Antibody drugs conjugates in non-small cell lung cancer: current status and challenges

Abstract

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.

Keywords: ADC; NSCLC; antibody–drug conjugate; biomarkers; non–small cell lung cancer; thoracic oncology.

Figure 1.

Structure and mechanism of action of antibody–drug conjugates (ADCs): The basic structure of an ADC and its mechanistic features including internalization into the cell, release of payload, bystander killing effect, and anti-tumor immunity via effector cells.

Figure 2.

Concentric-circle schematic of ADC targets in NSCLC. The center circle shows targets with FDA-approved ADCs (HER2, TROP2, and c-MET). The next annulus highlights pivotal and late-phase development (EGFR, ITGB6, and HER3). The following ring depicts agents in early clinical development (PD-L1, AXL, TF, and B7-H3). The outermost circle includes emerging and translational targets (CD71, FRα, CD166, and PTK7). Abbreviations: ADC, antibody–drug conjugate; B7-H3, B7 homolog 3; CD166, activated leukocyte cell adhesion molecule; CD71, transferrin receptor-1; EGFR, epidermal growth factor receptor; FRα, folate receptor α; HER2, human epidermal growth factor receptor 2; ITGB6, integrin β6; NSCLC, non–small cell lung cancer; PD-L1, programmed death-ligand 1; PTK7, protein tyrosine kinase 7; TF, tissue factor; TROP2, trophoblast cell-surface antigen 2.