DLL3 (Delta Like Canonical Notch Ligand 3)

P=N/A, N=20, Recruiting, The First Affiliated Hospital of Xiamen University

These findings demonstrate a distinct surface antigen landscape in testicular GCTs, with CLDN6, EGFR, and TROP2 emerging as leading candidates for further translational evaluation. Enrichment of these targets highlights antigenic heterogeneity within GCTs and supports further validation in appropriate disease settings including metastatic, post-treatment, and relapsed or refractory disease.

While several molecular alterations show compelling biological rationale and encouraging clinical signals, few biomarkers have achieved prospective validation sufficient for routine implementation. The next phase of progress will depend on biomarker-enriched trial designs, harmonized testing strategies, and integration of multi-omic profiling to overcome biological heterogeneity and therapeutic resistance.

Moving beyond immune checkpoint inhibitors (ICI), targeting DLL3 with tarlatamab in previously treated ES-SCLC generated an unprecedented response...Due to tumor heterogeneity and plasticity, rational combinations pursuing broader cancer cell vulnerabilities are likely necessary in the future to prevent relapse. Better tools for response monitoring are urgently needed to gauge progress.

Early monitoring and prompt supportive management during initial treatment cycles are essential. These findings broaden current knowledge of tarlatamab safety in real-world practice and support prospective studies to pharmacovigilance-based signal stratification and monitoring strategies.

P1/2, N=53, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2026 --> Jun 2027 | Trial primary completion date: Jun 2026 --> Jun 2027

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

T cell-redirecting therapies represent a central pillar in modern oncology, delivering high response rates across hematologic malignancies with expanding roles in earlier treatment settings. Future progress will depend on improving durability, optimizing sequencing, mitigating toxicity, and enhancing real-world deliverability through next-generation and multitarget platforms.

These challenges highlight an important shift-SCCE is no longer a clinical "black box" but rather a frontier that demands resolution through a translational lens. By realigning fragmented basic research with clinical evidence, this review not only presents a comprehensive picture of SCCE but also aims to provide clear therapeutic direction for this malignancy.

SCLC therapy has shifted from uniform cytotoxic treatment to a tiered, mechanism-driven algorithm that incorporates PD-L1 blockade, targeted cytotoxics, myeloprotection and refined radiotherapy, raising long-term survival above 20% in selected populations. From a European-practice perspective, current best practice is platinum-etoposide plus a PD-L1 inhibitor for treatment-naïve ES-SCLC, thoracic consolidation radiotherapy in selected responders, lurbinectedin or DLL3-directed clinical trials at relapse, and durvalumab consolidation after chemoradiation in LS-SCLC. Outstanding challenges include a low absolute survival gain from chemo-IO, the absence of validated predictive biomarkers, lineage plasticity, and unequal global access to new agents.

P1/2, N=30, Recruiting, Peking University First Hospital | Initiation date: Jun 2025 --> Oct 2025

Tarlatamab, a representative agent in this class, has been approved for clinical use, and multiple TCE agents are currently under clinical development. Although DLL3-TCE shows promising prospects in the clinical management of SCLC, as a novel therapeutic modality, many clinicians still lack an in-depth understanding of their mechanisms of action, appropriate patient populations, and clinical management. To standardize the clinical application of DLL3-TCE in China, the Small Cell Lung Cancer Expert Committee of the Chinese Society of Clinical Oncology convened a consensus panel to develop the Chinese Expert Consensus on Delta-like Ligand 3-T Cell Engager Therapy for SCLC based on evidence-based medicine and expert practical experience, with the aim of providing standardized guidance for the clinical use of DLL3-TCE agents..