Advances in Antibody-Based Therapies for the Treatment of Relapsed Small-Cell Lung Cancer
Key Clinical Takeaways:
- Key Outcomes: Antibody-based therapies—particularly DLL3-directed agents—have demonstrated clinically meaningful activity in relapsed SCLC, with the T-cell engager tarlatamab achieving durable responses and FDA accelerated approval; next-generation ADCs targeting TROP2, B7-H3, and SEZ6 show promising early efficacy.
- Design/Population: Comprehensive literature review of key clinical studies evaluating antibody–drug conjugates and T-cell engagers in patients with relapsed or refractory small-cell lung cancer.
- Clinical Relevance: Antigen-specific immunotherapies represent a major shift in SCLC treatment, offering biomarker-driven alternatives to cytotoxic chemotherapy, though optimization of target selection and management of treatment-related toxicities remain critical.
Antibody-based therapies are reshaping the treatment paradigm for relapsed SCLC by enabling antigen-specific targeting with clinically meaningful activity beyond traditional chemotherapy, according to findings from a comprehensive review.
Small-cell lung cancer (SCLC) remains one of the most lethal solid tumors, marked by rapid growth, early dissemination, and almost inevitable relapse following first-line therapy. Although the addition of immune checkpoint inhibitors to platinum-based chemotherapy has modestly improved outcomes in the frontline setting, treatment options after progression are limited and survival remains poor. These challenges have fueled growing interest in biomarker-directed strategies that move beyond traditional cytotoxic approaches.
A recent comprehensive review of the literature highlights significant advances in antibody-based therapies for SCLC, particularly antibody–drug conjugates (ADCs) and T-cell engagers (TCEs). These agents are designed to selectively target antigens enriched on SCLC cells, enabling more precise tumor killing while potentially improving durability of response. Among available targets, delta-like ligand 3 (DLL3) has emerged as the most clinically validated to date.
The DLL3-directed bispecific TCE tarlatamab has demonstrated meaningful and durable responses in previously treated extensive-stage SCLC, with a manageable cytokine release syndrome profile. These results ultimately led to accelerated FDA approval, marking a major milestone for antigen-specific immunotherapy in this disease. In parallel, DLL3-targeted ADCs have shown mixed efficacy, emphasizing the critical role of payload potency, linker chemistry, and antigen density in determining clinical success.
Beyond DLL3, several next-generation ADCs are expanding the therapeutic landscape. Early-phase studies targeting antigens such as TROP2, B7-H3, and SEZ6 have reported encouraging antitumor activity, in some cases achieving response rates that exceed those of existing second-line cytotoxic therapies. However, treatment-related toxicities—including myelosuppression, interstitial lung disease, and hepatic injury—remain important considerations as these agents move forward in clinical development.
“Collectively, these emerging immunotherapies illustrate a shift toward antigen-specific targeting in a disease historically defined by limited therapeutic innovation,” study authors concluded.
“Continued optimization of antigen selection, payload and linker engineering, and biomarker-driven trial design will be critical for translating early promise into durable clinical benefit and reshaping the treatment landscape for SCLC,” they added.
Source:
Wang K, Taing K, Hsu R, et al. Updates on antibody drug conjugates and bispecific T-cell engagers in SCLC. Antibodies. Published online January 4, 2026. https://www.mdpi.com/2073-4468/15/1/4
