Real-world persistence with fingolimod for the treatment of multiple sclerosis: A systematic review and meta-analysis.

OBJECTIVE: To systematically review reports of fingolimod persistence in the treatment of relapsing-remitting multiple sclerosis (RRMS) across data sources and practice settings, and to develop a consensus estimate of the 1-year real-world persistence rate. METHODS: A systematic literature review was conducted (MEDLINE, EMBASE, and abstracts from selected conferences [2013-2015]) to identify observational studies reporting 1-year fingolimod persistence among adult patients with RRMS (sample size ≥50). A random-effects meta-analysis was performed to estimate a synthesized 1-year persistence rate and to assess heterogeneity across studies. RESULTS: Of 527 publications identified, 25 real-world studies reporting 1-year fingolimod persistence rates were included. The studies included patients from different data sources (e.g., administrative claims, electronic medical records, or registries), used different definitions of persistence (e.g., based on prescriptions refills, patient report, or prescription orders), and spanned multiple geographic regions. Reported 1-year persistence rates ranged from 72%-100%, and exhibited statistical evidence of heterogeneity (I2 = 93% of the variability due to heterogeneity across studies). The consensus estimate of the 1-year persistence rate was 82% (95% confidence interval: 79%-85%). CONCLUSIONS: Across heterogeneous study designs and patient populations found in real-world studies, the consensus 1-year fingolimod persistence rate exceeded 80%, consistent with persistence rates identified in the recently-completed trial, PREFERMS.

A Risk Score for Fluconazole Failure among Patients with Candidemia.

This study aimed to develop a prediction model to identify patients with candidemia who were at high risk of failing fluconazole treatment. Adult patients in the United States with candidemia who received fluconazole during hospitalization were selected from the Cerner Health Facts Hospital Database (04/2004 to 03/2013). Fluconazole failure was defined as switching/adding another antifungal, positive Candida culture ≥10 days after fluconazole initiation, or death during hospitalization. Patients were randomized into modeling and validation samples. Using the modeling sample, a regression analysis of least absolute shrinkage and selection operator was used to select risk predictors of fluconazole failure (demographics, Candida species, initiation of fluconazole before positive culture and after admission, and comorbidities, procedures, and treatments during the 6 months before admission and fluconazole initiation). The prediction model was evaluated using the validation sample. We found that of 987 identified patients (average age of 61 years, 51% male, 72% Caucasian), 49% failed and 51% did not fail fluconazole treatment. Of those who failed, 70% switched or added another antifungal, 21% had a second positive Candida test, and 42% died during hospitalization. Nine risk factors were included in the prediction model: days to start fluconazole after admission, Candida glabrata or Candida krusei infection, hematological malignancy, venous thromboembolism (VTE), enteral nutrition, use of nonoperative intubation/irrigation, and other antifungal use. All but VTE were associated with a higher risk of failure. The model's c-statistic was 0.65, with a Hosmer-Lemeshow test P value of 0.23. In summary, this prediction model identified patients with a high risk of fluconazole failure, illustrating the potential value and feasibility of personalizing candidemia treatment.

Real-World Analysis of Medical Costs and Healthcare Resource Utilization in Elderly Women with HR+/HER2- Metastatic Breast Cancer Receiving Everolimus-Based Therapy or Chemotherapy.

INTRODUCTION: The objective of this study was to analyze medical costs and healthcare resource utilization (HRU) associated with everolimus-based therapy or chemotherapy among elderly women with hormone-receptor-positive, human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC). METHODS: Elderly women (≥65 years) with HR+/HER2- mBC who failed a non-steroidal-aromatase-inhibitor and subsequently began a new line of treatment with everolimus-based therapy or chemotherapy for mBC (index therapy) during July 20, 2012 to March 31, 2014 were identified from two large commercial claims databases. All-cause, BC-, and adverse event (AE)-related medical costs (2014 USD), and all-cause and AE-related HRU per patient per month (PPPM) were compared between patients treated with everolimus-based therapy and chemotherapy across their first four lines of therapy for mBC. Adjusted costs and HRU differences were estimated by pooling all lines and using multivariable models adjusted for differences in patient characteristics. RESULTS: In total, 925 elderly patients (mean age approximately 73 years) with HR+/HER2- mBC met the inclusion criteria; 230 received everolimus-based therapy (240 lines) and 737 received chemotherapy (939 lines). Compared with chemotherapy, everolimus-based therapy was associated with significantly lower total all-cause PPPM medical services costs (adjusted mean difference: $4007), driven by lower inpatient ($1994) and outpatient ($1402) costs; lower BC-related medical services costs ($3129), driven by both BC-related inpatient ($1883) and outpatient costs ($913); and lower AE-related medical services costs ($1873; all P < 0.01). Additionally, compared to patients treated with chemotherapy, patients treated with everolimus-based therapy had fewer all-cause outpatient visits (adjusted incidence rate ratio = 0.69), BC-related outpatient visits (0.66), other-medical-service visits (0.65), and AE-related HRU (0.59), which was driven by significantly fewer AE-related outpatient visits (0.56; all P < 0.01). Subgroup analyses comparing medical costs of everolimus-based therapy with capecitabine monotherapy showed consistent results overall. CONCLUSION: This retrospective claims database analysis of elderly women with HR+/HER2- mBC in the United States showed that everolimus-based therapy was associated with significantly lower all-cause, BC-related, and AE-related medical services costs and less use of healthcare resources compared with chemotherapy. FUNDING: Novartis.

