Antibody-drug conjugates (ADCs) are an important therapeutic option in advanced non-small cell lung cancer (NSCLC), but the right patient selection remains a major challenge. Professor David P. Carbone, Director, Thoracic Oncology Center, Ohio State University Medical Center, Ohio, US, discussed the evolving role of biomarkers in guiding therapy with ADC.
Carbone noted that target protein expression is often not a reliable predictor of clinical benefit, and that more sophisticated methods of patient selection are important. Unlike conventional targeted therapies, ADCs deliver chemotherapy selectively to tumour cells expressing specific surface antigens. However, their activity depends on many factors other than antigen expression, such as drug internalisation, linker stability, intracellular payload release, and resistance mechanisms. This makes finding reliable predictive biomarkers considerably more complex.
The HER2 protein illustrates this complexity. While HER2 overexpression is observed in a proportion of NSCLC cases, activating HER2 mutations occur in only a small subset. Carbone noted that patients with HER2-mutant disease derive meaningful benefit from the HER2-directed ADC trastuzumab deruxtecan, with objective response rates approaching 55 percent and median progression-free survival (PFS) of approximately 8 months, findings consistent with the DESTINY-Lung01 clinical programme.[N Engl J Med 2022;386:241-251] In contrast, HER2 protein overexpression measured by immunohistochemistry has not demonstrated a consistent association with treatment outcomes and is not an approved biomarker for patient selection.
Another promising target is trophoblast cell-surface antigen 2 (TROP2), which is widely expressed in NSCLC and several other solid tumours. Carbone presented data from the TROPION-Lung05 trial, which showed promising activity for the TROP2-directed ADC datopotamab deruxtecan in heavily pretreated patients with actionable genomic alterations. Clinical responses were especially favourable in patients with EGFR-mutated tumours, supporting EGFR mutation status as a useful predictive biomarker for this therapeutic class. [J Clin Oncol 2025;43(10):1254-1265]
However, translating these benefits to larger populations with NSCLC has been more difficult. Studies of TROP2-directed ADCs in patients without actionable driver mutations have generally not been as impressive, suggesting that current biomarker strategies remain lacking. Carbone highlighted emerging work using normalised membrane ratio (NMR) analysis, derived from artificial intelligence, to quantify TROP2 membrane expression. While this digital pathology approach remains investigational, it has demonstrated promise in retrospectively identifying patients likely to benefit from treatment and is currently being evaluated prospectively in phase III clinical trials.
Carbone also included an overview of next-generation TROP2 ADCs, such as sacituzumab tirumotecan. Early research seems to demonstrate an enhanced efficacy compared to standard chemotherapy, with higher response rates in patients with higher TROP2 expression. Early data presented at American Society of Clinical Oncology (ASCO) Annual Meeting 2026 have also suggested a potential benefit when combined with pembrolizumab, but these findings are still investigational and require further validation. [J Clin Oncol 2026;44:8506]
Carbone summarised that ADCs are rapidly broadening the therapeutic landscape for lung cancer, but biomarker development has not been keeping pace. Current data for some ADCs suggest that genomic alterations such as HER2 and EGFR mutations may be more informative predictive biomarkers than protein expression alone. Novel technologies like AI-assisted biomarker analysis may improve patient selection and maximise benefit of therapy. Optimising patient selection is one of the most urgent priorities in the advancement of ADC therapy in NSCLC until more robust predictive biomarkers are available.