Antibody drugs conjugates in non-small cell lung cancer: current status and challenges
Arjun Syal1, May-Lucie Meyer2,3, Kenneth Angelino2
1Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Morningside and West, New York, NY 10019, United States.
Background:
Antibody-drug conjugates (ADCs) are an emerging class of therapeutics that combine the specificity of monoclonal antibodies with cytotoxic or immune-stimulatory payloads. In non-small cell lung cancer (NSCLC), they offer a novel strategy with potential in both first-line therapy and in cases to overcome resistance to existing targeted and immune-based therapies.
Objective:
To review the clinical development, efficacy, safety, biomarker strategies, and emerging targets of ADCs in NSCLC, with a focus on implications for practice and ongoing challenges.
Methods:
We conducted a comprehensive literature review of published trials, conference abstracts, and press releases evaluating ADCs in NSCLC, with attention to target antigens, clinical trial outcomes, and biomarker approaches.
Results:
ADCs targeting HER2, TROP2, and c-MET have received regulatory approval in NSCLC, with demonstrated efficacy-particularly in biomarker-selected populations. Bispecific HER3/epidermal growth factor receptor (EGFR)-directed ADCs have shown encouraging activity in early phase studies, with ongoing trials expected to clarify durability and optimal patient selection. Other targets such as ITGB6, B7-H3, and AXL have shown early signals of efficacy. Predictive biomarkers vary in reliability, and mutation, amplification, or protein expression do not uniformly predict response. Toxicity and acquired resistance remain key challenges; improved diagnostics may enhance patient selection.
Conclusion:
ADCs are poised to reshape the therapeutic landscape of NSCLC. Their success will hinge on refining biomarker strategies, managing toxicity, and integrating resistance-mitigating approaches such as bispecific constructs or rational combinations. As research advances, ADCs may become essential components of personalized therapy across a range of molecular and histologic NSCLC subtypes.
Insights
Antibody-drug conjugates (ADCs) are transforming non-small cell lung cancer (NSCLC) treatment, showing efficacy in targeted populations. Further research is needed to refine biomarkers and manage resistance for optimal patient outcomes.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Antibody-drug conjugates (ADCs) represent a novel therapeutic class in oncology, merging monoclonal antibody specificity with potent cytotoxic payloads.
- In non-small cell lung cancer (NSCLC), ADCs offer a promising strategy for both first-line treatment and overcoming resistance to current therapies.
Purpose of the Study:
- To comprehensively review the clinical development, efficacy, safety, and biomarker strategies of ADCs in NSCLC.
- To identify emerging targets and discuss implications for clinical practice and ongoing challenges in ADC therapy for NSCLC.
Main Methods:
- A systematic literature review was performed, encompassing published clinical trials, conference abstracts, and press releases.
- Data extraction focused on ADC targets, clinical outcomes, and the reliability of various biomarker approaches in NSCLC.
Main Results:
- Approved ADCs targeting HER2, TROP2, and c-MET demonstrate significant efficacy, particularly in biomarker-selected NSCLC patients.
- Emerging targets like HER3/EGFR, ITGB6, B7-H3, and AXL show early promise, while bispecific constructs are under investigation.
- Biomarker reliability for predicting response remains a challenge, with toxicity and acquired resistance being key hurdles.
Conclusions:
- ADCs are set to significantly alter the NSCLC therapeutic landscape, emphasizing the need for refined biomarker strategies and toxicity management.
- Integrating resistance-mitigating approaches and improving diagnostics will be crucial for maximizing ADC benefits in personalized NSCLC therapy.
