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

Community Pharmacists role in obesity treatment in Kuwait: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Obesity is a growing health concern in Kuwait. Obesity has been identified as a key risk factor for many chronic diseases including hypertension, dyslipidemia and type 2 diabetes mellitus. It has been shown that community pharmacists' involvement is associated with successful weight management in developed countries. This study was conducted to investigate the role of community pharmacists in obesity counseling, and to identify the barriers to counseling in Kuwait.</p> <p>Methods</p> <p>A descriptive cross-sectional study involved 220 community pharmacies that were selected via stratified and systematic random sampling. A pretested self-administered questionnaire collected information on frequency and comfort level with obesity counseling, and the perceived effectiveness of four aspects of obesity management (diet and exercise, prescribed antiobesity medications, diet foods, and nonprescription products and dietary supplements). Information on perceived confidence in achieving positive outcomes as a result of counseling and barriers to counseling was also collected. Descriptive and Spearman’ r analysis were conducted using SPSS version 17. Responses with Likert scale rating 1(low score) to 5 (high score) and binary choices (yes/no) were presented as mean (SD) and (95% CI), respectively.</p> <p>Results</p> <p>The response rate was 93.6%. The overall mean (SD) responses indicated that pharmacists counseled obese patients sometimes to most of the time, 3.67 (1.19) and were neutral to comfortable with counseling about aspects of obesity management, 3.77 (1.19). Respondents perceived obesity management aspects to be somewhat effective, 3.80 (1.05). Of the four aspects of obesity management, diet and exercise, and diet foods were the highest ranked in terms of frequency of counseling, comfort level and perceived effectiveness. Pharmacists were neutral to confident in achieving positive outcomes as a result of obesity counseling, 3.44 (1.09). Overall mean responses of counseling obese patients by pharmacists were positively correlated with their perceived comfort with counseling and perceived effectiveness of obesity management aspects. The most anticipated barriers to obesity counseling were lack of patient awareness about pharmacists' expertise in counseling 76.2% (95% CI: 69.7-81.7) and pharmacists’ opinions that obese patients lack willpower and are non-adherent to weight reduction interventions 71.8% (95% CI: 65.1-77.8).</p> <p>Conclusions</p> <p>Strengths, weaknesses and barriers related to obesity counseling by pharmacists in Kuwait were identified, and suggestions were provided to strengthen that role.</p