Abstract CT514: A phase I, open-label, dose-escalation study investigating a low-density lipoprotein receptor-related protein (LRP) 5/6 inhibitor, BI 905677, in patients with advanced solid tumors
Authors: Élez Elena , Lenz Heinz-Josef , de Jonge Maja , Yaeger Rona , Doi Toshihiko , Pronk Linda , Teufel Michael , Marzin Kristell , Tabernero Josep 
Published: June 2022

Abstract
Background: Ligand-dependent Wnt signaling, mediated by LRP5/6, is highly activated in a subset of solid tumors. Activation leads to accumulation of intracellular β-catenin and expression of β-catenin-dependent genes that promote cancer cell proliferation and treatment resistance. BI 905677 is a bi-paratopic antibody that binds LRP5/6 and blocks binding of Wnt ligands. This study (NCT03604445) aimed to identify the maximum tolerated dose (MTD) and determine the recommended dose for BI 905677 in patients with advanced solid tumors. Pharmacokinetics and efficacy will also be evaluated.
Methods: This is a Phase I, open-label, non-randomized study of BI 905677, administered intravenously, in patients with advanced, unresectable and/or metastatic solid tumors. Patients were refractory to or not eligible for standard therapy. Patients were treated at increasing intravenous doses of BI 905677 (0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 2.4, 2.8 and 3.6 mg/kg every 3 weeks [q3w]) until progression. Subsequent patients within a cohort were treated ≥ 72 hours apart to allow adequate monitoring for cytokine release syndrome and implementation of preventive measures if required.
Results: As of November 23, 2021, 37 patients have received BI 905677. The median age was 56 years (range 32-77) and most were male (65%) and had ECOG PS 1 (51%). At 3.6 mg/kg, 3/3 patients experienced dose-limiting toxicities (DLTs) and dose was reduced to 2.8 mg/kg, which was determined as the MTD. Patients received a median of 2.0 cycles (range 1-6). Across all dose levels, 19 patients (51%) experienced Grade ≥ 3 adverse events (AEs). The most common Grade ≥ 3 AEs were vomiting (11%), hyponatremia (8%), anemia (5%), diarrhea (5%), abdominal pain (5%), nausea (5%), hypokalemia (5%), pain (5%) and increased alkaline phosphatase (5%). No related Grade ≥ 3 AEs were reported for doses ≤ 1.6 mg/kg, and BI 905677 was considered well tolerated ≤ 2.8 mg/kg. There were two Grade 5 events not related to study drug (tumor lysis syndrome and disease progression). DLTs observed at 3.6 mg/kg were hyponatremia, increased β-CTX expression (&gt; 2-fold versus baseline), diarrhea, hyperbilirubinemia and vomiting. Exposure to BI 905677 increased in an approximately dose-proportional manner over the complete dose groups tested. No drug accumulation between Cycle 1 and Cycle 2 was observed for any cohort. Only six patients presented with anti-drug antibodies (ADAs), including one with pre-existing ADAs. Axin2 expression by reverse transcription PCR was reduced in paired skin biopsies but no dose dependency was observed. Across all doses, the best response was stable disease (n = 13; 35%).
Conclusions: BI 905677 was well tolerated, with the MTD established as 2.8 mg/kg q3w. An expansion cohort to evaluate the activity of BI 905677 in a molecularly selected population for Wnt ligand dependence is planned.
Citation Format: Elena Élez, Heinz-Josef Lenz, Maja de Jonge, Rona Yaeger, Toshihiko Doi, Linda Pronk, Michael Teufel, Kristell Marzin, Josep Tabernero. A phase I, open-label, dose-escalation study investigating a low-density lipoprotein receptor-related protein (LRP) 5/6 inhibitor, BI 905677, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT514.