DLL3 (Delta Like Canonical Notch Ligand 3)

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.

Tarlatamab is associated with higher CRS and ICANS rates in real-world settings than observed in trials. Prophylactic tocilizumab may mitigate these toxicities in high-risk patients and should be considered for incorporation into treatment protocols.

Acquired resistance to tarlatamab is associated in some cases with loss of DLL3 expression, but persistence of other targetable neuro-endocrine epitopes; in other patients, DLL3 is retained on CTCs, but accompanied by systemic markers of T cell dysfunction. Quantitation of DLL3-positive CTCs identifies patients likely to benefit from tarlatamab, and longitudinal monitoring may guide therapeutic decision-making at the time of acquired resistance.

Treatment with second-generation androgen receptor (AR) inhibitors, such as enzalutamide, can trigger lineage plasticity, promoting the transdifferentiation of PCa cells into an AR-independent, poorly differentiated neuroendocrine phenotype (NEPC)...Conclusions. These findings establish HOC as a multifaceted therapeutic entity capable of disrupting key NEPC oncogenic networks, highlighting its potential as a novel lead intervention for aggressive NEPC.

P1/2, N=138, Recruiting, Molecular Partners AG | Not yet recruiting --> Recruiting | Trial completion date: Sep 2030 --> Sep 2032