title: Population Pharmacokinetic/Pharmacodynamic Modeling of Tumor Size Dynamics in Pembrolizumab-Treated Advanced Melanoma.
abstract: Pembrolizumab is a potent immune-modulating antibody active in advanced melanoma, as demonstrated in the KEYNOTE-001, -002, and -006 studies. Longitudinal tumor size modeling was pursued to quantify exposure-response relationships for efficacy. A mixture model was first developed based on an initial dataset from KEYNOTE-001 to describe four patterns of tumor growth and shrinkage. For subsequent analyses, tumor size measurements were adequately described by a single consolidated model structure that captured continuous tumor size with a combination of growth and regression terms, as well as a fraction of tumor responsive to therapy. This revised model structure provided a framework to efficiently evaluate the impact of covariates and pembrolizumab exposure. Both models indicated that exposure to the drug was not a significant predictor of tumor size response, demonstrating that the dose range evaluated (2 and 10 mg/kg every 3 weeks) is likely near or at the plateau of maximal response.
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Chatterjee
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.|Former employee of Merck, currently employed at PD-Value, Houten, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Elassaiss-Schaap
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.|Former employee of Merck, currently employed at SGS Exprimo NV, Mechelen, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Lindauer
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Turner
authors.affiliation: Merck Serono, Darmstadt, Germany.|Former employee of Merck, currently employed at Roche, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Sostelly
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: T
authors.initials: T
authors.lastname: Freshwater
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mayawala
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ahamadi
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Stone
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.|Former employee of Merck, currently employed at Quantitative Solutions, a Certara company, Oss, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: de Greef
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Kondic
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: de Alwis
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data; D004305:Dose-Response Relationship, Drug; D006801:Humans; D038622:Internationality; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects* / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C582435:pembrolizumab