2. Academic Validation
  3. Phase I Dose-Escalation Results for the Delta-Like Ligand 3/CD3 IgG-Like T-Cell Engager Obrixtamig (BI 764532) in Patients With Delta-Like Ligand 3+ Small Cell Lung Cancer or Neuroendocrine Carcinomas

Phase I Dose-Escalation Results for the Delta-Like Ligand 3/CD3 IgG-Like T-Cell Engager Obrixtamig (BI 764532) in Patients With Delta-Like Ligand 3+ Small Cell Lung Cancer or Neuroendocrine Carcinomas

  • J Clin Oncol. 2025 Sep 20;43(27):3021-3031. doi: 10.1200/JCO-25-00363.
Martin Wermke 1,  Valentina Gambardella 2,  Yasutoshi Kuboki 3,  Enriqueta Felip 4,  Miguel F Sanmamed 5,  Olatunji B Alese 6,  Cyrus M Sayehli 7,  Edurne Arriola 8,  Jürgen Wolf 9,  Liza C Villaruz 10,  Julia Bertulis 11,  Matus Studeny 12,  Mohamed Bouzaggou 13,  Xiaoyan Fang 14,  Daniel Morgensztern 15
Affiliations

Affiliations

  • 1 TU Dresden University of Technology, NCT/UCC Early Clinical Trial Unit, Dresden, Germany.
  • 2 Department of Medical Oncology, Hospital Clínico Universitario, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain.
  • 3 Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan.
  • 4 Department of Oncology, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
  • 5 Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
  • 6 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA.
  • 7 Interdisciplinary Study Center with ECTU, Medical Clinic and Polyclinic II of the University Hospital, Würzburg, Germany.
  • 8 Department of Medical Oncology, Hospital del Mar-CIBERONC (Centro de Investigación Biomédica en Red de Oncología), Cancer Research Program, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain.
  • 9 Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany.
  • 10 Division of Hematology/Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA.
  • 11 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany.
  • 12 Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany.
  • 13 Boehringer Ingelheim France S.A.S., Reims, France.
  • 14 Boehringer Ingelheim (China) Investment Co, Ltd, Shanghai, China.
  • 15 Washington University School of Medicine, St Louis, MO.
PMID: 40706016 DOI: 10.1200/JCO-25-00363
Abstract

Purpose: We report phase I results for obrixtamig (BI 764532), a delta-like ligand 3 (DLL3)/CD3 IgG-like T-cell engager, in patients with previously treated DLL3-positive small cell lung Cancer (SCLC), extrapulmonary neuroendocrine carcinomas (epNECs), or large cell neuroendocrine carcinoma of the lung (LCNEC-L).

Methods: Patients received escalating intravenous obrixtamig doses using four regimens: a fixed dose once every 3 weeks (A); a fixed dose once weekly (B1); a step-up dose once weekly for two weeks and target dose once weekly (B2); and a step-up dose once weekly for 3 weeks, target dose once weekly for 3 weeks, and once every 3 weeks thereafter (B3). The primary objective was maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics, and tumor response (RECIST v1.1).

Results: As of February 21, 2024, 168 patients received obrixtamig, 72% received ≥2 lines of previous Anticancer therapy, and 51% received previous anti-PD-1/PD-L1 therapy. Seven dose-limiting toxicities occurred during MTD evaluation (Regimen A, n = 1; Regimen B2, n = 6). MTD was not reached. The most common treatment-related adverse event was cytokine release syndrome (any grade: 57%; grade ≥3: 3%); most cases occurred early and were reversible. Across all doses, regimens, and tumor types, the overall response rate (ORR) was 23% (95% CI, 17.4% to 30.2%), the median duration of response (DoR) was 8.5 months (95% CI, 6.2 to not reached), and the 6-month DoR rate was 70% (95% CI, 53% to 88%). All patients in Regimens B2/B3 received the minimum effective dose (≥90 μg/kg once weekly or once every 3 weeks), achieving an ORR of 28% (95% CI, 20.7% to 35.9%). With Regimens B2/B3, ORRs were 21% (95% CI, 12.9% to 33.1%), 27% (95% CI, 17.4% to 39.6%), and 70% (95% CI, 39.7% to 89.2%) for SCLC, epNECs, and LCNEC-L, respectively.

Conclusion: The demonstrated tolerability and efficacy of obrixtamig regimens, administered as step-up followed by target doses of 90-1,080 μg/kg (once weekly or once every 3 weeks), in patients with heavily pretreated DLL3-positive tumors support further exploration in SCLC, epNEC, and LCNEC-L.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P990932
    99.9%, Anti-CD3E/DLL3 Antibody
    CD3