Cancer Therapy: Clinical A Phase I Monotherapy Study of RG7212, a First-in- Class Monoclonal Antibody Targeting TWEAK Signaling in Patients with Advanced Cancers Ulrik N. Lassen 1 , Didier Meulendijks 2 , Lilian L. Siu 3 , Vaios Karanikas 4 , Morten Mau-Sorensen 1 , Jan H.M. Schellens 2 , Derek J. Jonker 5 , Aaron R. Hansen 3 , Mary E. Simcox 6 , Kathleen J. Schostack 6 , Dean Bottino 6 , Hua Zhong 6 , Markus Roessler 7 , Suzana M. Vega-Harring 7 , Tiantom Jarutat 7 , David Geho 6 , Ka Wang 6 , Mark DeMario 6 , and Glenwood D. Goss 5 Abstract Purpose: Tumor necrosis factor (TNF)–like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible mol- ecule 14 (Fn14) are a ligand–receptor pair frequently overex- pressed in solid tumors. TWEAK:Fn14 signaling regulates multi- ple 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 pro- portional 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 regres- sion was observed and prolonged stable disease was demonstrat- ed 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. Introduction Tumor necrosis factor (TNF)–like weak inducer of apoptosis (TWEAK) is a widely expressed member of the TNF superfamily identified as having proapoptotic activity in combination with gamma-interferon (1). Other studies have identified TWEAK as a multifunctional cytokine involved in diverse cellular processes encompassing tissue repair and remodeling (particularly in bone and skeletal muscle; ref. 2–4), promotion of inflammation, cel- lular proliferation, angiogenesis, and cell survival (5, 6). TWEAK mediates signaling through its cognate receptor fibroblast growth factor-inducible molecule 14 (Fn14), which is broadly expressed in nearly all nonhematopoietic cell types. TWEAK is synthesized as a transmembrane protein with a C-terminal extracellular region containing a TNF homology domain (1, 7). Full-length TWEAK is proteolytically cleaved at furin endoprotease site(s) resulting in a soluble cytokine. Circu- lating TWEAK ligand trimerizes to bind and activate Fn14. Intra- cellular signaling is then mediated through the Fn14 cytoplasmic domain via TNF receptor–associated factors (TRAF) 1, 2, 3, and 5. This results in activation of canonical and noncanonical NFkB pathways as well as MAPK signaling (Fig. 1; ref. 8). TWEAK:Fn14 signaling plays a role in numerous pathologic processes, including rheumatoid arthritis (9, 10), systemic lupus erythematosis (11), ischemic stroke (12), and cancer (8). TWEAK and Fn14 expressed in tumor tissue may activate proliferation, invasion, angiogenesis, and inflammation (8, 13, 14). Other studies have identified TWEAK as curtailing the innate immune response and inhibiting the transition to adaptive immunity (15). High expression of Fn14 has been shown in several tumor types, 1 Department of Oncology, The Finsen Centre, Rigshospitalet, Copen- hagen, Denmark. 2 Department of Clinical Pharmacology, The Nether- lands Cancer Institute, Amsterdam, the Netherlands. 3 Ontario Cancer Institute/Princess Margaret Cancer Centre,Toronto, Ontario, Canada. 4 Roche Pharmaceutical Research and Early Development, Transla- tional Medicine Oncology, Roche Innovation Center Zurich, Schlieren, Switzerland. 5 Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada. 6 Roche Translational Clinical Research Center Inc., New York, New York. 7 Roche Diagnostics GmbH, Penzberg, Germany. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Author: Ulrik Lassen, Department of Oncology 5072, The Finsen Centre, Rigshospitalet, Copenhagen, Denmark. Phone: 45-35458923; Fax: 45- 35454391; E-mail: ulrik.lassen@rh.regionh.dk doi: 10.1158/1078-0432.CCR-14-1334 Ó2014 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 21(2) January 15, 2015 258 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/21/2/258/2028710/258.pdf by guest on 14 June 2022