Treatment patterns and factors associated with the use of everolimus among post-menopausal women with HR+/HER2- metastatic breast cancer: a retrospective US claims study.

OBJECTIVE: To assess the real-world use of everolimus in the treatment of hormone-receptor-positive/human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic-breast-cancer (mBC). METHODS: Postmenopausal women with HR+/HER2- mBC who initiated a new therapy for mBC between 20 July 2012 and 31 March 2014 after a non-steroidal-aromatase-inhibitor were identified from two commercial claims databases. Multivariate logistic regressions were used to identify factors associated with everolimus use versus endocrine-monotherapy or chemotherapy. Dosing patterns and adherence to everolimus were summarized. RESULTS: A total of 940 everolimus, 6,134 endocrine-monotherapy, and 3,410 chemotherapy regimens were included across patients' first four lines of therapy. Patients with bone and visceral metastases were more likely to use everolimus versus endocrine-monotherapy. Patients with more comorbidities, visceral or central-nervous-system metastases, and prior chemotherapy use for mBC were less likely to use everolimus versus chemotherapy. Approximately 80% of patients initiated everolimus at label-recommended-dose of 10 mg daily; 60-70% of patients had a medical possession ratio >0.8 to everolimus, and consistently high adherence was observed across lines of therapy. CONCLUSIONS: For HR+/HER2- mBC, patients treated with everolimus had more severe disease than patients treated with endocrine-monotherapy but less severe disease than patients treated with chemotherapy. Most patients used everolimus according to label-recommended dose and adherence was high across lines of therapy.

Comparison of medical costs and healthcare resource utilization of post-menopausal women with HR+/HER2- metastatic breast cancer receiving everolimus-based therapy or chemotherapy: a retrospective claims database analysis.

OBJECTIVE: To analyze medical costs and healthcare resource utilization (HRU) associated with everolimus-based therapy or chemotherapy among post-menopausal women with hormone-receptor-positive, human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC). METHODS: Patients with HR+/HER2- mBC who discontinued a non-steroidal aromatase inhibitor and began a new line of treatment with everolimus-based therapy or chemotherapy (index therapy/index date) between July 20, 2012 and April 30, 2014 were identified from two large claims databases. All-cause, BC-related, and adverse event (AE)-related medical costs (in 2014 USD) and all-cause HRU per patient per month (PPPM) were analyzed for both treatment groups across patients' first four lines of therapies for mBC. Adjusted differences in costs and HRU between the everolimus and chemotherapy treatment group were estimated pooling all lines and using multivariable generalized linear models, accounting for difference in patient characteristics. RESULTS: A total of 3298 patients were included: 902 everolimus-treated patients and 2636 chemotherapy-treated patients. Compared to chemotherapy, everolimus was associated with significantly lower all-cause (adjusted mean difference = $3455, p < 0.01) and BC-related ($2510, p < 0.01) total medical costs, with inpatient ($1344, p < 0.01) and outpatient costs ($1048, p < 0.01) as the main drivers for cost differences. Everolimus was also associated with significantly lower AE-related medical costs ($1730, p < 0.01), as well as significantly lower HRU (emergency room incidence rate ratio [IRR] = 0.83; inpatient IRR = 0.74; inpatient days IRR = 0.65; outpatient IRR = 0.71; BC-related outpatient IRR = 0.57; all p < 0.01). CONCLUSIONS: This retrospective claims database analysis of commercially-insured patients with HR+/HER2- mBC in the US showed that everolimus was associated with substantial all-cause, BC-related, and AE-related medical cost savings and less utilization of healthcare resources relative to chemotherapy.

Effectiveness of Everolimus Versus Endocrine Monotherapy or Chemotherapy Among HR+/HER2- mBC Patients With Multiple Metastatic Sites.

