DLL3 (Delta Like Canonical Notch Ligand 3)

P2, N=87, Recruiting, Grupo Espanol de Tumores Neuroendocrinos | Not yet recruiting --> Recruiting | Initiation date: Aug 2025 --> Dec 2025

P1/2, N=232, Active, not recruiting, Harpoon Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Recruiting --> Active, not recruiting

ImmunoPET identified &lsqb;89Zr]Zr-DFO-TDI-Y-010 as the top-performing diagnostic tracer, with excellent in vivo biodistribution and tumor-to-background-organ ratios consistently >4. Therapeutic studies with &lsqb;177Lu]Lu-CHX-A"-DTPA-TDI-Y-010 demonstrated strong antitumor effects, significantly improving (P <0.05) overall survival compared with the benchmark clone &lsqb;177Lu]Lu-CHX-A"-DTPA-SC16.56 in two SCLC tumor models (NCI-H82 and Lu149) and achieving comparable overall survival in a NEPC tumor model.

Our findings suggest that flare reaction occurs within days of initiating tarlatamab, possibly attributable to acute immune activation, as reported in BiTE therapies. Awareness of this possibility may help avoid premature discontinuation of effective treatment.

P=N/A, N=8, Not yet recruiting, Eastern Theater Command General Hospital of the Chinese People's Liberation Army (Jinling Hospital, Affiliated to Nanjing University Medical School);

P1, N=100, Not yet recruiting, CancerCancer Hospital, Chinese Academy of Medical Sciences; Cancer Hospital, Chinese Academy of Medical Sciences Hospital

Although some ADCs have been limited due to toxicity-related issues, numerous other ADCs have entered clinical trial phases and demonstrated encouraging efficacy, with ORRs of 33.3 %-68.0 % and median PFS of 4.0-7.6 months. In this review, we systematically summarize ADCs currently in clinical trials and preclinical research for SCLC, and comprehensively discuss their pharmacodynamic characteristics, therapeutic effects, adverse effects, and strategies for optimising treatment.

P1, N=9, Not yet recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

The pervasive absence of HER2, folate receptor alpha, DLL3, TROP-2, and nectin-4 expression in SCSTs suggests ADCs targeting these antigens may be of limited clinical benefit. The design of clinical trials investigating the use of tissue factor-targeting ADCs for the treatment of adult GCTs warrants future consideration.

Further, multimodal single-cell transcriptomic and immune repertoire analyses revealed that TCE-IL2 combination therapy controlled tumors by recruiting and activating new CD8 + T cells into the tumor microenvironment. These findings demonstrate that TCE-mediated anti-tumor responses function through a CD8 + T cell clonal replacement mechanism that can be augmented by cytokine therapy.

Due to biological heterogeneity and limited evidence, tNEPC requires individualised, interdisciplinary management. This review summarises current insights into the pathogenesis, diagnosis, and therapeutic strategies of tNEPC and provides an outlook on future developments.

DLL3 has emerged as the most clinically relevant target to date, with the bispecific TCE tarlatamab demonstrating meaningful and durable response, manageable cytokine-release toxicity, and ultimately achieving accelerated FDA approval for previously treated extensive-stage SCLC... Collectively, these emerging immunotherapies illustrate a shift toward antigen-specific targeting in a disease historically defined by limited therapeutic innovation. Continued optimization of antigen selection, payload and linker engineering, and biomarker-driven trial design will be critical for translating early promise into durable clinical benefit and reshaping the treatment landscape for SCLC.