Co-occurrence of NTRK fusions with other genomic biomarkers in cancer patients

Abstract

Abstract Background Larotrectinib is the first therapy approved in the U.S. for locally advanced or metastatic solid tumors with neurotropic tyrosine receptor kinase (NTRK) gene fusions. NTRK gene fusions have been documented with variable frequency across numerous tumor types; limited data exist regarding the relationship of NTRK gene fusions with other targetable biomarkers. This study evaluated the co-occurrence of NTRK gene fusions with other therapy molecular markers in cancer patients. Methods This retrospective study included cancer patients from a de-identified Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB) who had next-generation sequencing (NGS) between Jan 2011 and July 2018. The co-occurrence frequencies of NTRK gene fusions with the following markers was determined using NGS assays including FoundationOne and FoundationOne Heme: tumor mutation burden (TMB), microsatellite instability (MSI), ALK, BRAF, ERBB2, EGFR, ROS1, and KRAS. Results An evaluable sample of 15,971 of 33,398 patients in the CGDB had one of 18 histologies where at least one NTRK fusion patient was identified. NTRK gene fusions were identified in 29 patients: 55% (16/29) were female; 69% (20/29) were Caucasians. The median age was 60 years (Q1-Q3: 49.0-65.0). Fifteen different fusion partners were identified; the most frequent were ETV6-NTRK3 (n\xa0=\xa08), TPM3-NTRK1 (n\xa0=\xa06), and TPR-NTRK1 (n\xa0=\xa03). Co-occurring genomic alterations are shown in the table. Table: 102P . Co-occurring biomarkers * Patients with NTRK gene fusions (N\xa0=\xa029), % (n) TMB High (>20 mut/mB) TMB Medium ( 5 mut/mB) 20.7 (6/29) 10.3 (3/29) MSI (high) 17.6 (3/17) ** ALK rearrangement 0.0 (0/29) BRAF alteration 3.5 (1/29) ERBB2 amplification 0.0 (0/29) EGFR alteration 3.5 (1/29) ROS1 alteration 0.0 (0/29) KRAS alteration 10.3 (3/29) * Variants of “known” or “likely” functional status were included ** MSI status missing for 12 patients Conclusions The study confirmed the rarity of NTRK gene fusions in cancer patients. Co-occurrence of the biomarkers ALK, BRAF, ERBB2, EGFR, ROS1, or KRAS was uncommon. These results highlight the importance of identifying patients with NTRK gene fusion-driven cancers, through molecular testing, who will benefit from the use of selective TRK kinase inhibitors across different solid tumors. Editorial acknowledgement Michael Sheldon, PhD, of Scion, London, UK, funded by Bayer. Legal entity responsible for the study Bayer. Funding Bayer. Disclosure X. Jiao: Full / Part-time employment: Bayer. A. Lokker: Full / Part-time employment: Flatiron Health; Shareholder / Stockholder / Stock options: CVS Health, Roche, Medtronic, Sangamo Therapeutics. J. Snider: Full / Part-time employment: Flatiron Health; Shareholder / Stockholder / Stock options: Roche. E. Castellanos: Full / Part-time employment: Flatiron Health. S. Nanda: Full / Part-time employment: Bayer. V. Fisher: Full / Part-time employment: Foundation Medicine. J. Zong: Full / Part-time employment: Bayer. K. Keating: Full / Part-time employment: Bayer. M. Fellous: Full / Part-time employment: Bayer.