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

Abstract

Purpose: 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.Experimental Design: Patients with Fn14-positive tumors (IHC!1þ) 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 à 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.

Phase I Study of Enavatuzumab, a First-in-Class Humanized Monoclonal Antibody Targeting the TWEAK Receptor, in Patients with Advanced Solid Tumors

“…Lassen and colleagues have recently reported on a phase 1 study of RG7212, a monoclonal antibody targeting TWEAK, reporting good tolerability (no DLTs and no significant hepatopancreatic toxicities), expected pharmacodynamic changes, and some evidence of antitumor activity (16). RG7212 was shown to reduce tumor TWEAK-TweakR signaling in an exposure-dependent manner (17). To our knowledge, our study is the first phase 1 clinical trial of a humanized IgG1 antibody to TweakR.…”

Disruption of the TWEAK/Fn14 pathway prevents 5-fluorouracil-induced diarrhea in mice

“…Previous studies reported that TWEAK/Fn14 signaling promotes invasion, migration, and survival in many types of cancer cells, including glioblastoma, neuroblastoma, and breast cancer cells[20-22]. One study demonstrated therapeutic benefits when using a TWEAK-blocking antibody for cancer therapy[23]. These reports indicated that TWEAK/Fn14 signaling relates to tumor progression and blocking the TWEAK/Fn14 pathway could be beneficial in cancer treatment.…”

TWEAK/Fn14 signaling in tumors

“…22,28,90,91 RG7212, a neutralizing monoclonal antibody (mAb) targeting TWEAK, can inhibit TWEAK/Fn14 signaling and suppress the growth of solid tumors in patients. 33,34 In preclinical trials, RG7212 blocked TWEAK/Fn14 signaling, NF-κB activation, and cytokine secretion in cultured tumor cells and even inhibited tumor growth in murine models. 35 Phase I studies were conducted in recent years, showing that RG7212 possesses excellent tolerability and favorable pharmacokinetics as administered systemically.…”