PURPOSE: This review compared the real-world effectiveness of everolimus-based therapy versus endocrine monotherapy or chemotherapy in postmenopausal hormone receptor positive (HR+)/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) patients with multiple metastatic sites. METHODS: This retrospective chart review examined a nationwide sample of postmenopausal HR+/HER2- mBC women with ≥2 non-lymph-node metastatic sites. Patients must have initiated everolimus-based therapy (monotherapy or combination therapy including everolimus), endocrine monotherapy (any endocrine agent), or chemotherapy (monotherapy or combination with another chemotherapeutic or endocrine agent) for mBC between July 1, 2012 and August 15, 2013 after nonsteroidal aromatase inhibitor failure. Progression-free survival and time on treatment were compared using Kaplan-Meier analysis and Cox proportional hazard models, adjusting for line of therapy and baseline characteristics. FINDINGS: One hundred patients received everolimus-based therapy, 79 received endocrine monotherapy, and 86 received chemotherapy. Everolimus-based therapy was associated with significantly longer progression-free survival and time on treatment than endocrine monotherapy and chemotherapy. IMPLICATIONS: Among HR+/HER2- mBC patients with multiple metastatic sites, everolimus-based therapy was associated with better real-world effectiveness than endocrine monotherapy or chemotherapy.

Time on treatment of everolimus and chemotherapy among postmenopausal women with hormone-receptor-positive/human-epidermal-growth-factor-receptor-2-negative metastatic breast cancer: a retrospective claims study in the US.

OBJECTIVE: This study aimed to compare time on treatment (TOT) among patients treated with everolimus and chemotherapy, two commonly used treatments for hormone-receptor-positive/human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC). METHODS: Postmenopausal women with HR+/HER2- mBC who initiated ≥1 new line of therapy for mBC during 20 July 2012-31 March 2014 after a non-steroidal aromatase inhibitor were identified from MarketScan and PharMetrics databases (2002Q1-2014Q2) using a claims-based algorithm. Patients were classified into treatment groups by regimen and line of therapy, and were followed until discontinuation of therapy, end of insurance eligibility, or data cut-off (30 June 2014). Discontinuation was defined as a treatment gap of ≥60 days; patients who did not discontinue were censored at the end of follow-up. TOT was compared between everolimus, chemotherapy, and capecitabine monotherapy using Kaplan-Meier analyses and multivariable Cox models adjusting for line of therapy, age, insurance, de novo mBC diagnosis, prior use of chemotherapy for mBC, sites of metastases, and Charlson comorbidity index. RESULTS: Across the first four lines of therapies for mBC, a total of 940 everolimus, 3410 chemotherapy, and 721 capecitabine monotherapy regimens were included. Based on the different lines of therapies, the median TOT ranged from 5.5 to 7.2 months for everolimus, 4.3 to 4.7 months for chemotherapy, and 3.5 to 6.0 months for capecitabine monotherapy. Pooling all lines of therapies, everolimus was associated with significantly longer TOT compared to chemotherapy (multivariable-adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI]: 0.62-0.76) or capecitabine monotherapy (multivariable-adjusted HR = 0.73, 95% CI: 0.64-0.83). Longer TOT was consistently observed for everolimus for each line of therapy. LIMITATIONS: Proxies used for identifying HR + /HER2- mBC and treatment line, lack of certain clinical factors in claims data, generalizability limited to commercially insured patients in the US. CONCLUSIONS: This study found that HR+/HER2- mBC patients receiving everolimus experienced significantly longer TOT than those receiving chemotherapy overall or capecitabine monotherapy.

Real-World Effectiveness of Everolimus Subsequent to Different First Targeted Therapies for the Treatment of Metastatic Renal Cell Carcinoma: Synthesis of Retrospective Chart Reviews.

BACKGROUND: The effect of first targeted therapy on outcomes with second targeted therapy for metastatic renal cell carcinoma is not well known. The purpose of this study was to compare outcomes for patients receiving a second targeted therapy with everolimus by type of first targeted therapy. PATIENTS AND METHODS: Data were drawn from 3 separate retrospective chart reviews conducted in 2011, 2012, and 2014. Inclusion criteria and study design were similar across the 3 studies. To be included in this analysis, patients had to meet the following criteria: aged ≥ 18 years; received first targeted therapy with pazopanib, sunitinib, or sorafenib; and received second targeted therapy with everolimus. Overall survival, time to treatment failure, and time to treatment discontinuation outcomes were measured from second targeted therapy initiation. Outcomes were compared among treatment groups by Cox proportional hazard models adjusting for demographic and clinical characteristics. Hazard ratios for overall survival, time to treatment failure, and time to treatment discontinuation obtained from the 3 chart reviews were synthesized in meta-analyses. RESULTS: Of 696 patients treated with everolimus as second targeted therapy, 605 patients received first targeted therapy with sunitinib/sorafenib and 91 with pazopanib. After synthesizing the hazard ratios from all studies in meta-analyses, there were no significant differences in study outcomes between patients receiving sunitinib/sorafenib versus those receiving pazopanib as first targeted therapy. CONCLUSION: There were no significant differences among outcomes while receiving second targeted therapy with everolimus for patients treated with pazopanib versus sunitinib/sorafenib as first targeted therapy.

