title: Exposure and Tumor Fn14 Expression as Determinants of Pharmacodynamics of the Anti-TWEAK Monoclonal Antibody RG7212 in Patients with Fn14-Positive Solid Tumors.
abstract: OBJECTIVE
  The TWEAK-Fn14 pathway represents a novel anticancer target that is being actively investigated. Understanding the relationship between pharmacokinetics of anti-TWEAK therapeutics and tumor pharmacodynamics is critical. We investigated exposure-response relationships of RG7212, an anti-TWEAK mAb, in patients with Fn14-expressing tumors.
  
  
  METHODS
  Patients with Fn14-positive tumors (IHC ≥ 1+) treated in a phase I first-in-human study with ascending doses of RG7212 were the basis for this analysis. Pharmacokinetics of RG7212 and dynamics of TWEAK were determined, as were changes in tumor TWEAK-Fn14 signaling in paired pre- and posttreatment tumor biopsies. The objectives of the analysis were to define exposure-response relationships and the relationship between pretreatment tumor Fn14 expression and pharmacodynamic effect. Associations between changes in TWEAK-Fn14 signaling and clinical outcome were explored.
  
  
  RESULTS
  Thirty-six patients were included in the analysis. RG7212 reduced plasma TWEAK to undetectable levels at all observed RG7212 exposures. In contrast, reductions in tumor Fn14 and TRAF1 protein expression were observed only at higher exposure (≥ 300 mg*h/mL). Significant reductions in tumor Ki-67 expression and early changes in serum concentrations of CCL-2 and MMP-9 were observed exclusively in patients with higher drug exposure who had high pretreatment tumor Fn14 expression. Pretreatment tumor Fn14 expression was not associated with outcome, but a trend toward longer time on study was observed with high versus low RG7212 exposure.
  
  
  CONCLUSIONS
  RG7212 reduced tumor TWEAK-Fn14 signaling in a systemic exposure-dependent manner. In addition to higher exposure, relatively high Fn14 expression might be required for pharmacodynamic effect of anti-TWEAK monoclonal antibodies.
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Didier
authors.initials: D
authors.lastname: Meulendijks
authors.affiliation: Department of Oncology, The Finsen Centre, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Ulrik N
authors.initials: UN
authors.lastname: Lassen
authors.affiliation: Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Zurich, Switzerland.
authors.forename: Vaios
authors.initials: V
authors.lastname: Karanikas
authors.affiliation: Department of Oncology, The Finsen Centre, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Mau-Sorensen
authors.affiliation: Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Jonker
authors.affiliation: Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Hansen
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Simcox
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Schostack
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
authors.forename: Dean
authors.initials: D
authors.lastname: Bottino
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Penzberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Roessler
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Penzberg, Germany.
authors.forename: Suzana M
authors.initials: SM
authors.lastname: Vega-Harring
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Penzberg, Germany.
authors.forename: Tiantom
authors.initials: T
authors.lastname: Jarutat
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Geho
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
authors.forename: Karen
authors.initials: K
authors.lastname: Wang
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
authors.forename: Mark
authors.initials: M
authors.lastname: DeMario
authors.affiliation: Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada.
authors.forename: Glenwood D
authors.initials: GD
authors.lastname: Goss
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Pharmaceutical Sciences, Science Faculty, Utrecht University, Utrecht, the Netherlands. j.schellens@nki.nl.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D014408:Biomarkers, Tumor / Q000097:blood*; D018932:Chemokine CCL2 / Q000097:blood; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy*; D000074049:Cytokine TWEAK; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood* / Q000235:genetics; D047990:TNF Receptor-Associated Factor 1 / Q000378:metabolism; D000074050:TWEAK Receptor; D016896:Treatment Outcome; D000079424:Tumor Necrosis Factor Inhibitors; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D000074049:Cytokine TWEAK; C000601202:RG7212; D018124:Receptors, Tumor Necrosis Factor; D047990:TNF Receptor-Associated Factor 1; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D000079424:Tumor Necrosis Factor Inhibitors; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9