Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.

BACKGROUND: For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. METHODS: We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. FINDINGS: Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. INTERPRETATION: Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. FUNDING: Bristol-Myers Squibb.

Relating relapse and T2 lesion changes to disability progression in multiple sclerosis: a systematic literature review and regression analysis.

BACKGROUND: In the treatment of multiple sclerosis (MS), the most important therapeutic aim of disease-modifying treatments (DMTs) is to prevent or postpone long-term disability. Given the typically slow progression observed in the majority of relapsing-remitting MS (RRMS) patients, the primary endpoint for most randomized clinical trials (RCTs) is a reduction in relapse rate. It is widely assumed that reducing relapse rate will slow disability progression. Similarly, MRI studies suggest that reducing T2 lesions will be associated with slowing long-term disability in MS. The objective of this study was to evaluate the relationship between treatment effects on relapse rates and active T2 lesions to differences in disease progression (as measured by the Expanded Disability Status Scale [EDSS]) in trials evaluating patients with clinically isolated syndrome (CIS), RRMS, and secondary progressive MS (SPMS). METHODS: A systematic literature review was conducted in Medline, Embase, CENTRAL, and PsycINFO to identify randomized trials published in English from January 1, 1993-June 3, 2013 evaluating DMTs in adult MS patients using keywords for CIS, RRMS, and SPMS combined with keywords for relapse and recurrence. Eligible studies were required to report outcomes of relapse and T2 lesion changes or disease progression in CIS, RRMS, or SPMS patients receiving DMTs and have a follow-up duration of at least 22 months. Ultimately, 40 studies satisfied these criteria for inclusion. Regression analyses were conducted on RCTs to relate differences between the effect of treatments on relapse rates and on active T2 lesions to differences between the effects of treatments on disease progression (as measured by EDSS). RESULTS: Regression analysis determined there is a substantive clinically and statistically significant association between concurrent treatment effects in relapse rate and EDSS; p < 0.01. Lower treatment effects were associated with higher relative rates of disease progression. Significant associations between T2 lesion measures and EDSS measures also were found (p < 0.05), with some suggestion that the strength of the association may differ for older versus newer DMTs. CONCLUSIONS: Treatment differences in relapse reduction and T2 lesions are positively related to differences in disease progression over the first two years of treatment.

Survival, costs, and health care resource use by line of therapy in US Medicare patients with newly diagnosed glioblastoma: a retrospective observational study.

BACKGROUND: Glioblastoma (GBM) is associated with poor prognosis, large morbidity burden, and limited treatment options. This analysis evaluated real-world treatment patterns, overall survival, resource use, and costs among Medicare patients with GBM. METHODS: This retrospective observational study evaluated Medicare patients age 66 years or older with newly diagnosed GBM using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data from 2007 through 2013. Patients were followed from diagnosis to death or end of follow-up. An algorithm defined treatment patterns as lines of therapy (LOTs). The Kaplan-Meier method was used to estimate overall survival for the full sample as well as by LOT, surgical resection, Charlson Comorbidity Index (CCI), tumor size, and age. Resource use and costs during the follow-up period were reported in terms of total and per-patient-per-month (PPPM) estimates. RESULTS: A total of 4308 patients with GBM were identified (median age, 74 years; CCI of 0, 52%). The most commonly used first LOT was temozolomide (82%), whereas chemotherapy + bevacizumab was most prevalent for second-line (42%) and third-line (58%) therapy. The median overall survival was 5.9 months for resected patients and 3 months for unresected patients, with considerable heterogeneity depending on patient characteristics. A great proportion of patients had claims for an ICU admission (86.2%), skilled nursing facility (76.9%), and home health (56.0%) in the postdiagnosis period. The cumulative mean cost was $95 377 per patient and $18 053 PPPM, mostly attributed to hospitalizations. CONCLUSIONS: Limited treatment options, poor survival, and economic burden emphasize the need for novel interventions to improve care for Medicare patients with GBM.

The direct medical costs of undiagnosed chronic obstructive pulmonary disease.

OBJECTIVE: To estimate the costs of undiagnosed chronic obstructive pulmonary disease (COPD) by describing inpatient, outpatient, and pharmacy utilization in the years before and after the diagnosis. METHODS: A total of 6,864 patients who were enrolled in the Lovelace Health Plan for at least 12 months during the study period (January 1, 1999 through December 31, 2004) were identified. The first date that utilization was attributed to COPD was considered the first date of diagnosis. Each COPD case was matched to up to three age- and sex-matched controls. All utilization and direct medical costs during the study period were compiled monthly and compared based on the time before and after the initial diagnosis. RESULTS: Total costs were higher by an average of $1,182 per patient in the 2 years before the initial COPD diagnosis, and $2,489 in the 12 months just before the initial diagnosis, compared to matched controls. Most of the higher cost for undiagnosed COPD was attributable to hospitalizations. Inpatient costs did not increase after the diagnosis was made, but approximately one-third of admissions after the diagnosis were attributed to respiratory disease. Outpatient and pharmacy costs did not differ substantially between cases and matched controls until just a few months before the initial diagnosis, but remained 50% to 100% higher than for controls in the 2 years after diagnosis. CONCLUSIONS: Undiagnosed COPD has a substantial impact on health-care costs and utilization in this integrated managed care system, particularly for hospitalizations.

