DLL3 (Delta Like Canonical Notch Ligand 3)

P1, N=339, Recruiting, Zai Lab (Shanghai) Co., Ltd. | N=112 --> 339

These updated European guidelines provide a comprehensive framework for standardized, high-quality care in stage I-III SCLC and establish a reference standard to harmonize radiotherapy approaches and inform the design of upcoming clinical trials.

P3, N=670, Not yet recruiting, Boehringer Ingelheim | Trial completion date: Apr 2029 --> Jul 2029

P1/2, N=30, Recruiting, Peking University First Hospital

Following three months of maintenance therapy with atezolizumab, new metastatic lesions in the liver and brain developed. Tarlatamab induced complete resolution of the metastatic lesions in the liver and brain, without adverse events attributable to tarlatamab. This case underscores the potential value of delta-like ligand 3-targeted therapy with tarlatamab in metastatic digestive neuroendocrine carcinoma, a rare and highly aggressive malignancy with few effective treatment options.

Acquired resistance to tarlatamab plus anti-PD-1 in SCLC was associated with low DLL3 antigen expression particularly in the setting of phenotypic switch to a non-small cell lung cancer morphology and an increasingly immunosuppressive TME. Therefore, combination strategies that incorporate immune checkpoint blockade or myeloid-targeted therapies may be warranted to enhance treatment outcomes.

We discuss how CSR type, density on cancer cells, and its mechanism of endocytosis, as well as the conjugate design for cellular uptake, tissue distribution, ligand size, and linker stability, collectively determine tumor drug accumulation and therapeutic efficacy. From representative examples, we elucidate the rationale for judicious refinement of these parameters, guiding the development of more potent ligands and drug conjugates to enhance the therapeutic efficacy of cytotoxic agents.

However, conventional biomarkers-including PD-L1 expression and tumor mutational burden-remain unreliable in SCLC, and the mechanisms underlying therapeutic resistance are still insufficiently understood. Future efforts should prioritize the refinement of molecular subtyping frameworks, the establishment of robust biomarker-guided patient stratification, the elucidation of resistance pathways, and the development of precision immunotherapies tailored to SCLC heterogeneity.

DLL3 expression level is retained or increased in the majority of recurrent gliomas. Inclusion in trials with DLL3-targeting agents in recurrent glioma based on primary tumor material is justified, depending on the required level of DLL3 positivity for inclusion.

Histopathologic assessment of background organs demonstrated mild to moderate kidney and ovary toxicity in the SC16 group compared with the highest-dose TDI-Y-010 cohort (37.0 kBq). [225Ac]Ac-mcp-TDI-Y-010 exhibited excellent antitumor efficacy with mild and transient hematologic toxicity, supporting its potential as a radioimmunotherapeutic agent for patients with DLL3-expressing neuroendocrine cancers.

Ongoing studies are exploring rational combinations with hormonal, other targeted, and immune-based therapies to enhance efficacy, overcome resistance, and expand the role of ADCs in advanced prostate cancer. Herein, we provide a comprehensive overview of the clinical development of ADCs in advanced prostate cancer.

P1, N=110, Not yet recruiting, Moonlight Bio, Inc