New Data Underscores Need for Refined Biomarker Strategies in NSCLC Antibody-Drug Conjugate Therapy
Recent clinical trial results presented at major oncology conferences and published in leading medical journals highlight the evolving landscape of antibody-drug conjugate (ADC) therapy for non-small cell lung cancer (NSCLC), revealing that current biomarker strategies may be insufficient to fully predict treatment response. While ADCs targeting HER2, EGFR, and c-Met have shown promise and received accelerated FDA approval, emerging data suggest a need for more precise patient selection criteria to maximize benefit and avoid unneeded treatment.
The increasing availability of ADCs represents a significant advancement for NSCLC patients, particularly those with limited treatment options.Though, relying solely on established biomarkers like HER2 overexpression, EGFR mutation status, or c-Met protein levels isn’t always enough. researchers are now investigating more nuanced approaches, such as normalized membrane ratio scoring for TROP2, to better identify patients most likely to respond to specific ADCs.This shift is crucial because ADCs are often associated with significant toxicities, and identifying responders a priori is essential for optimizing the risk-benefit ratio.
DESTINY-Lung03 part 1, presented at the IASLC 2024 World Conference on Lung Cancer (September 7-10, 2024, San Diego, CA; Abstract OA16.05), showcased trastuzumab deruxtecan monotherapy in pretreated HER2-overexpressing nonsquamous NSCLC.Similarly, the phase 2 HORIZON-Lung trial, published in Lancet Oncology (2025;26(4):437-446; doi:10.1016/S1470-2045(25)00012-9), detailed the efficacy of trastuzumab rezetecan in advanced HER2-mutant NSCLC.
The FDA granted accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated NSCLC on June 23, 2025 (FDA, Accessed November 15, 2025, https://www.fda.gov/drugs/resources-data-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer), a decision supported by a pooled analysis presented by Ahn et al. in J Thorac Oncol (2025;20(11):1669-1682; doi:10.1016/j.jtho.2025.06.002). Telisotuzumab vedotin-tllv also received accelerated FDA approval (May 14, 2025, Accessed November 15, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-telisotuzumab-vedotin-tllv-nsclc-high-c-met-protein-overexpression) for NSCLC with high c-Met protein overexpression.
The LUMINOSITY trial, initially presented by Camidge et al.in J Clin Oncol (2024;42(supp; 25):3000-3011; doi:10.1200/JCO.24.00720) and updated by Girad et al. in J Thorac Oncol (2025;20(suppl 1):S21-S23; doi:10.1016/S1556-0864(25)00213-8), investigated telisotuzumab vedotin in previously treated c-Met protein-overexpressing advanced EGFR-wildtype NSCLC. Furthermore, research presented by Garassion et al. in J Thorac Oncol (2024;19(10):S2-S3; doi:10.1016/j.jtho.2024.09.015) suggests that normalized membrane ratio of T
