TROP2 NMR as a Predictive Biomarker for Dato-DXd: Clinical Insights From TROPION-LUNG01

The TROPION-LUNG01 study was a randomized clinical trial comparing datopotamab deruxtecan[YQ1] with docetaxel in patients with both squamous and nonsquamous NSCLC, including those with and without actionable genomic alterations. Patients with tumors harboring actionable genomic alterations had previously undergone targeted therapy and chemotherapy, whereas those without such alterations had received chemotherapy and immunotherapy. The trial demonstrated a statistically significant improvement in median PFS for patients treated with datopotamab deruxtecan overall. However, the benefit varied by histology, with the squamous cohort showing worse outcomes compared with docetaxel, whereas the nonsquamous group experienced a significant PFS benefit and a trend toward improved overall survival.

An important aspect of the trial was the use of the TROP2 NMR as a predictive biomarker. Interestingly, a lower NMR score (indicating more cytoplasmic expression relative to membrane expression) correlated with better internalization of the drug payload and greater therapeutic response. This finding was somewhat counterintuitive but aligns with the hypothesis that internalization is necessary for efficacy. Among patients treated with datopotamab deruxtecan, those classified as NMR positive had a response rate nearly double that of NMR-negative patients. Importantly, the NMR biomarker was not prognostic in the docetaxel arm, as outcomes were similar regardless of NMR status, supporting its role as a predictive marker specific to the targeted therapy.

Although the NMR test was initially developed and validated in populations with nonsquamous, nonactionable genomic alterations, exploratory analyses suggest potential applicability across broader groups, including squamous histology and tumors with genomic alterations. Though outcomes for squamous cell carcinoma overall were less favorable with datopotamab deruxtecan, subsets of patients within this group might still derive benefit, warranting further investigation. Future studies and ongoing trials are expected to clarify the use of this biomarker in diverse patient populations and help optimize patient selection, ultimately advancing precision medicine approaches for lung cancer treatment.

[YQ1]Global note: Should each mention of datopotamab deruxtecan be Dato-DXd instead?