Clinical outcomes among HR+/HER2- metastatic breast cancer patients with multiple metastatic sites: a chart review study in the US.

BACKGROUND: Hormone receptor-positive, human epidermal growth factor receptor-2-negative (HR+/HER2-) is the most common type of metastatic breast cancer (mBC). While mBC patients generally have poor prognosis with limited progression-free survival (PFS) and overall survival (OS), those with multiple metastatic sites may have even worse clinical outcomes due to multiple organ involvement. This study aimed to compare clinical outcomes including PFS, time on treatment (TOT), and OS between HR+/HER2- mBC patients with multiple metastases versus those with a single metastasis in a real-world clinical setting. METHODS: This was a retrospective chart review study of postmenopausal HR+/HER2- mBC women who had failed a non-steroidal aromatase inhibitor in the adjuvant or metastatic setting and initiated a new treatment for mBC between 07/01/2012 and 04/15/2013. Patients were classified to one of two study groups (multiple metastases or single metastasis) based on the number of non-lymph-node metastases at the initiation of the new treatment. PFS, TOT and OS were compared between the two groups using Kaplan-Meier analyses and multivariable Cox proportional hazard models adjusting for patient disease and treatment characteristics. Separate Cox models were conducted including models with an interaction term between line of therapy and study group to assess the impact of multiple metastases on clinical outcomes across different lines of therapy. RESULTS: A total of 699 patient charts were collected, including 291 patients with multiple metastases and 408 single metastasis patients. Worse performance status and a higher proportion of prior chemotherapy for mBC were observed among patients with multiple metastases. Overall, patients with multiple metastases had significantly shorter PFS [adjusted hazard ratio (HR) = 1.55, 95 % confidence interval (CI) 1.21-1.98], TOT (adjusted HR = 1.33, 95 % CI 1.05-1.67), and OS (adjusted HR = 1.77, 95 % CI 1.15-2.74) than single metastasis patients. Similar outcomes were observed in each line of therapy. CONCLUSIONS: Among HR+/HER2- mBC patients, patients with multiple metastases had significantly shorter PFS, TOT, and OS than single metastasis patients, highlighting the substantial clinical burden and unmet need for more efficacious treatments for the former group of patients.

Real-world effectiveness of everolimus-based therapy versus fulvestrant monotherapy in HR(+)/HER2(-) metastatic breast cancer.

AIMS: Assessing real-world effectiveness of everolimus-based therapy (EVE) versus fulvestrant monotherapy (FUL) among postmenopausal women with hormone receptor-positive (HR(+))/HER2(-) metastatic breast cancer (mBC) after progression on nonsteroidal aromatase inhibitor (NSAI). DATA & METHODS: Medical charts of community-based patients who received EVE or FUL for mBC after NSAI were examined. Progression-free survival (PFS), time on treatment and time to chemotherapy were compared using Kaplan-Meier curves and Cox proportional hazards models adjusting for line of therapy and patient characteristics. RESULTS & CONCLUSION: 192 patients received EVE and 156 FUL. After adjusting for patient characteristics, EVE was associated with significantly longer PFS than FUL (hazard ratio: 0.71; p = 0.045). EVE was associated with better PFS than FUL among NSAI-refractory postmenopausal HR(+)/HER2(-) mBC patients.

Real-world effectiveness of everolimus-based therapy versus endocrine monotherapy and chemotherapy in patients of HR+/HER2- breast cancer with liver metastasis in the USA.

