Unlocking New Horizons in Small Cell Lung Cancer Therapy: The Role of Antibody–Drug Conjugates

In the ongoing effort to expand options for small cell lung cancer (SCLC), antibody–drug conjugates (ADCs) are drawing attention. These therapies show promise for patients with limited options, though current evidence is early-phase and randomized, survival-focused trials and safety monitoring are ongoing.

Ifinatamab deruxtecan, a B7-H3–directed ADC, has shown encouraging activity in ES-SCLC in early studies, with ongoing trials continuing to evaluate its efficacy and safety. Recent findings presented at the IASLC 2025 meeting described high response rates among patients previously treated for extensive-stage disease, supporting further investigation of this approach.

The targeting of distinctive markers like B7-H3 and DLL3 not only enables antigen-directed ADC therapy but also opens discussions on broader oncology strategies. Because ADCs are designed to bind cell-surface antigens, they can enhance therapeutic specificity and efficacy by delivering cytotoxic payloads directly to tumor cells that express the target.

The focus now shifts to SHR-4849, a Delta-like ligand 3 (DLL3)-directed ADC under early investigation. According to a first-in-human study, SHR-4849 has shown promise in relapsed SCLC by demonstrating early anti-tumor activity and maintaining a manageable safety profile.

Managing the heterogeneity in SCLC remains challenging, particularly when conventional treatments lack efficacy. Variation in B7-H3 and DLL3 expression may inform which ADCs are most appropriate, underscoring biomarker-driven enrollment in trials. These presentations point to practical shifts under investigation, including potential incorporation of ADCs into post-platinum settings and biomarker-informed trial enrollment.

IASLC 2025 findings highlight emerging roles for ADCs under investigation; current NCCN/ESMO guidelines have not broadly incorporated these agents pending phase 3 data. Growing clinical evidence is prompting reevaluation of post–first-line options, with ADCs being studied primarily in relapsed or previously treated SCLC.

Key Takeaways

• Biomarker-driven ADC strategies targeting B7-H3 and DLL3 are being explored primarily after relapse, reflecting the need for more precise options in ES-SCLC.
• ADCs targeting B7-H3 and DLL3 are investigational in SCLC and are not yet standard of care; guideline adoption awaits phase 3 results.