NTRK1 Fusions identified by non-invasive plasma next-generation sequencing (NGS) across 9 cancer types

Background Activating fusions of the NTRK1, NTRK2 and NTRK3 genes are drivers of carcinogenesis and proliferation across a broad range of tumour types in both adult and paediatric patients. Recently, the FDA granted tumour-agnostic approvals of TRK inhibitors, larotrectinib and entrectinib, based on significant and durable responses in multiple primary tumour types. Unfortunately, testing rates in clinical practice remain quite low. Adding plasma next-generation sequencing of circulating tumour DNA (ctDNA) to tissue-based testing increases the detection rate of oncogenic drivers and demonstrates high concordance with tissue genotyping. However, the clinical potential of ctDNA analysis to identify NTRK fusion-positive tumours has been largely unexplored. Methods We retrospectively reviewed a ctDNA database in advanced stage solid tumours for NTRK1 fusions. Results NTRK1 fusion events, with nine unique fusion partners, were identified in 37 patients. Of the cases for which clinical data were available, 44% had tissue testing for NTRK1 fusions; the NTRK1 fusion detected by ctDNA was confirmed in tissue in 88% of cases. Here, we report for the first time that minimally-invasive plasma NGS can detect NTRK fusions with a high positive predictive value. Conclusion Plasma ctDNA represents a rapid, non-invasive screening method for this rare genomic target that may improve identification of patients who can benefit from TRK-targeted therapy and potentially identify subsequent on- and off-target resistance mechanisms.

Automated summary

This study retrospectively reviewed a ctDNA database in advanced stage solid tumors to identify NTRK1 fusions, and found NTRK1 fusion events in 37 patients with nine unique fusion partners. 44% of cases had tissue testing for NTRK1 fusions, and the NTRK1 fusions detected by ctDNA were confirmed in tissue in 88% of cases. This study reports for the first time that minimally-invasive plasma NGS can detect NTRK fusions with a high positive predictive value.