A Phase I Monotherapy Study of RG7212, a First-in-Class Monoclonal Antibody Targeting TWEAK Signaling in Patients with Advanced Cancers

Abstract

Purpose: Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) are a ligand-receptor pair frequently overexpressed in solid tumors. TWEAK:Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFkB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1k monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14.Experimental Design: Dose escalations, over a 200-to 7,200-mg range, were performed with patients enrolled in weekly (QW), bi-weekly (Q2W), or every-three-week (Q3W) schedules. Primary objectives included determination of dose and safety profile. Secondary endpoints included assessments related to inhibition of TWEAK:Fn14 signaling, tumor proliferation, tumor immune cell infiltration, and pharmacokinetics.Results: In 192 treatment cycles administered to 54 patients, RG7212 was well-tolerated with no dose-limiting toxicities observed. More than 95% of related adverse events were limited to grade 1/2. Pharmacokinetics were dose proportional for all cohorts, with a t 1/2 of 11 to 12 days. Pharmacodynamic changes included clearance of free and total TWEAK ligand and reductions in tumor Ki-67 and TRAF1. A patient with BRAF wild-type melanoma who received 36 weeks of RG7212 therapy had tumor regression and pharmacodynamic changes consistent with antitumor effects. Fifteen patients (28%) received 16 or more weeks of RG7212 treatment.Conclusion: RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced TWEAK:Fn14 signaling. Tumor regression was observed and prolonged stable disease was demonstrated in multiple heavily pretreated patients with solid tumors. These encouraging results support further study of RG7212. Clin Cancer Res; 21(2); 258-66. Ó2014 AACR.

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

“…Patients and study design have been described in detail previously (6). Fifty-four patients were treated in a phase I, first-inhuman, multiple ascending dose study with single-agent RG7212 administered intravenously (in doses of 200-7,200 mg) on weekly (QW), every-2-week (Q2W), and every-3-week (Q3W) schedules (NCT01383733).…”

“…Pharmacokinetics of RG7212 and the effects of RG7212 on serum TWEAK have been described in detail previously (6). Briefly, free TWEAK concentrations dropped to below the lower limit of quantitation (LLQ) shortly after initiation of treatment and complete inhibition of TWEAK was maintained in cycles 1 through four across all dose levels.…”

“…The effect of RG7212-induced TWEAK inhibition on tumor antiproliferative effects was investigated by measuring changes in tumor Ki-67 expression, as measured by IHC (6). In patients with low exposure to RG7212, tumor Ki-67 expression increased by 4%, whether there was 25% reduction in Ki-67 expression in patients that had high exposure (P ¼ 0.020).…”

“…Although Fn14 is normally highly regulated and expressed at low levels, it is found to be persistently overexpressed in various solid tumor types, such as gastric/gastroesophageal cancer, hepatobiliary cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), and breast cancer (5,6). Tumor tissues, as well as different tumor cell lines, have been found to express TWEAK (3,7), and expression of TWEAK correlates with metastasis in breast cancer (8).…”

“…In multiple Fn14-expressing tumor xenografts in mice, RG7212 demonstrated single-agent tumor growth inhibition (15). In a phase I, first-in-human study, RG7212 had a favorable safety profile and showed early signs of activity in patients with Fn14-expressing tumors (6).…”