Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication.

BACKGROUND: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. PATIENTS AND METHODS: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. RESULTS: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). CONCLUSIONS: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design.

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).

BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8 mg/kg loading dose, then 6 mg/kg every 3 weeks (q3w)] and pertuzumab (840 mg loading dose, then 420 mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. CLINICALTRIALS.GOV: NCT01572038.

[Bisprolol in heart failure: efficacy and costs in a French setting according to CIBIS II]. / Bisoprolol dans l'insuffisance cardiaque: efficacité et coûts dans le cadre français selon CIBIS II.

After a significant mortality benefit with bisoprolol in heart failure was demonstrated in CIBIS-II, an economic evaluation has been performed in cost-effectiveness terms. Average direct costs per patient were based on clinical data from 231 French patients, and measured in the perspective of the French National Health Insurance, effectiveness being expressed in terms of life days gained per patient. The extra cost of bisoprolol treatment and follow-up (averaging FF 1300 per 1.3 years) is outweighed by the reduction in hospitalization costs (representing a saving of FF 10,500 per patient) and other medication costs. Finally, bisoprolol therapy induces benefits in terms of both cost and survival: on average FF 9500 and 11 life days per patient. Sensitivity analyses confirm these results.

Quality of life in multiple sclerosis in France, Germany, and the United Kingdom. Cost of Multiple Sclerosis Study Group.

OBJECTIVE: To assess the quality of life (QoL) of patients with multiple sclerosis in France, Germany, and the United Kingdom with a cross sectional study. METHODS: Patients were classified into three severity groups according to the expanded disability severity scale (EDSS); stage I, II, and III, corresponding to mild (EDSS 1.0-3.5), moderate (EDSS 4.0-6.0), or severe (EDSS 6.5-8.0) multiple sclerosis respectively. Ninety patients with multiple sclerosis and 30 control patients without multiple sclerosis were recruited in each country. Control patients were matched to the patients with multiple sclerosis according to age and sex. Quality of life was assessed using the functional status questionnaire (FSQ). RESULTS: The aspects of QoL that were mostly affected in the three countries under study were physical function and general wellbeing. Social role function decreased with increased severity of disease in France and in particular in Germany. Multiple sclerosis did not seem to have an impact on psychological function. The QoL of control patients was systematically higher than that of patients with multiple sclerosis. CONCLUSIONS: Use of such a generic scale showed that progression of multiple sclerosis is accompanied by a decrease in QoL and suggested that this could be a relevant measurement in assessing the effect of treatment and progression of disease. Variation between countries, however, may be important.

Economic evaluation of multiple sclerosis in the UK, Germany and France.

A cross-sectional cost-of-care study was performed to assess the economic burden of multiple sclerosis (MS) in France, Germany and the UK. Patients were stratified into 3 groups according to the Expanded Disability Severity Scale (EDSS): stages I, II and III, corresponding to mild (EDSS 1.0 to 3.5), moderate (EDSS 4.0 to 6.0) and severe (EDSS 6.5 to 8.0) MS, respectively. 90 patients with MS and 30 non-MS control patients were recruited in each country. Control patients were matched to the patients with MS on the basis of age and gender. Demographic, clinical and economic data during the 3-month period prior to entry were collected in patient interviews. Total costs included actual expenditures, such as direct medical and non-medical costs, as well as indirect costs. From the societal perspective, the total cost of MS for 3 months was estimated at 1,928 US dollars, 3,941 US dollars and 5,678 US dollars in France, 2,772 US dollars, 2,056 dollars and 5701dollars in Germany, and 5,125 US dollars, 6,751 US dollars and 14, 622 US dollars in the UK, for stage I, II and III patients, respectively. The major medical cost driver in the UK was outpatient consultations, whereas hospitalisations were the major component in Germany and France. The major cost in the UK arose from the dependence of patients with MS on caregivers, which caused high non-medical, societal costs compared with France and Germany. From both the societal and health insurance perspectives in each country, costs for control patients were lower than those for stage I MS patients. MS represents a major financial burden on the individual, the family, health services and society, and these costs increase with MS progression.

A multinational economic evaluation of rhDNase in the treatment of cystic fibrosis.

Economic evaluations of pharmaceuticals are increasingly being conducted in conjunction with randomized phase III clinical trials to meet the demand for pharmacoeconomic data when new products are launched. While the need for such data is often global, the trials in which relevant information may be collected are often conducted in only one or a limited number of countries. A critical issue is how data from pivotal clinical trials in one setting can serve as the basis for pharmacoeconomic evaluations in others. We address this issue and report on four economic evaluations that we undertook in conjunction with a recent U.S. phase III clinical trial of recombinant human deoxyribonuclease (rhDNase), which is used to improve pulmonary function in patients with cystic fibrosis (CF). The objective of these evaluations was to estimate the potential impact of rhDNase therapy in France, Germany, Italy, and the United Kingdom on the direct costs of medical care for the treatment of respiratory tract infections (RTIs) in patients with CF. Analyses of economic impact were undertaken both with and without adjustment for differences in practice patterns between the United States and the countries of interest. Our findings suggest that rhDNase therapy may reduce the cost of RTI-related care by between US$600 and US$1,100 over a 24-week period; the cost of rhDNase is not included in these figures, as a price was unavailable when our analyses were undertaken. Despite methodologic challenges, economic evaluations that meet the information needs of decision makers in diverse countries can nonetheless be undertaken in conjunction with phase III clinical trials.