Small cell lung cancer (SCLC) represents one of the most aggressive malignancies, with a 5-year survival rate under 7% and over 200,000 deaths annually worldwide. Despite recent advances incorporating immune checkpoint inhibitors into first-line treatment, more than 80% of patients experience relapse within 12 months, highlighting the urgent need for novel therapeutic approaches in the second-line setting.
Delta-like ligand 3 (DLL3) has emerged as a promising therapeutic target, offering new hope for patients with refractory SCLC. As Dr. Ravi Salgia from City of Hope emphasized during the 2025 Bridging the Gaps in Lung Cancer consensus meeting, "Clearly, DLL3 and B7H3 are important targets. At the same time, we've shown that the mitochondrial functionality in SCLC is important [to target], so those are some interesting therapies that should come to fruition."
DLL3 as a Therapeutic Target
DLL3 demonstrates remarkable tumor selectivity, with overexpression in 70-80% of SCLC cases while showing negligible expression in normal tissues. The largest systematic review to date reported DLL3 positivity in 80-93.5% of SCLC tumors using a threshold of ≥1% tumor cells, with high expression (≥50% or ≥75%) observed in 45.8-79.5% and 47.3-75.6% of cases, respectively.
Functioning as a non-canonical Notch modulator, DLL3 plays a complex role in SCLC biology. It lacks the canonical DSL domain required for Notch receptor activation, instead forming intracellular interactions that inhibit signaling via ligand cis-inhibition and receptor retention in the Golgi apparatus. This Notch-suppressive activity drives the maintenance of neuroendocrine differentiation and stem-like properties in SCLC tumor cells.
Clinical Breakthrough with Tarlatamab
The most significant clinical advancement in DLL3-targeted therapy came with tarlatamab (AMG757), a bispecific T-cell engager that received FDA approval in 2024 for extensive-stage SCLC progressing during or after chemotherapy. Tarlatamab demonstrates enhanced pharmacokinetics and low picomolar potency against SCLC cells, recruiting T cells to DLL3-expressing tumors and triggering MHC-I-independent activation.
In the phase II DeLLphi-301 trial, tarlatamab achieved comparable response rates (40% vs. 32%) and progression-free survival (4.9 vs. 3.9 months) across SCLC patients irrespective of DLL3 expression thresholds. This surprising finding suggests the involvement of DLL3-independent immune activation mechanisms, challenging traditional biomarker-driven approaches.
However, clinical implementation faces significant challenges. Cytokine release syndrome occurred in 52% of tarlatamab-treated patients, with grade ≥3 events in 1% of cases. Any-grade treatment-related adverse events affected 90.7% of patients, stemming from on-target, off-tissue activity due to low-level DLL3 expression in normal tissues.
Lessons from Early Setbacks
The development path for DLL3-targeted therapies has not been without obstacles. Rovalpituzumab tesirine (Rova-T), the first DLL3-targeting antibody-drug conjugate, showed initial promise in phase I trials but ultimately failed in phase III studies due to significant toxicity and lack of survival benefit.
The TRINITY phase II trial revealed that 63% of participants experienced grade 3-5 adverse events, including pleural effusions and photosensitivity. Two subsequent phase III trials (MERU and TAHOE) showed no survival benefit compared to standard therapies, coupled with severe toxicities such as edema and thrombocytopenia, leading to discontinuation of clinical development.
Key factors contributing to Rova-T's failure included target heterogeneity, with only 68% of patients having high DLL3 expression, and payload toxicity from the pyrrolobenzodiazepine dimer that caused dose-limiting vascular leak syndrome. Additionally, chemotherapy-induced DLL3 downregulation may have reduced the treatment window, as stable DLL3 expression was observed in less than 30% of post-chemotherapy SCLC biopsies.
Next-Generation Approaches
Learning from early setbacks, researchers are developing improved DLL3-targeted strategies. FZ-AD005, a next-generation antibody-drug conjugate, incorporates a topoisomerase I inhibitor payload, Fc-silencing technology to reduce off-target effects, and an optimized drug-to-antibody ratio for enhanced tumor delivery. A first-in-human clinical trial approved in April 2024 is currently evaluating its therapeutic potential.
CAR-T cell therapy represents another promising avenue. DLL3-targeted CAR-T cells demonstrate potent specificity and cytotoxicity against SCLC cell lines, even those with extremely low DLL3 expression (≤1000 molecules/cell). In preclinical studies, DLL3 CAR-T cell infusion induced complete tumor regression in systemic and subcutaneous SCLC models.
To overcome limitations of traditional CAR-T approaches, researchers have developed IL-18-engineered DLL3-targeted CAR-T cells, showing enhanced activation, reduced exhaustion, and synergistic efficacy with anti-PD-1 therapy in preclinical models.
Trispecific and Combination Strategies
Advanced engineering approaches are yielding promising results. HPN328, a trispecific T-cell activation construct, integrates DLL3-targeting, albumin-binding for extended half-life, and CD3-binding for T-cell engagement. In a phase 1/2 trial, 40% of SCLC patients achieved target lesion reduction, with no grade ≥3 adverse events observed in responders.
Combination strategies are also showing promise. Ongoing trials are evaluating tarlatamab combined with PD-1/PD-L1 inhibitors, based on preclinical evidence that DLL3 BiTEs with PD-1 blockade improve antitumor efficacy compared to monotherapy.
Biomarker Development and Personalized Medicine
The field is moving toward more sophisticated biomarker approaches. SLFN11 has emerged as a biomarker of interest, associated with sensitivity to DNA-damaging agents and potentially serving as a predictive marker in both second- and third-line settings.
Technological innovations are addressing implementation challenges. DLL3-targeted PET imaging using 89Zr-labeled SC16.56 antibodies achieved 92% sensitivity in detecting DLL3+ metastases, while longitudinal studies reveal that circulating tumor cell DLL3 expression fluctuates during therapy, with >50% reductions predicting radiographic response 8 weeks earlier than conventional CT metrics.
Future Directions
The future of DLL3-targeted therapy lies in addressing current limitations through innovative approaches. Researchers are exploring rational combinations such as pairing immunotherapy with agents like lurbinectedin, or combining lurbinectedin with mitochondrial inhibitors, as these mechanistically guided combination regimens are expected to be key components of evolving SCLC treatment paradigms.
As the field shifts toward biomarker-informed clinical decision-making, the integration of molecular subcategorization of SCLC into distinct genomic subtypes aims to match targeted therapies to specific molecular profiles. This personalized approach, combined with real-time monitoring through liquid biopsy and advanced imaging, represents the next frontier in SCLC treatment.
Despite challenges including tumor heterogeneity, immune evasion mechanisms, and treatment-related toxicities, DLL3-targeted therapies represent a significant advancement in SCLC treatment. The approval of tarlatamab marks a milestone achievement, while ongoing development of next-generation approaches offers hope for improved outcomes in this historically difficult-to-treat malignancy.
