Exposure and Tumor Fn14 Expression as Determinants of Pharmacodynamics of the Anti-TWEAK Monoclonal Antibody RG7212 in Patients with Fn14-Positive Solid Tumors

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...

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Bibliographic Details
Published in:	Clinical cancer research 2016-02, Vol.22 (4), p.858-867
Main Authors:	Meulendijks, Didier, Lassen, Ulrik N, Siu, Lillian L, Huitema, Alwin D R, Karanikas, Vaios, Mau-Sorensen, Morten, Jonker, Derek J, Hansen, Aaron R, Simcox, Mary E, Schostack, Kathleen J, Bottino, Dean, Zhong, Hua, Roessler, Markus, Vega-Harring, Suzana M, Jarutat, Tiantom, Geho, David, Wang, Karen, DeMario, Mark, Goss, Glenwood D, Schellens, Jan H M
Format:	Article
Language:	eng
Subjects:	Adult Aged Aged, 80 and over Antibodies, Monoclonal - pharmacokinetics Antibodies, Monoclonal - therapeutic use Antibodies, Monoclonal - toxicity Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Antineoplastic Agents - toxicity Biomarkers, Tumor - blood Chemokine CCL2 - blood Colorectal Neoplasms - blood Colorectal Neoplasms - drug therapy Cytokine TWEAK Female Gene Expression Humans Male Matrix Metalloproteinase 9 - blood Maximum Tolerated Dose Middle Aged Receptors, Tumor Necrosis Factor - blood Receptors, Tumor Necrosis Factor - genetics TNF Receptor-Associated Factor 1 - metabolism Treatment Outcome Tumor Necrosis Factors - antagonists & inhibitors TWEAK Receptor Young Adult
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Summary:	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. 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. 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. 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.
ISSN:	1078-0432 1557-3265