Abstract LB_A16: DareonTM-5: An open-label Phase II trial of BI 764532, a DLL3-targeting T cell engager, in patients with relapsed/refractory small cell lung cancer or other neuroendocrine carcinomas
Authors: Gambardella Valentina , Greystoke Alastair , Reck Martin , Liu Meiruo , Mueller Martha , Duenzinger Ulrich , Bergsland Emily B , Owonikoko Taofeek 
Published: December 2023

Abstract
Background: Small cell lung cancer (SCLC), extra-pulmonary neuroendocrine carcinomas (epNECs) and large cell NECs (LCNECs) of the lung are difficult-to-treat, aggressive tumors with limited treatment (Tx) options. Standard of care for metastatic disease is platinum-based chemotherapy ± immunotherapy. However, nearly all patients (pts) relapse, and outcomes are poor. Hence, alternative therapies are needed. Delta-like ligand 3 (DLL3), a Notch ligand, is highly expressed on the cell surface of SCLCs, epNECs and LCNECs. BI 764532, a humanized IgG-like T cell engager, binds to DLL3-positive tumor cells and CD3 on T-cells and promotes T cell-mediated cytotoxicity. In an ongoing first-in-human trial, BI 764532 exhibited promising efficacy and manageable tolerability in pts with DLL3-positive SCLC, epNEC and LCNEC of the lung (NCT04429087). Here we describe a planned Phase II dose optimization trial to assess safety/efficacy of two different doses of BI 764532 monotherapy in pts with progressive/recurrent SCLC, epNEC or LCNEC of the lung (NCT05882058).
Methods: The trial will recruit adult pts (n = ~120; ~70 sites; ~15 countries) with histologically/cytologically confirmed relapsed/refractory SCLC, epNEC or LCNEC of the lung who have received ≥2 (SCLC) or ≥1 (epNEC/LCNEC) prior lines of therapy, including ≥1 platinum-based regimen. Pts with mixed tumor histology are permitted if the SCLC/NEC component is predominant (≥50% of tumor tissue). Pts will be randomized 1:1 to receive one of two dose levels of intravenous BI 764532 (3-week cycles) stratified by tumor type (n ~ 60/arm). Tx will continue until disease progression, undue toxicity, withdrawal of consent or any other documented criteria for stopping Tx (maximum Tx duration: 36 months). Interim analyses for dose selection are planned after 30 pts have been followed for ≥6 and ≥12 weeks or have stopped Tx. A third interim efficacy analysis will be conducted when 60 pts per dose have been followed for ≥12 weeks or have stopped Tx. Key exclusion criteria: ECOG PS ≥2; untreated/symptomatic brain metastases or leptomeningeal disease; active/previous history of interstitial lung disease/pneumonitis; previous Tx with DLL3-targeting therapies; Tx with other anti-cancer drug &lt;4 weeks prior to first administration of BI 764532; unresolved toxicity from prior anti-tumor Tx; diagnosis of immunodeficiency, or intake of immunosuppressive therapy ≤7 days prior to first administration of BI 764532. Primary endpoints: objective response (RECIST v1.1; investigator assessment); occurrence of Tx-emergent adverse events (TEAEs) during the on-Tx period. Secondary endpoints: duration of objective response; progression-free survival; disease control; overall survival; pt-reported outcomes; TEAEs leading to discontinuation during the on-Tx period. Further endpoints: pharmacokinetics (PK); prespecified and exploratory biomarker analysis (archival tumor tissue is required). The comparison of the two target doses in this trial will be based on the totality of data, including safety, efficacy, PK and biomarker data.
Citation Format: Valentina Gambardella, Alastair Greystoke, Martin Reck, Meiruo Liu, Martha Mueller, Ulrich Duenzinger, Emily B Bergsland, Taofeek Owonikoko. DareonTM-5: An open-label Phase II trial of BI 764532, a DLL3-targeting T cell engager, in patients with relapsed/refractory small cell lung cancer or other neuroendocrine carcinomas [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A16.