Christian Rolfo1, Alexander Drilon2, David Hong3, Caroline McCoach4,5, Afshin Dowlati6, Jessica J Lin7, Alessandro Russo8, Alison M Schram2, Stephen V Liu9, Jorge J Nieva10, Timmy Nguyen6, Shahrooz Eshaghian11, Michael Morse12, Scott Gettinger13, Mohammad Mobayed14, Sarah Goldberg13, Emilio Araujo-Mino15, Neelima Vidula7, Aditya Bardia7, Janakiraman Subramanian16, Deepa Sashital17, Thomas Stinchcombe12, Lesli Kiedrowski18, Kristin Price18, David R Gandara19. 1. Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai System & Icahn School of Medicine, Mount Sinai, New York, NY, USA. christian.rolfo@mssm.edu. 2. Memorial Sloan Kettering Cancer Center, New York, NY, USA. 3. Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. 4. University of California, San Francisco, CA, USA. 5. Genentech, South San Francisco, CA, USA. 6. University Hospitals Cleveland Medical Center, Cleveland, OH, USA. 7. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. 8. Thoracic Oncology & Experimental Therapeutics Program, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. 9. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. 10. Keck School of Medicine of USC, Section Head - Solid Tumors, USC/Norris Cancer Center, Los Angeles, CA, USA. 11. James R. Berenson, MD, Inc., West Hollywood, CA, USA. 12. Duke Cancer Institute, Division of Medical Oncology, Durham, NC, USA. 13. Yale Comprehensive Cancer Center, New Haven, CT, USA. 14. ProMedica Bay Park Hospital Cancer, Sylvania, OH, USA. 15. Kymera Cancer Center and University of New Mexico, Roswell, NM, USA. 16. Saint Lukes Cancer Institute/University of Missouri, Kansas City, MO, USA. 17. US Oncology Network, Texas Oncology, Baytown, TX, USA. 18. Guardant Health, Redwood City, CA, USA. 19. UC Davis Comprehensive Cancer Center, Sacramento, CA, USA.
Abstract
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.
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.
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