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Antibody-Drug Conjugates in SCLC: DLL3, B7-H3, TROP2, and Beyond
Federico Monaca1, Igor Gomez-Randulfe2, Javier Torres-Jiménez3
1Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
Abstract:
Extensive-stage SCLC is an aggressive form of lung cancer with a dismal prognosis, and despite the advent of chemoimmunotherapy, survival outcomes remain poor, with limited second-line options available. Antibody-drug conjugates (ADCs) have emerged as an innovative therapeutic class in this context, leveraging tumor-associated antigens to deliver cytotoxic payloads with improved selectivity. ADCs targeting DLL3, TROP2, B7-H3, and SEZ6, together with earlier phase agents directed against CEACAM5, PTK7, and other emerging antigens, are advancing through clinical development and have demonstrated encouraging antitumor activity in second- and later-line settings. Primary and acquired resistance together with the limitations of current biomarkers for patient selection and response monitoring remain the major challenges to effective ADC implementation. This narrative review summarizes preliminary clinical data on ADCs, with particular emphasis on target biology, key molecular design features, potential central nervous system penetration, and the emerging safety profile. It also evaluates combination strategies with immune checkpoint and DNA-damage response inhibitors, the interplay and optimal sequencing with DLL3-directed T-cell engagers, and existing standards of care and future directions.
Insights
Antibody-drug conjugates (ADCs) show promise for extensive-stage small-cell lung cancer (ES-SCLC) patients, offering new treatment options beyond chemo-immunotherapy. Further research is needed to overcome resistance and optimize patient selection for these novel therapies.
Area of Science:
- Oncology
- Pharmacology
Background:
- Extensive-stage small-cell lung cancer (ES-SCLC) has a poor prognosis despite current treatments.
- Limited second-line treatment options exist for ES-SCLC.
- Chemo-immunotherapy has not significantly improved survival outcomes.
Purpose of the Study:
- To review the clinical data of antibody-drug conjugates (ADCs) for ES-SCLC.
- To discuss ADC target biology, molecular design, and safety profiles.
- To evaluate combination strategies and future directions for ADC therapy in ES-SCLC.
Main Methods:
- Narrative review of preliminary clinical data on ADCs.
- Emphasis on target antigens (DLL3, TROP2, B7-H3, SEZ6, CEACAM5, PTK7).
- Evaluation of combination strategies and sequencing with other therapies.
Main Results:
- ADCs targeting various antigens demonstrate encouraging antitumour activity in second- and later-line settings.
- Challenges include primary and acquired resistance, and limitations in biomarkers.
- Preliminary data on safety profiles and CNS penetration are emerging.
Conclusions:
- ADCs represent a promising therapeutic class for ES-SCLC, with several agents in clinical development.
- Overcoming resistance and improving patient selection through biomarkers are critical for effective implementation.
- Combination strategies and optimal sequencing with other therapies require further investigation.
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