OBJECTIVE: This study investigated the comparative effectiveness of everolimus-based therapy (EVE) versus endocrine monotherapy (ET) and chemotherapy (CT) in the treatment of hormone-receptor-positive human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients with liver metastasis. METHODS: Medical charts of patients treated by community oncologists were examined. Eligible patients included postmenopausal women with HR+/HER2- mBC with liver metastasis who received EVE, ET or CT between 1 July 2012 and 15 April 2013 after non-steroidal aromatase inhibitor use. Time on treatment (TOT) and progression-free survival (PFS) were compared between EVE and ET or CT using Kaplan-Meier analyses and Cox proportional hazards models. RESULTS: Among the 202 patients in the study, 82 received EVE, 49 ET, and 71 CT. After adjusting for baseline characteristics, EVE was associated with significantly longer TOT than ET (hazard ratio [HR]: 0.49; 95% CI: 0.28 - 0.86) or CT (HR: 0.35; 95% CI: 0.22 - 0.55), and significantly longer PFS than ET (HR: 0.48; 95% CI: 0.27 - 0.87). PFS was not significantly different with EVE versus CT (HR: 0.76; 95% CI: 0.44 - 1.32). CONCLUSIONS: EVE had significantly longer TOT and PFS than ET and longer TOT than CT among postmenopausal HR+/HER2- mBC patients with liver metastasis.

Everolimus-Based Therapy versus Chemotherapy among Patients with HR+/HER2- Metastatic Breast Cancer: Comparative Effectiveness from a Chart Review Study.

Objective. To compare the real-world effectiveness of everolimus-based therapy and chemotherapy in postmenopausal women with hormone-receptor-positive/human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC). Methods. This retrospective chart review examined a nationwide sample of postmenopausal HR+/HER2- mBC women in community-based oncology practices. Patients received everolimus-based therapy or chemotherapy for mBC between 07/01/2012 and 04/15/2013, after failure of a non-steroidal aromatase inhibitor. Overall survival (OS), progression-free survival (PFS), and time on treatment (TOT) were compared using Kaplan-Meier analysis and Cox proportional hazards models adjusting for line of therapy and baseline characteristics. Results. 234 and 137 patients received everolimus-based therapy and chemotherapy. Patients treated with everolimus-based therapy tended to have less aggressive mBC than patients treated with chemotherapy. Multivariate-adjusted Cox models showed that everolimus-based therapy was associated with significantly longer OS [hazard ratio (HR) = 0.37, 95% confidence interval (CI): 0.22-0.63], PFS (HR = 0.70, 95% CI = 0.50-0.97), and TOT (HR = 0.34, 95% CI: 0.25-0.45) than chemotherapy. Adjusted comparative effectiveness results were generally consistent across lines of therapy. Conclusion. In this retrospective chart review of postmenopausal HR+/HER2- mBC patients, treatment with everolimus-based therapy was associated with longer OS, PFS, and TOT than chemotherapy.

Comparative effectiveness of everolimus-based therapy versus endocrine monotherapy among postmenopausal women with HR+/HER2- metastatic breast cancer: a retrospective chart review in community oncology practices in the US.

BACKGROUND: Everolimus-based therapy and endocrine monotherapy are used among postmenopausal women with hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (mBC) whose disease progressed or recurred on a non-steroidal aromatase inhibitor (NSAI). However, limited evidence exists regarding the real-world comparative effectiveness of these agents. METHODS: This retrospective chart review examined postmenopausal HR+/HER2- mBC patients in community-based oncology practices who received everolimus-based therapy or endocrine monotherapy (index therapy) as any line of therapy for mBC between 1 July 2012 and 15 April 2013 after NSAI failure. Time on treatment (TOT), progression-free survival (PFS), and time to chemotherapy (TTC) from index therapy initiation were compared using Kaplan-Meier analyses and Cox proportional hazards models adjusting for baseline characteristics. RESULTS: A total of 243 and 270 patients received everolimus-based therapy or endocrine monotherapy in a quota-based sample. Patients treated with everolimus-based therapy had a higher proportion of visceral metastases, high tumor burden, and use of prior chemotherapies for mBC. After adjusting for baseline characteristics, everolimus-based therapy was associated with significantly longer TOT (HR = 0.67, 95% CI: 0.51-0.87) and PFS (HR = 0.75, 95% CI: 0.57-0.98) than endocrine monotherapy. No significant difference was found between everolimus-based therapy and endocrine monotherapy in TTC (HR = 0.81, 95% CI: 0.52-1.27). Results stratified by line of therapy were generally consistent with the overall results. LIMITATIONS: Limitations include recall and information bias with potentially absent or erroneous chart data, unobserved factors due to non-randomization, inability to measure outcome assessments paired with measuring outcomes prior to exposures, and potential patient selection bias associated with chart review. CONCLUSIONS: Among a nationwide sample of postmenopausal HR+/HER2- mBC patients treated in community oncology settings, treatment with everolimus-based therapy was associated with significantly longer TOT and PFS compared to endocrine monotherapy.