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dc.contributor.authorSanghavi, Kinjal
dc.contributor.authorVuppala, Pradeep
dc.contributor.authorIvaturi, Vijay
dc.contributor.authorHamuro, Lora
dc.contributor.authorRoy, Amit
dc.contributor.authorSuryawanshi, Satyendra
dc.date.accessioned2021-05-10T15:12:15Z
dc.date.available2021-05-10T15:12:15Z
dc.date.issued2021-05-06
dc.identifier.urihttp://hdl.handle.net/10713/15614
dc.description.abstractNivolumab monotherapy is approved as adjuvant treatment for melanoma, based on results from the pivotal CheckMate 238 trial. We present a model-based benefit-risk assessment of nivolumab in adjuvant melanoma supporting a posology change from a weight-based to a less frequent, flat-dosing regimen. The exposure-response (E-R) relationship for efficacy was evaluated using recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) endpoints from the CheckMate 238 trial. The E-R for safety was evaluated using data from 14 studies across a broad range of doses in several tumor types, using grade 3+ adverse events (AEs) and grade 2+ immune-mediated AEs (IMAEs) endpoints. Nivolumab trough exposures were not significant predictors of RFS or DMFS. Covariates significantly associated with increased risk of disease recurrence or death were PD-L1 (< 5% cutoff), lower baseline lactate dehydrogenase, and higher age. Covariates associated with increased risk of distant metastasis or death were PD-L1 (< 5% cutoff) and higher age. Higher nivolumab Cmax1 (maximum concentration after first dose) was significantly associated with grade 2+ IMAEs, but not grade 3+ AEs. The risk of grade 3+ AEs was significantly lower in adjuvant versus advanced melanoma. PS > 0 was associated with higher incidences of grade 2+ IMAEs and grade 3+ AEs. Female patients had significantly higher incidence of grade 2+ IMAEs than male patients. Nivolumab monotherapy in adjuvant melanoma demonstrated a relatively flat E-R relationship over the range of exposures produced by 3 mg/kg every 2 weeks and predicted a comparable benefit-risk profile to flat-dosing regimens.en_US
dc.description.urihttps://doi.org/10.1002/psp4.12642en_US
dc.language.isoenen_US
dc.publisherWiley-Blackwellen_US
dc.relation.ispartofCPT: Pharmacometrics & Systems Pharmacologyen_US
dc.rightsThis article is protected by copyright. All rights reserved.en_US
dc.subjectCovariatesen_US
dc.subjectExposure Responseen_US
dc.subjectModel-based drug developmenten_US
dc.subjectMonoclonal antibodiesen_US
dc.subjectOncologyen_US
dc.subjectSurvival Analysisen_US
dc.titleNivolumab Exposure-Response Analysis for Adjuvant Treatment of Melanoma Supporting a Change in Posologyen_US
dc.typeArticleen_US
dc.identifier.doi10.1002/psp4.12642
dc.identifier.pmid33955714
dc.source.countryUnited States


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