Model-based evaluation of the efficacy and safety of nivolumab once every 4 weeks across multiple tumor types

Abstract

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.

ESMO Management and treatment adapted recommendations in the COVID-19 era: Lung cancer

“…Based on pharmacokinetic modelling and exposureresponse analyses, immune checkpoint inhibitors (ICIs) schedule should be modified/delayed to reduce clinical visit, using 4-weekly nivolumab 480 mg [30][31][32][33][34] or 6-weekly pembrolizumab 400 mg [35][36][37] , instead of the standard 2-weekly or 3-weekly, when appropriate and where allowed from National Regulatory Agency (high priority).…”

How Mathematical Modeling Could Contribute to the Quantification of Metastatic Tumor Burden Under Therapy: Insights in Immunotherapeutic Treatment of Non-Small Cell Lung Cancer

“…For this, it might be helpful to consider the concept of early tumor shrinkage [48]. There are discussions whether higher doses of Nivolumab in shorter application intervals could be applied in the initial therapy stage to achieve this early tumor shrinkage by faster reaching the drug serum steady state and thus providing better responses [67,68]. The tumor size distributions shown in Figure 3 for patient KE-02 confirm this approach quantitatively.…”

How Mathematical Modeling Could Contribute to the Quantification of Metastatic Tumor Burden Under Therapy: Insights in Immunotherapeutic Treatment of Non-Small Cell Lung Cancer

“…For this, it might be helpful to consider the concept of early tumor shrinkage [48]. There are discussions whether higher doses of Nivolumab in shorter application intervals could be applied in the initial therapy stage to achieve this early tumor shrinkage by faster reaching the drug serum steady state and thus providing better responses [63,64]. The tumor size distributions shown in Figure 3 for patient KE-02 confirm this approach quantitatively.…”