Insights on Resistance Mechanisms and Sequencing Strategies for DLL3-Targeted and ADC Therapies in ES-SCLC

Despite improvements in treatment, extensive-stage small cell lung cancer (ES-SCLC) patients frequently experience relapse even after promising therapies. Current research focuses heavily on overcoming resistance to therapies, particularly in the relapse setting. One of the most exciting advances involves antibody-drug conjugates (ADCs)—a “Trojan horse” approach where antibodies deliver potent chemotherapy directly into cancer cells, showing high response rates in heavily pretreated patients. Targets such as DLL3 and B7-H3, which are highly expressed on SCLC cells, are promising candidates for ADCs, bispecific T-cell engagers, and other immune-based therapies. However, understanding mechanisms of resistance—whether through downregulation of targets or immune cell exhaustion—is crucial to optimizing sequencing and combination of these agents.

The next generation of therapies includes bispecific and trispecific T-cell engagers that harness the immune system by directing T cells to tumor cells expressing SCLC-specific markers like DLL3. Early clinical trials, including armored CAR T-cell therapies, show encouraging signals of efficacy with manageable toxicity profiles. These immune-based therapies are expanding rapidly, offering new hope for treatment-resistant disease. Additionally, emerging data suggest some ADCs have intracranial activity, which is particularly important given the high incidence of brain metastases in SCLC patients and the limitations of radiation therapy.

A major ongoing challenge remains identifying reliable biomarkers to guide therapy selection and monitor resistance. Unlike other cancers, PD-L1 expression has not proven a useful predictive marker in SCLC. Continued translational research is essential to unravel the tumor and immune microenvironment complexity, enabling precision medicine approaches that improve response durability, reduce toxicity, and ultimately extend patient survival.