Abstract A092: Phase 1 trial of RO6874813, a novel bispecific FAP-DR5 antibody, in patients with solid tumors
Authors: Bendell Johanna , Blay Jean-Yves , Cassier Philippe , Bauer Todd , Terret Catherine , Mueller Claudia , Morel Anthony , Chesne Evelyne , Xu Zhi-xin , Tessier Jean , Ceppi Maurizio , James Ian , Wilson Sabine , Quackenbush Elizabeth , Ochoa de Olza Maria , Tabernero Josep , De Miguel Maria , Calvo Emiliano 
Published: August 2018

Abstract
Introduction: FAP-DR5 (RO6874813) is a novel bispecific antibody that binds with high and low affinity to fibroblast activation protein (FAP) and death receptor 5 (DR5), respectively. FAP-driven binding of RO6874813 mediates the high levels of DR5 clustering that are required for triggering cell death. Here, we present ongoing phase 1 data in patients with advanced solid tumors who were treated with escalating doses of single agent RO6874813 and assessed for tolerability. Methods: Study endpoints are safety and tolerability (primary) and antitumor activity (secondary). The study uses a continuous reassessment method (CRM) design for dose escalation. Patients received drug (IV ≤ 90 min) weekly (QW) or every other week (Q2W), starting with a run-in dose on Cycle 0/Day 1 (C0/D1) of 0.5 mg/kg for all cohorts to characterize linear and nonlinear pharmacokinetics (PK) . Doses administered at C1/D1 ranged from 1.0 to 45 mg/kg (3 or more patients per cohort). Dosing continued until progression of disease (PD) or toxicity occurred. Plasma biomarkers (BM) of DR5 binding (TRAIL, the DR5 ligand) and apoptosis (ccCK18) were measured at multiple timepoints. Archival or fresh tumor samples collected prior to RO6874813 treatment were analyzed for target expression by IHC and mRNA (qRT-PCR), cellular infiltrates, and apoptosis. Results: As of 26 April 2017, 32 patients have been treated with RO6874813. Patients had a median of 3.5 prior regimens (range 1-11) and received a median of 4 (range 2-21) doses of RO6874813. One patient (NSCLC) remains on treatment; 31 discontinued treatment (30 for PD; 1 for subject decision). A maximum tolerated dose has not been reached. The most common treatment-related adverse events (TR-AEs) were: fatigue (21.9%); nausea (15.6%), and infusion-related reactions (9.4%). Grade (Gr) ≥3 TR-AEs occurred in 2 patients (6.25%): anemia and asthenia (both Gr 3, occurring in 1 patient each). No Gr 4/5 TR-AEs and no protocol-defined DLTs were reported. No AE led to permanent study drug withdrawal; 5 patients died from PD, one within 30 days of their last dose. Thirty-one patients were evaluated for antitumor activity: using RECIST criteria, 1 PR (NSCLC; time on treatment = 324 days, ongoing) and 6 stable diseases (SD; median duration 42 days) were observed. 28 patients were evaluated by PET, with 2 (7%) FDG partial metabolic responses (EORTC criteria) seen. No difference was found between QW (used with select doses) and Q2W schedules for safety, antitumor activity, and PK/PD parameters. RO6874813 serum concentrations increased linearly with dose and revealed saturation of TMDD at ≥ 5 mg/kg (Q2W). For the single patient with a PR (30 mg/kg; Q2W), the Cmax at C1 exceeded that of other patients and showed accumulation over time, despite two dose interruptions for Gr 2 neutropenia. Blood BM analyses revealed a significant upregulation of TRAIL and ccCK18 after dosing in this and other patients, suggesting apoptotic activity. FAP and DR5 were expressed in tumor tissue of all patients. Conclusions: RO6874813 demonstrated a favorable safety profile in patients with multiple solid tumor types, and dose escalation and regimen optimization continue. Preliminary antitumor activity was observed in a patient with heavily pretreated NSCLC. Analyses required to support the hypothesis that FAP-binding mediates sufficiently high levels of DR5 clustering for apoptosis induction are ongoing.
Citation Format: Johanna Bendell, Jean-Yves Blay, Philippe Cassier, Todd Bauer, Catherine Terret, Claudia Mueller, Anthony Morel, Evelyne Chesne, Zhi-xin Xu, Jean Tessier, Maurizio Ceppi, Ian James, Sabine Wilson, Elizabeth Quackenbush, Maria Ochoa de Olza, Josep Tabernero, Maria De Miguel, Emiliano Calvo. Phase 1 trial of RO6874813, a novel bispecific FAP-DR5 antibody, in patients with solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A092.