To inform the benefit–risk assessment of nivolumab in patients with advanced melanoma, analyses of efficacy and safety exposure–response (E–R) relationships were conducted with data from patients with advanced melanoma enrolled in two clinical studies (phase I and phase III) who received nivolumab 0.1–10.0 mg/kg every 2 weeks. E‐R efficacy analyses were performed by relating the nivolumab time‐averaged concentration after the first dose (Cavg1) to two endpoints: RECIST objective response (OR) and overall survival (OS). E–R safety analyses characterized the relationship between nivolumab Cavg1 and the hazard of all‐causality adverse events leading to discontinuation or death (AE‐DC/D). Nivolumab exposure represented by Cavg1 was not a significant predictor of OR, OS, or the hazard of AE‐DC/D. E–R efficacy and safety relationships were relatively flat over the exposure range.

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Background: Nivolumab 480 mg every 4 weeks (Q4W) is approved in the European Union, United States, and several other markets across multiple tumor types. Its approval was supported by quantitative efficacy/safety analyses bridging to 3 mg/kg every 2 weeks (Q2W). Patients and methods: The benefiterisk profile of nivolumab 480 mg Q4W relative to 3 mg/kg Q2W was evaluated using population pharmacokinetic modeling and exposureeresponse (EeR) analyses for safety and efficacy. Pharmacokinetic exposures were predicted for 3203 patients with melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), squamous cell carcinoma of the head and neck, urothelial carcinoma, or classical Hodgkin lymphoma. Quantitative models analyzed EeR to predict 480-mg Q4W safety across all indications and efficacy for melanoma, NSCLC, and RCC. Intratumoral receptor occupancy (RO) was predicted for parameters representing different tumor types. Results: Time-averaged concentrations for 480 mg Q4W versus 3 mg/kg Q2W were higher during the first 28 days (26.8%) and similar at steady state (5.2%). The maximum concentration (C max) after the first dose was higher (110.4%), and the trough concentration at day 28 was lower (À22.1%) with 480 mg Q4W versus 3 mg/kg Q2W. The C max achieved with 480 mg Q4W was lower than the previously established safe dose of 10 mg/kg Q2W. The probability of adverse events for key safety end points was similar for 480 mg Q4W and 3 mg/kg Q2W. The predicted overall survival and objective response rates with 480 mg Q4W were comparable to 3 mg/kg Q2W. The predicted high intratumoral RO provided additional evidence to support 480 mg Q4W across tumor types. Conclusions: The benefiterisk profile for nivolumab 480 mg Q4W was predicted to be similar to that of 3 mg/kg Q2W across tumor types while providing a convenient and flexible option for patients and their caregivers.

Background Daily new COVID-19 cases from January to April 2020 demonstrate varying patterns of SARS-CoV-2 transmission across different geographical regions. Constant infection rates were observed in some countries, whereas China and South Korea had a very low number of daily new cases. In fact, China and South Korea successfully and quickly flattened their COVID-19 curve. To understand why this was the case, this paper investigated possible aerosol-forming patterns in the atmosphere and their relationship to the policy measures adopted by select countries. Objective The main research objective was to compare the outcomes of policies adopted by countries between January and April 2020. Policies included physical distancing measures that in some cases were associated with mask use and city disinfection. We investigated whether the type of social distancing framework adopted by some countries (ie, without mask use and city disinfection) led to the continual dissemination of SARS-CoV-2 (daily new cases) in the community during the study period. Methods We examined the policies used as a preventive framework for virus community transmission in some countries and compared them to the policies adopted by China and South Korea. Countries that used a policy of social distancing by 1-2 m were divided into two groups. The first group consisted of countries that implemented social distancing (1-2 m) only, and the second comprised China and South Korea, which implemented distancing with additional transmission/isolation measures using masks and city disinfection. Global daily case maps from Johns Hopkins University were used to provide time-series data for the analysis. Results The results showed that virus transmission was reduced due to policies affecting SARS-CoV-2 propagation over time. Remarkably, China and South Korea obtained substantially better results than other countries at the beginning of the epidemic due to their adoption of social distancing (1-2 m) with the additional use of masks and sanitization (city disinfection). These measures proved to be effective due to the atmosphere carrier potential of SARS-CoV-2 transmission. Conclusions Our findings confirm that social distancing by 1-2 m with mask use and city disinfection yields positive outcomes. These strategies should be incorporated into prevention and control policies and be adopted both globally and by individuals as a method to fight the COVID-19 pandemic.

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