High-risk patients with hypertension: Are we doing enough?

Despite the increasing risk of cardiovascular disease, especially in patients with multiple risk factors, blood pressure (BP) control remains suboptimal. This study investigated real-world BP goal attainment and prescribing patterns for high-risk patients. A retrospective chart review study was conducted in patients treated by eight large primary care physician group practices between December 2003 and May 2006. A total of 1,917 hypertensive patients were identified with >/=1 risk factors: African-American ethnicity (634); diabetes (851); advanced age (1,123); body mass index (BMI) 25 kg/m(2) (1,614). BP control rate was 46% overall, and similar in the advanced age and overweight/obese subpopulations, but substantially lower (28%) in the diabetic subpopulation. Systolic blood pressure >/=20 mm Hg above the Joint National Committee on Prevention, Detection, Evaluation, and Treatment Report recommendation was found in 13% of the overall, advanced age and overweight/obese subpopulations, and in 20% of diabetics and 18% of African-Americans. Overall, 62% of patients received >/=2 antihypertensive while 36% of diabetics, 31% of African-Americans, 28% of advanced age, and 26% of overweight/obese patients received >/=3 antihypertensive classes. Despite availability of multiple antihypertensive classes, BP control rates were still suboptimal in this study's high-risk patients. There is a need for awareness and more aggressive treatment in high-risk patients given their increased risk of poor outcomes.

Barriers to counseling patients with obesity: a study of Texas community pharmacists.

OBJECTIVE: To assess barriers to the counseling of obese patients and identify pharmacists' characteristics associated with these barriers. DESIGN: Cross-sectional mail survey. SETTING: Texas. PARTICIPANTS: 139 community pharmacists. INTERVENTION: Self-administered questionnaire. MAIN OUTCOME MEASURES: Respondents' perceived barriers to pharmacists' counseling of obese patients. RESULTS: The top three barriers to counseling included lack of time (76.8%), lack of patient demand or expectations (55.8%), and lack of reimbursement/compensation (49.3%). Pharmacists indicated that they rarely to sometimes counseled obese patients and were somewhat comfortable with counseling about obesity management. They perceived obesity management strategies to be somewhat effective in weight loss, but were neutral regarding their confidence in achieving positive outcomes with counseling. Pharmacists who were more experienced were more likely to indicate that obesity is controllable without medications. Those who considered obesity controllable without medications were significantly more likely to view the various obesity management strategies as less effective, compared with those who did not share this belief. Pharmacists who viewed lack of privacy as a barrier were significantly less confident in achieving positive outcomes as a result of counseling. Creating awareness among patients about pharmacists' ability to counsel was perceived as most important in overcoming barriers. CONCLUSION: Pharmacists identified several barriers to counseling of obese patients. Pharmacists' demographics and beliefs about obesity were significantly associated with their perceived barriers.

Combating the obesity epidemic: community pharmacists' counseling on obesity management.

BACKGROUND: Obesity is reaching an epidemic proportion in the US. Nearly two-thirds (64.7%) of US adults are overweight or obese. Given the myriad of issues related to the management of obesity, community pharmacists can facilitate weight loss among their patients. OBJECTIVE: To identify factors that influence the frequency of counseling obese patients by community pharmacists. METHODS: A mail survey was sent to a random sample of 400 Texas community pharmacists. The questionnaire collected information on frequency of counseling obese patients, perceived comfort level with counseling obese patients, perceived effectiveness of various obesity treatments, and perceived confidence in achieving positive outcomes as a result of counseling. Demographic information was also collected. Descriptive statistics, correlational analyses, and t-tests were used to examine the data. RESULTS: A usable response rate of 35.2% was obtained (139 completed surveys out of 395 assumed delivered). Overall, pharmacists counseled patients rarely to sometimes about various aspects of obesity management. Correlational analyses revealed that pharmacists' frequency of counseling about obesity management was significantly and positively associated with their comfort level with counseling obese patients (r = 0.47; p < 0.001). Higher levels of confidence in achieving positive outcomes as a result of counseling (r = 0.39; p < 0.001) and higher levels of perceived effectiveness of obesity management options (r = 0.18; p = 0.037) were also significantly associated with higher levels of counseling about obesity management. CONCLUSIONS: Obesity counseling by pharmacists was positively correlated with their perceived comfort with counseling obese patients, confidence in achieving positive outcomes, and effectiveness of obesity management options.