Cancers with NTRK gene fusions: Molecular characteristics and prognosis

Introduction: The neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, 2, and 3 have emerged as oncogenic drivers, and their resultant tropomyosin receptor kinase (TRK) proteins are targets for precision medicines. Larotrectinib, a selective TRK inhibitor, and entrectinib, a multikinase inhibitor, have been approved for patients (pts) with TRK fusion cancer. This study was conducted to evaluate the molecular characteristics and prognosis of TRK fusion cancer in a real-world setting. Methods: This is a retrospective study using the de-identified Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB) that includes pts with a diagnosis of cancer who had comprehensive genomic profiling (CGP) between Jan 2011 and Jul 2018 (Version Nov. 2018). Pts were classified based on the status of their NTRK gene: cohort 1 included pts with NTRK gene fusions and cohort 2 included pts with wild-type NTRK genes (WT-TRK). Within each tumor type, matching was conducted between the two cohorts using the Mahalanobis distance method with a ratio of 1:4 (cohort 1: cohort 2) on demographic and clinical characteristics including age, albumin, antineoplastic use, ECOG performance status, practice type, and year of CGP report. Descriptive analyses were provided for patient and molecular characteristics. Kaplan-Meier method and Cox regression were used for overall survival (OS) analysis with the date of the CGP report as the index date. Results: Of 33,398 pts in the CGDB, 29 pts across 18 histologies had an NTRK gene fusion and 12,456 pts had the same histologies with WT-TRK. In pts with NTRK gene fusions, NTRK1 was involved in 18 (62.1%), NTRK2 in 3 (10.3%), and NTRK3 in 8 (27.6%) of the observed fusion events. Co-occurrence of specific biomarkers (ALK, BRAF, ERBB2, EGFR, ROS1, KRAS) was rare, and lower in pts with NTRK gene fusions than in WT-TRK pts; however, high TMB and MSI were more common in pts with NTRK gene fusions than in WT-TRK pts (TMB high 20.7% vs. 2.8% and MSI high 10.3% vs. 0.9%, respectively). 27 pts from cohort 1 were matched with 102 pts in cohort 2. Demographic and baseline clinical characteristics were generally similar between the matched cohorts. A median OS from CGP report date of 16.5 months (95% CI 11.5-22.5) was observed for the WT-TRK pts, compared with 12.5 months (95% CI 9.5—not reached) for the pts with TRK fusion cancer. The proportional hazards ratio comparing pts with TRK fusion vs. WT-TRK cancer was 1.436 (95% CI 0.612-3.373). Conclusions: Pts with TRK fusion cancer had lower co-occurrence of other oncogenic biomarkers but had higher frequencies of MSI-high and TMB-high vs. pts with WT-TRK cancer. While no clear differences in OS were seen, there was a trend to shorter OS for pts with TRK fusion cancer. Further study allowing for inclusion of additional prognostic factors is needed to confirm the prognostic value of NTRK gene fusions. Citation Format: Lyudmila Bazhenova, Xiaolong Jiao, Andrew Lokker, Jeremy Snider, Emily Castellanos, Shivani Nanda, Virginia Fisher, Jihong Zong, Karen Keating, Marc Fellous. Cancers with NTRK gene fusions: Molecular characteristics and prognosis [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 09.