Antibody drugs conjugates in small-cell lung cancer: present-day status and promises
Arjun Syal1, May-Lucie Meyer2,3,4, Kenneth Angelino2,3
1Department of Internal Medicine, Icahn School of Medicine, Mount Sinai Morningside and West, New York, NY 10019, United States.
Introduction:
Small-cell lung cancer (SCLC) accounts for 15% of lung cancers and is characterized by an aggressive disease course and historically poor prognosis. Although tumors in most patients respond to initial chemotherapy, relapse is nearly universal and treatment options remain limited. Antibody-drug conjugates (ADCs) have emerged as a novel therapeutic class with the potential to address this unmet need.
Methods:
ClinicalTrials.gov, PubMed, and their associated references and press releases were queried for the search terms "antibody-drug -conjugates" and "SCLC." Only English-language sources were included.
Results:
Multiple ADCs targeting diverse antigens have been evaluated in relapsed or refractory SCLC. Topoisomerase I inhibitor payloads have generated the most consistent activity across delta-like protein 3, TROP2, B7-H3, and SEZ6 targets, while microtubule and pyrrolobenzodiazepine-based constructs have not demonstrated durable benefit. Despite encouraging response rates, progression-free survival has remained short, reflecting intrinsic resistance, antigen heterogeneity, and toxicity-related dose limitations.
Conclusion:
While ADCs have generated encouraging response rates in SCLC, durability has remained limited. Future development will require optimization of payloads, linkers, and trial design to determine whether ADCs can achieve a sustained role in this disease.
Insights
Antibody-drug conjugates (ADCs) show promise for small-cell lung cancer (SCLC) by targeting cancer cells. However, limited durability necessitates further research into optimizing treatments for this aggressive disease.
Area of Science:
- Oncology
- Pharmacology
- Translational Medicine
Background:
- Small-cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis and limited treatment options.
- Initial chemotherapy response in SCLC is often followed by universal relapse, highlighting an unmet clinical need.
- Antibody-drug conjugates (ADCs) represent a novel therapeutic class with potential for SCLC treatment.
Purpose of the Study:
- To review the current landscape of antibody-drug conjugates (ADCs) evaluated in small-cell lung cancer (SCLC).
- To assess the efficacy and limitations of ADCs in treating relapsed or refractory SCLC.
- To identify future directions for ADC development in SCLC.
Main Methods:
- Literature search of ClinicalTrials.gov and PubMed for studies on ADCs and SCLC.
- Inclusion of English-language sources and associated references/press releases.
- Analysis of evaluated antigens, payloads, and clinical outcomes.
Main Results:
- Multiple ADCs targeting various antigens have been investigated in relapsed/refractory SCLC.
- Topoisomerase I inhibitor payloads demonstrated consistent activity across multiple targets (e.g., DLL3, TROP2, B7-H3, SEZ6).
- Despite encouraging response rates, progression-free survival remains limited due to resistance, heterogeneity, and toxicity.
Conclusions:
- ADCs have shown promising response rates in SCLC but lack durable efficacy.
- Optimization of payloads, linkers, and trial designs is crucial for future ADC development in SCLC.
- Further research is needed to establish a sustained role for ADCs in SCLC treatment.
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