Impact of DLL3-Directed Immunotherapy on the Small Cell Lung Cancer Landscape

Small cell lung cancer (SCLC) remains one of the most aggressive thoracic malignancies, defined by rapid progression, early metastasis, and high relapse rates. Until recently, therapies beyond first-line chemoimmunotherapy offered only modest survival improvements, but a review published in May of 2025 in the American Society of Clinical Oncology Educational Book highlights the emergence of DLL3-directed immunotherapy as a promising shift in this landscape.

Central to this development is tarlatamab, a first-in-class bispecific T-cell engager that received accelerated FDA approval in May 2024 for relapsed or refractory SCLC. The review underscores the rationale for DLL3 targeting, while also addressing key issues in toxicity management, care delivery, and access. Here’s a brief look at the review and its findings.

Mechanism and Molecular Target

Tarlatamab binds DLL3—a tumor-associated antigen highly expressed in SCLC, particularly in the ASCL1-driven neuroendocrine subtype—and CD3 on T cells, redirecting immune cytotoxicity toward the tumor. DLL3’s surface expression and its limited presence in normal tissue make it a compelling therapeutic target.

Efficacy from DeLLphi-301

FDA approval of tarlatamab was based on the DeLLphi-301 trial, which enrolled patients previously treated with at least two lines of therapy. The selected 10-milligram dose achieved an objective response rate of 40 percent, a disease control rate of 70 percent, and a median overall survival of 15.2 months. Nearly half of participants were alive at 18 months. Intracranial activity was also notable, with over half of patients with brain metastases experiencing significant tumor shrinkage.

Toxicity and Management Strategies

With those results in mind, toxicity remains a central consideration. Cytokine release syndrome (CRS) was reported in just over half of patients, predominantly grade one or  two.

Immune effector cell-associated neurotoxicity syndrome (ICANS) was infrequent and largely limited to patients with brain metastases. These events typically emerged early and resolved with supportive care. Severe cases were confined to a higher, non-selected dose. The authors describe ongoing mitigation efforts, including steroid premedication and IL-6 blockade, that could facilitate safer outpatient administration.

Still, patient-reported outcomes from DeLLphi-301 indicate that quality-of-life measures improve over time, despite early declines during toxicity-prone cycles. As with other T-cell–engaging therapies, global health status tends to recover by the fourth cycle.

Treatment Considerations

Initial protocols required inpatient monitoring after the first two doses, posing challenges for scalability. However, findings from the DeLLphi-300 trial support a shortened six-to-eight-hour outpatient observation model with structured follow-up, offering a feasible alternative for broader implementation.

Cost is also a significant barrier. Tarlatamab’s cumulative cost over a full course can exceed six figures, and existing reimbursement mechanisms, particularly for inpatient care, may not cover total expenditures. These constraints could limit adoption in lower-resourced settings.

Outlook for DLL3-Directed Therapies

The success of tarlatamab has sparked a pipeline of DLL3-targeted therapies. Bispecific and trispecific constructs, antibody-drug conjugates, CAR-T and CAR-NK therapies, and radioligand strategies are all under active investigation, aiming to refine delivery, reduce toxicity, and expand benefit across high-grade neuroendocrine cancers.

The next chapter in DLL3-directed therapy will depend on more than drug development. Equitable access will require outpatient delivery models, toxicity management frameworks, and payment systems that reflect real-world cost. Future progress will also hinge on molecular stratification to identify subgroups most likely to benefit. Tarlatamab may be the first approved agent in this space, but it’s important that the field adapt to support what comes next.

Reference

Aijaz A, Pannu S, Abushukair H, et al. Taking a Bite Out of Small Cell Lung Cancer By Leveraging Precision-Directed Delta-Like Ligand-3 Therapies. Am Soc Clin Oncol Educ Book. 2025;45(3):e472794.