TROP2 NMR and Its Potential as a Predictive Biomarker

This segment explores the biologic rationale for the NMR and its potential to address key limitations of conventional TROP2 testing. Dr. Santos begins by describing that although TROP2 is widely expressed in NSCLC and represents an attractive therapeutic target, clinical experience has shown that high surface expression alone does not reliably predict response to TROP2-directed ADCs. Preclinical data help explain this disconnect by demonstrating that ADC efficacy depends not only on target binding but also on intracellular processing and payload release following internalization.

Because some ADCs, such as datopotamab deruxtecan, rely on stable linkers that require cellular uptake for activation, variability in internalization and intracellular trafficking may influence therapeutic effectiveness. This observation highlights the need for biomarkers that capture functional aspects of target biology rather than static expression levels alone.

Dr. Wistuba defines TROP2 NMR as a computational pathology-derived metric that quantifies the relationship between membrane and cytoplasmic TROP2 expression. Unlike traditional IHC, which focuses primarily on membrane staining, NMR incorporates cytoplasmic localization, an important surrogate for internalization and intracellular processing. The analysis requires whole-slide digital imaging and specialized algorithms, reflecting the growing role of artificial intelligence-enabled pathology.

Dr. Santos describes NMR as providing a more dynamic view of tumor biology, describing it as “a movie rather than a snapshot.” Exploratory analyses from clinical trial datasets, including TROPION-Lung01, suggest that patients with higher NMR values may experience improved response rates and longer progression-free survival with TROP2-directed therapy.

Overall, this segment positions TROP2 NMR as a promising tool to address a major unmet need: identifying patients most likely to benefit from ADC therapy and potentially informing biomarker development for future targeted agents.