi-experimental studies were identified for inclusion. The quality of included studies was poor, and none was conducted in the UK. Eight studies reported re-sting data (systemic reactions ranged from 0.0% to 36.4%) and ARs (systemic reactions ranged from 0.0% to 38.1% and none was fatal). No included studies reported quality of life. No published economic evidence relevant to the decision problem was identified. The manufacturer of PhVIT did not submit any clinical effectiveness or cost-effectiveness evidence to the National Institute for Health and Clinical Excellence in support of PhVIT. The results of the Assessment Group's (AG) base-case analysis show that the comparison of PhVIT + HDA + AAI versus AAI + HDA yields an incremental cost-effectiveness ratio (ICER) of £18,065,527 per QALY gained; PhVIT + HDA + AAI versus avoidance advice only yields an ICER of £7,627,835 per QALY gained. The results of the sensitivity analyses and scenario analyses showed that the results of the base-case economic evaluation were robust for every plausible change in parameter made. The results of the 'High Risk of Sting Patients' subgroup analysis show that PhVIT + HDA + AAI dominates both AAI + HDA and avoidance advice only (i.e. is less expensive and more effective). The 'VIT Anxiety QoL Improvement' subgroup analysis shows that PhVIT + HDA + AAI versus HDA + AAI has an ICER of £23,868 per QALY gained, and PhVIT + HDA + AAI versus avoidance advice only yields an ICER of £25,661 per QALY gained. LIMITATIONS: This review is limited to the use of Pharmalgen in the treatment of hymenoptera venom allergy and therefore does not assess the effectiveness of VIT in general. CONCLUSIONS: The current use of PhVIT in clinical practice in the NHS appears to be based on limited and poor-quality clinical effectiveness research. Available evidence indicates that sting reactions following the use of PhVIT are low and that the ARs related to treatment are minor and easily treatable. The results of the AG's de novo economic evaluation demonstrate that PhVIT + AAI + HDA compared with AAI + HDA and with avoidance advice only yields ICERs in the range of £8-20M per QALY gained. Two subgroups ('High Risk of Sting Patients' and 'VIT Anxiety QoL Improvement') were considered in the economic evaluation and the AG concludes that the use of PhVIT + AAI + HDA may be cost-effective in both groups. Future research should focus on clearly identifying groups of patients most likely to benefit from treatment and ensure that clinical practice is focussed on these groups. Furthermore, given the paucity of UK data in this area it would be informative if data could be collected routinely when VIT is administered in the NHS (e.g. rates of systemic adverse reactions to VIT, rates of systemic reactions to bee/wasp stings). FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of Technology Appraisal No. 90): a systematic review and economic analysis.

