DLL3 (Delta Like Canonical Notch Ligand 3)

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..

In a predominantly Hispanic, heavily pre-treated real-world population with high CNS disease burden, Tarlatamab demonstrated feasible administration, manageable immune-mediated toxicity, and clinically meaningful antitumor activity.

P3, N=430, Not yet recruiting, PrECOG, LLC.

Among cases with follow-up data (n=35), all 17 tumors with disease progression were DLL3 positive (13 RET-mutated tumors, 1 RAS-mutated tumor, and 3 RET/RAS wild-type tumors), including 5 with moderate expression and 12 with high expression. Most MTCs express DLL3; moreover, DLL3 expression is associated with lymph node metastases at diagnosis and disease progression, indicating that DLL3 may be an effective therapeutic target in MTC.

The treatment arsenal for small cell lung cancer could soon include antibody-drug conjugates, with early data from three phase I studies indicating robust response rates to CD56-targeting DXC006, DLL-3-targeting BL-M14D1, and B7-H3-targeting SYS6043. The latter also appears active in other tumor types, including ovarian and breast cancers. As well, phase II findings on a fourth ADC candidate, HER2-targeting trastuzumab brengitecan, suggest its strong efficacy in platinum-resistant ovarian cancer.

From approval of immune checkpoint inhibitors and lurbinectedin, a newer chemotherapy agent, to novel immunotherapies such as tarlatamab, a DLL3-CD3 bispecific T-cell engager, and other upcoming promising drugs, the therapeutic armamentarium for SCLC is steadily expanding. In this study, we review the current landscape of both systemic therapy as well as radiation therapy for SCLC, with a focus on major developments over the past decade, current standards of care, and novel therapeutics that are expected to revolutionize the treatment of this aggressive malignancy.

Anti-DLL3 CAR-Ms demonstrate significant potential for solid tumor treatment and may offer a viable clinical strategy for SCLC in the future.

P1, N=18, Active, not recruiting, Boehringer Ingelheim | Trial completion date: Jun 2026 --> Sep 2027 | Trial primary completion date: May 2026 --> Aug 2027

This review elucidates the molecular networks driving immune resistance and highlights clinical breakthroughs in these emerging modalities. Finally, we outline a strategic roadmap for next-generation precision oncology, integrating advantages of biomarkers in treatment, dynamic liquid biopsy for stratification, optimized toxicity management, and the leverage of reverse translation.

For EGFR-mutant NSCLC, sequential development of tyrosine kinase inhibitors (TKIs) from first- to third-generation agents-culminating in osimertinib-has markedly improved survival. Similarly, successive generations of ALK inhibitors, including alectinib, brigatinib, and lorlatinib, have extended disease control, particularly within the central nervous system. The introduction of antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan for HER2-mutant NSCLC, and emerging TKIs like zongertinib, represent new therapeutic milestones...Beyond lung cancer, our group, in collaboration with Juntendo University ARO (academic research organization) and fifteen institutions in Japan, conducted the MARBLE phase II trial of atezolizumab plus chemotherapy for thymic carcinoma, achieving a 56% objective response rate and 9.6-month median progression-free survival, supporting potential ICI approval in Japan...The DLL3-targeted BiTE tarlatamab significantly improved overall survival to 13.6 months in the phase III DeLLphi-304 trial for relapsed SCLC, with manageable cytokine release syndrome. Collectively, these advances signify a shift toward biologically driven, molecular-targeted or immune-integrated therapy, aiming to transform lung cancer into a chronic, manageable disease in the future, hopefully.

From this review, although still based on limited literature evidence and mostly derived from retrospective and small SCPC sub-cohorts,18F-FDG PET/CT currently appears as the most reliable tracer for SCPC, aiding tumor detection and prognostication when PSMA/choline imaging fails. In the preclinical setting, DLL3/CDCP1-targeted agents emerge as promising theranostics tools. Multimodal imaging approach and prospective trials are needed for standardization and patient-based SCPC management.

P1/2, N=11, Not yet recruiting, Novartis Pharma AG