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DLL3 as a Neuroendocrine Carcinoma Target

Neuroendocrine cancers of the genitourinary tract are poorly differentiated with an awful prognosis. Most commonly, small cell carcinoma of the lung draws the most attention, and treatment of high-grade neuroendocrine carcinomas tends to follow the treatment paradigms for lung neuroendocrine tumors. Although de novo neuroendocrine carcinomas of the genitourinary tract are rare, we are seeing greater incidence due to treatment resistance, as a result of potent androgen receptor (AR) directed therapies for patients with prostate cancer.1 Loss of AR expression and downstream signaling is now occurring in approximately 20% of castration-resistant prostate cancers.2 As a result, treatment-emergent neuroendocrine tumors are essentially reprogramming through lineage plasticity.3

Treatment for high grade neuroendocrine tumors, including those of the prostate and bladder, generally includes platinum combination chemotherapy. Although it is frequently initially effective in shrinking the tumor, durable responses are infrequent, and relapse usually occurs quickly and rather furiously. Beyond platinum chemotherapy, treatment options are limited with poor response rates. For small cell lung carcinoma, atezolizumab4 and lurbinectidin5 also have FDA approvals, the latter on the accelerated approval pathway for a 35% objective response rate in 105 patients, due to the unmet need.

Delta-like ligand 3 (DLL3) is a Notch ligand expressed in the nervous system during embryonic development.6,7 It has a role in cell fate decisions, although its complete function is not well understood.8 When considering its role as a potential neuroendocrine carcinoma target, the reassuring thing is that DLL3 is highly expressed in the tumor but not in most adult tissue. DLL3 is not expressed in benign prostate tissues, only in 0.52% of localized prostate cancers, 12% of castration-resistant prostate adenocarcinomas, yet 76.6% of castration-resistant prostate neuroendocrine carcinomas.9

Although the expression data above is promising, Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate (ADC), targeted to DLL3, offered disappointing efficacy and significant toxicity in patients with small cell carcinoma of the lung.10 However, the problem was not the target; the problem was the ADC construct and linker, which released the cytotoxic payload in non-target tissues, resulting in off-target adverse effects.11

More contemporary studies with newer agents have shown much more promise. Tarlatamab (AMG-757) is a bispecific T-cell engager that is designed to redirect T cells to kill DLL3-expressing tumors. In a phase 2 trial of 220 previously treated (median 2 lines of therapy) small cell lung cancer patients, objective responses were seen in 40% (97.5% CI, 29-52%) in a 10 mg and 32% (97.5% CI, 21-44%) in a 100 mg dosing cohort.12 Cytokine release syndrome occurred in 51% and 61% in the 10 mg and 100 mg dosing cohorts, respectively. Grade 3 cytokine release syndrome was rare at 1% and 6%, respectively. This work has led to the FDA granting accelerated approval of tarlatamab for patients with extensive stage small cell lung cancer who have had disease progression on or after platinum-based chemotherapy.13

Tarlatamab has enrolled ~40 patients in a Phase 1b (DeLLpro-300) study in subjects with either de novo or treatment-emergent neuroendocrine prostate cancer (NCT04702737), and we eagerly await results. Meanwhile, other DLL3 targeting T cell engagers have started to present data. HPN328 is another DLL3 T cell engager (CD3) that is currently accruing to a phase 1/2 trial (NCT04471727) in patients with various neuroendocrine cancers. At the 2024 Genitourinary Cancers Symposium, data was presented on both the overall study population and the genitourinary cancer cohort. In 50 response evaluable patients, the objective response rate was 56%. In the reported 12-patient genitourinary neuroendocrine cancer cohort, the objective response rate was 58%, the complete response rate was 25%, and disease control rate was 83%. Cytokine release syndrome was the most common treatment-related adverse event (all grade, 58.8%, grade 3 or greater, 3.5%).14

Below, I list some actively accruing trials of agents that target DLL3. I’ve only included trials that specifically allow patients with neuroendocrine carcinomas of the genitourinary tract.

Ongoing clinical trials that target DLL3 neuroendocrine carcinomas of the genitourinary tract

  • SKYBRIDGE – Phase 1 trial of PT217 bispecific antibody against DLL3 and CD47, including neuroendocrine prostate carcinoma (NCT05652686)
  • Phase 1 trial of BI 76532 (DLL3 and CD3 bispecific antibody) in patients with small cell lung cancer and other neuroendocrine tumors positive for DLL3 (NCT04429087)
  • DAREON-5 – Phase 2 trial of BI 76532 in small cell lung cancer and neuroendocrine prostate carcinoma (NCT05882058)
  • Phase 1 trial of BI 764532 combined with Ezabenlimab (anti-PD-1 antibody) for small cell lung carcinoma and other neuroendocrine neoplasms that express DLL3 (NCT05879978)
  • DAREON-7 – Phase 1 trial of BI 764532 with platinum chemotherapy for first line treatment of advanced neuroendocrine carcinoma (NCT06132113)
  • Phase 1/2 trial of HPN328 monotherapy and with atezolizumab in patients with neuroendocrine lung, prostate, and other neuroendocrine carcinomas (NCT04471727)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Beltran H et al. The Role of Lineage Plasticity in Prostate Cancer Therapy Resistance. Clin Cancer Res 2019; 25:6916-24.
  2. Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013; 501:328-37.
  3. Aggarwal R et al. Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study. J Clin Oncol 2018; 36:2492-503.
  4. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-extensive-stage-small-cell-lung-cancerTan HL et al. Clin Cancer Res 2014; 20:890-903.
  5. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-lurbinectedin-metastatic-small-cell-lung-cancer
  6. Bulman MP, et al. Mutations in the human Delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet 2000; 24:438-41.
  7. Dunwoodie SL, et al. Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm. Development 2002; 129:1795-806.
  8. Ladi E, et al. The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J Cell Biol 2005; 170:983-92.
  9. Puca L, et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med 2019; 11(484):eaav0891.
  10. Blackhall F, et al. Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study. J Thorac Oncol 2021; 16:1547-58.
  11. Miller ML, et al. A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody-Drug Conjugates (ADCs). Mol Cancer Ther 2018; 17:650-60.
  12. Ahn MJ, et al. Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. N Engl J Med 2023; 389:2063-75.
  13. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer
  14. Beltran H, et al. Interim results from a phase 1/2 study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T-cell engager, in patients (pts) with neuroendocrine prostate cancer (NEPC) and other neuroendocrine neoplasms (NEN). J Clin Oncol 2024; 42:121.