BACKGROUND: Occlusive vascular events such as myocardial infarction (MI), ischaemic stroke and transient ischaemic attack (TIA) are the result of a reduction in blood flow associated with an artery becoming narrow or blocked through atherosclerosis and atherothrombosis. Peripheral arterial disease is the result of narrowing of the arteries that supply blood to the muscles and other tissues, usually in the lower extremities. The primary objective in the treatment of all patients with a history of occlusive vascular events and peripheral arterial disease is to prevent the occurrence of new occlusive vascular events. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole (MRD) alone or with aspirin (ASA) compared with ASA (and each other where appropriate) in the prevention of occlusive vascular events in patients with a history of MI, ischaemic stroke/TIA or established peripheral arterial disease. To consider the clinical effectiveness and cost-effectiveness of clopidogrel in patients with multivascular disease. This review is an update of the evidence base for the National Institute for Health and Clinical Excellence (NICE) guidance Technology Appraisal No. 90 (TA90) entitled Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (2005). DATA SOURCES: Four electronic databases (EMBASE, MEDLINE, Web of Science and The Cochrane Library) were searched for randomised controlled trials (RCTs) and economic evaluations. Submissions to NICE by the manufacturers of the interventions were also considered. REVIEW METHODS: A systematic review of clinical effectiveness and cost-effectiveness was conducted. To manage heterogeneity between trials, indirect analysis (using a mixed-treatment methodology) was performed on selected clinical outcomes. A new economic model was developed to assess incremental costs per life-year gained [quality-adjusted life-years (QALYs)]. RESULTS: For evidence of clinical effectiveness, four RCTs were identified: CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events), ESPRIT (European/Australasian Stroke Prevention in Reversible Ischaemia Trial), PRoFESS (Prevention Regimen For Effectively avoiding Second Strokes) and ESPS-2 (Second European Stroke Prevention Study). In CAPRIE (patients with MI, ischaemic stroke or peripheral arterial disease), statistically significant outcomes in favour of clopidogrel were noted for the primary outcome (first occurrence of ischaemic stroke, MI or vascular death) compared with ASA [relative risk reduction 8.7%; 95% confidence interval (CI) 0.3% to 16.5%; p = 0.043]. In ESPRIT (patients with ischaemic stroke/TIA) for the primary outcome (first occurrence of death from all vascular causes, non-fatal stroke, non-fatal MI or major bleeding complication), the risk of event occurrence was statistically significantly lower in the MRD + ASA arm than in the ASA arm [hazard ratio (HR) 0.80; 95% CI 0.66 to 0.98], with no statistically significant difference in bleeding events between the two arms. In PRoFESS (patients with ischaemic stroke) the rate of recurrent stroke of any type (primary outcome) was similar in the MRD + ASA and clopidogrel groups, and the null hypothesis (that MRD + ASA was inferior to clopidogrel) could not be rejected. In ESPS-2 (patients with ischaemic stroke/TIA), on the primary outcome of stroke, statistically significant differences in favour of MRD + ASA were observed compared with ASA and MRD alone (relative risk 0.76; 95% CI 0.63 to 0.93). The outcomes addressed in the mixed-treatment comparisons (limited by the available data) for the ischaemic stroke/TIA population confirmed the results of the direct comparisons. The 11 economic evaluations included in the review of cost-effectiveness indicated that for patients with previous peripheral arterial disease, ischaemic stroke or MI, clopidogrel is cost-effective compared with ASA, and for patients with previous ischaemic stroke/TIA, treatment with MRD + ASA is cost-effective compared with any other treatment in patients in the secondary prevention of occlusive vascular events. The relevance of the review was limited as the economic evaluations were not based on the most current clinical data. Cost-effectiveness results generated from the Assessment Group's de novo economic model suggested that the most cost-effective approach for patients with ischaemic stroke/TIA is clopidogrel followed by MRD + ASA then ASA. For patients with MI, the most cost-effective approach is ASA followed by clopidogrel. For patients with established peripheral arterial disease, the most cost-effective approach is clopidogrel followed by ASA. For patients with multivascular disease, clopidogrel followed by ASA is the most cost-effective approach. Incremental cost-effectiveness ratios (ICERs) were also calculated for patients who are intolerant to ASA. Assuming that the branded price for clopidogrel is used and TA90 guidance is not applied, all of the ICERs range between £2189 and £13,558 per QALY gained. Probabilistic sensitivity analyses were fully consistent with these findings. CONCLUSIONS: The evidence suggests that the most cost-effective treatment for patients with ischaemic stroke/TIA is clopidogrel followed by MRD + ASA followed by ASA; for patients with MI, ASA followed by clopidogrel; and for patients with established peripheral arterial disease or multivascular disease, clopidogrel followed by ASA. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The clinical effectiveness and cost-effectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a systematic review.

