Model-based evaluation of the efficacy and safety of nivolumab once every 4 weeks across multiple tumor types
JournalAnnals of Oncology
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AbstractBackground: 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 benefit-risk profile of nivolumab 480 mg Q4W relative to 3 mg/kg Q2W was evaluated using population pharmacokinetic modeling and exposure–response (E–R) 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 E–R 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 (Cmax) after the first dose was higher (110.4%), and the trough concentration at day 28 was lower (−22.1%) with 480 mg Q4W versus 3 mg/kg Q2W. The Cmax 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 benefit–risk 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. Copyright 2019 The Authors
SponsorsThis work was supported by Bristol-Myers Squibb (no grant number is applicable).
model-informed drug development
Q4W dosing frequency
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85078574824&doi=10.1016%2fj.annonc.2019.10.015&partnerID=40&md5=e54feb324c1dda1bc84b5204b4901b60; http://hdl.handle.net/10713/11699