DLL3 (Delta Like Canonical Notch Ligand 3)

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..

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