Model-based evaluation of the efficacy and safety of nivolumab once every 4 weeks across multiple tumor types
JournalAnnals of Oncology
MetadataShow full item record
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
- Model-informed drug development approach supporting approval of the 4-week (Q4W) dosing schedule for nivolumab (Opdivo) across multiple indications: a regulatory perspective.
- Authors: Bi Y, Liu J, Furmanski B, Zhao H, Yu J, Osgood C, Ward A, Keegan P, Booth BP, Rahman A, Wang Y
- Issue date: 2019 Apr 1
- Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer.
- Authors: Long GV, Tykodi SS, Schneider JG, Garbe C, Gravis G, Rashford M, Agrawal S, Grigoryeva E, Bello A, Roy A, Rollin L, Zhao X
- Issue date: 2018 Nov 1
- Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors.
- Authors: Zhao X, Suryawanshi S, Hruska M, Feng Y, Wang X, Shen J, Vezina HE, McHenry MB, Waxman IM, Achanta A, Bello A, Roy A, Agrawal S
- Issue date: 2017 Aug 1
- Benefit-risk assessment of nivolumab 240 mg flat dose relative to 3 mg/kg Q2W regimen in Japanese patients with advanced cancers.
- Authors: Bei D, Osawa M, Uemura S, Ohno T, Gobburu J, Roy A, Hasegawa M
- Issue date: 2020 Feb
- Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting.
- Authors: Morrissey KM, Marchand M, Patel H, Zhang R, Wu B, Phyllis Chan H, Mecke A, Girish S, Jin JY, Winter HR, Bruno R
- Issue date: 2019 Dec