BACKGROUND: Breast cancer is the most common cancer affecting women in the UK. Tamoxifen (TAM) is considered as the standard of care for many women with oestrogen receptor positive breast cancer. However, wide variability in the response of individuals to drugs at the same doses may occur, which may be a result of interindividual genetic differences (pharmacogenetics). TAM is known to be metabolised to its active metabolites N-desmethyl TAM and 4-hydroxytamoxifen by a number of CYP450 enzymes, including CYP2D6, CYP3A4, CYP2C9, CYP2C19 and CYP2B6. N-desmethyl TAM is further metabolised to endoxifen by CYP2D6. Endoxifen, which is also formed via the action of CYP2D6, is 30- to 100-fold more potent than TAM in suppressing oestrogen-dependent cell proliferation, and is considered an entity responsible for significant pharmacological effects of TAM. Thus, an association between the cytochrome P450 2D6 (CYP2D6) genotype and phenotype (expected drug effects) is believed to exist and it has been postulated that CYP2D6 testing may play a role in optimising an individual's adjuvant hormonal treatment. OBJECTIVES: To determine whether or not testing for cytochrome P450 2D6 (CYP2D6) polymorphisms in women with early hormone receptor positive breast cancer leads to improvement in outcomes, is useful for health decision-making and is a cost-effective use of health-care resources. DATA SOURCES: Relevant electronic databases and websites including MEDLINE, EMBASE and HuGENet [Centers for Disease Control and Prevention (Office of Public Health Genomics), Human Genome Epidemiology Network] were searched until July 2009. Further studies that became known to the authors via relevant conferences or e-mail alerts from an automatically updated search of the Scopus database were also included as the review progressed, up to March 2010. REVIEW METHODS: A systematic review of the clinical effectiveness and cost-effectiveness of CYP2D6 testing was undertaken. As it was not possible to conduct meta-analyses, data were extracted into structured tables and narratively discussed. An exploratory analysis of sensitivity and specificity was undertaken. A review of economic evaluations and models of CYP2D6 testing for patients treated with TAM was also carried out. RESULTS: A total of 25 cohorts were identified which examined clinical efficacy (overall survival and relapse/recurrence), adverse events and endoxifen plasma concentrations by genotype/phenotype. Significantly, six cohorts suggest extensive metabolisers (Ems) appear to have better outcomes than either poor metabolisers (PMs) or PMs + intermediate metabolisers in terms of relapse/recurrence; however, three cohorts report apparently poorer outcomes for EMs (albeit not statistically significant). There was heterogeneity across the studies in terms of the patient population, alleles tested and outcomes used and defined. One decision model proposing a strategy for CYP2D6 testing for TAM was identified, but this was not suitable for developing a model to examine the cost-effectiveness of CYP2D6 testing. It was not possible to produce a de novo model because of a lack of data to populate it. CONCLUSION: This is a relatively new area of research that is evolving rapidly and, although international consortia are collaborating, the data are limited and conflicting. Therefore, it is not possible to recommend pharmacogenetic testing in this patient population. Future research needs to focus on which alleles (including, or in addition to, those related to CYP2D6) reflect patient response, the link between endoxifen levels and clinical outcomes, and the appropriate pathways for implementation of such pharmacogenetic testing in patient care pathways.

Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor-positive breast cancer which over-expresses human epidermal growth factor 2 (HER2): a systematic review and economic analysis.

BACKGROUND: Breast cancer is the uncontrolled, abnormal growth of malignant breast tissue affecting predominantly women. Metastatic breast cancer (mBC) is an advanced stage of the disease when the disease has spread beyond the original organ. Hormone receptor status and human epidermal growth factor 2 (HER2) status are two predictive factors that are taken into consideration when estimating the prognosis of patients with breast cancer. OBJECTIVES: To review the clinical effectiveness and cost-effectiveness evidence base for lapatinib (LAP) in combination with an aromatase inhibitor (AI) and trastuzumab (TRA) in combination with an AI for the first-line treatment of patients who have hormone receptor-positive (HR+)/human epidermal growth factor 2-positive (HER2+) mBC. DATA SOURCES: Relevant electronic databases and websites, including MEDLINE, EMBASE and the Cochrane Library, were searched until May 2010. Further data were derived from the manufacturers' submissions for LAP + AI and TRA + AI. REVIEW METHODS: A systematic review of the clinical effectiveness and cost-effectiveness of LAP + AI and TRA + AI was undertaken. As it was deemed inappropriate to compare LAP + AI with TRA + AI, two separate assessments of cost-effectiveness versus AIs alone were undertaken. RESULTS: Three trials were included in the systematic review [the patient populations of the efficacy and safety of lapatinib combined with letrozole (EGF30008) trial, the efficacy and safety of trastuzumab combined with anastrozole (TAnDEM) trial and the efficacy and safety of letrozole combined with trastuzumab (eLEcTRA) trial]. As a result of differences in the exclusion criteria and because one trial was halted prematurely, comparisons across trials were believed to be inappropriate and meta-analysis was not possible. Individually, however, the findings from the trials all suggest that LAP + AI or TRA + AI results in improved progression-free survival and/or time to progression when compared with AIs alone. The trials do not show a statistically significant benefit in terms of overall survival. Two separate economic analyses were conducted based on the completed trials; neither LAP + AI nor TRA + AI was found to be cost-effective when compared with AI monotherapy. LIMITATIONS: Because of differences in the EGF30008 and the TAnDEM trials, the Assessment Group believes the indirect comparisons analyses conducted by the manufacturers are inappropriate and, for the same reason, chooses not to compare LAP + AI with TRA + AI in an economic evaluation. CONCLUSIONS: LAP + AI and TRA + AI appear to be clinically more effective than AI monotherapy, but neither is cost-effective compared with AIs alone. It was not possible to compare LAP + AI with TRA + AI. Future research should include research into treating mBC in the HR+/HER2+ population who are not TRA (or LAP) naive and into comparing the clinical effectiveness of AIs as monotherapy in patients with HER2+ and human epidermal growth factor 2-negative breast cancer. FUNDING: The National Institute for Health Research Technology Assessment programme.

Gefitinib 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 gefitinib for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in accordance with the licensed indication, based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence consisted of the IRESSA Pan-ASian Study (IPASS); a phase III open-label randomised controlled trial conducted in 87 centres in East Asia which compared the use of gefitinib with paclitaxel/carboplatin in 1217 chemotherapy (CTX)-naive patients with stage IIIB/IV pulmonary adenocarcinoma. The manufacturer's submission focused on a subgroup of patients in IPASS who were epidermal growth factor receptor (EGFR) gene mutation-positive (M+) (n = 261; 21% of the total IPASS population). The primary clinical outcome was progression-free survival (PFS). Secondary outcomes included overall survival, clinically relevant improvement in quality of life and adverse events (AEs). Cost-effectiveness was measured in terms of incremental cost per quality-adjusted life-year (QALY). In the overall population, PFS was significantly longer in patients treated with gefitinib than in those treated with paclitaxel/carboplatin (hazard ratio 0.74, 95% confidence interval 0.65 to 0.85; p < 0.0001). The manufacturer reported an incremental cost-effectiveness ratio (ICER) of 20,744 pounds per QALY gained for the target population. The probabilistic sensitivity analysis illustrated that for patients who are EGFR M+, gefitinib compared with doublet CTX was not likely to be cost-effective at what would usually be considered standard levels of willingness to pay for an additional QALY; the mean ICER for gefitinib EGFR M+ versus doublet CTX EGFR M+ was reported as 35,700 pounds per QALY. Additional analysis by the ERG included amendments to the base-case analysis, including an alternative approach to projecting survival, inclusion of two important additional comparators, sensitivity to EGFR M+ prevalence, and AE costs and disutilities. The manufacturer's submission provides clinical evidence to support the use of gefitinib in EGFR M+ patients with adenocarcinoma histology only. Before patients can be offered first-line treatment with gefitinib they must undergo EGFR mutation status testing which is currently not routinely available in the NHS. At the time of writing, the guidance document issued by NICE on 28 July 2010 states that 'Gefitinib is recommended as an option for the first-line treatment of people with locally advanced or metastatic non-small-cell lung cancer (NSCLC) if they test positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and the manufacturer provides gefitinib at the fixed price agreed under the patient access scheme'.

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-utility analysis of deferasirox compared to standard therapy with desferrioxamine for patients requiring iron chelation therapy in the United Kingdom.

OBJECTIVE: The primary objective of the study was to evaluate the cost-utility of deferasirox (Exjade) compared to standard therapy using desferrioxamine (Desferal) for the control of iron overload in patients receiving frequent blood transfusions. The perspective adopted was that of the National Health Service in the UK. METHODS: Phase II/III clinical trials have shown deferasirox in the recommended doses of 20-30 mg/kg per day to have similar efficacy to desferrioxamine at equivalent doses in the control of chronic iron overload. The main difference between them is in the mode of administration. Desferrioxamine is administered parenterally as a slow subcutaneous infusion typically infused 8-12 hours a day for 5-7 days a week. In comparison, deferasirox provides 24 hour chelation via a once daily oral tablet dispersed in water or juice. An excel based economic model was developed to evaluate the annual healthcare costs and quality of life, or utility, benefits associated with differences in mode of administration, using beta-thalassaemia as the reference case. A community utility study using time trade-off methods was performed to determine utility outcomes associated with iron chelation therapy (ICT) mode of administration. RESULTS: In the reference case (patient mean weight 42 kg), deferasirox 'dominated' desferrioxamine, i.e. resulted in lower net costs and higher quality adjusted life years (QALYs). Drug dose and cost is patient weight related. Incremental cost per QALY gained was pound 7775 for patients with a mean weight of 62 kg. CONCLUSIONS: The cost-utility analysis did not take drug compliance into account. However, Deferasirox is cost-effective compared to standard iron chelation therapy with desferrioxamine, due to the cost and quality of life benefits derived from a simpler and more convenient oral mode of administration.