Abstract CT545: Variability in NTRK gene fusions does not appear to impact response to larotrectinib
Authors: Ladanyi Marc , Roy-Chowdhuri Sinchita , Ritterhouse Lauren , Sahm Felix , Norenberg Ricarda , Shen Kui , Chen Chi , Fellous Marc , Brega Nicoletta , van Tilburg Cornelis M. , Lin Jessica J. , Brose Marcia S. , Lassen Ulrik N. , McDermott Ray , Laetsch Theodore W. , Hong David S. , Drilon Alexander , Rudzinski Erin R. 
Published: June 2022

Abstract
Introduction: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumor types. Gene fusions arise from inter- and intrachromosomal rearrangements involving the 3’ region of the NTRK gene and the 5’ end of a fusion partner gene, leading to the expression of a constitutively active tropomyosin receptor kinase (TRK) fusion protein. Larotrectinib is a highly selective and central nervous system (CNS)-active TRK inhibitor approved for the treatment of adult and pediatric patients with TRK fusion cancer. Larotrectinib has previously demonstrated an objective response rate (ORR) of 75% in 206 patients with non-primary CNS solid tumors (Hong et al, ASCO 2021). Here, we report on the TRK fusion exon junction organization in patients with TRK fusion cancer receiving larotrectinib.
Methods: Patients with non-primary CNS TRK fusion cancer treated with larotrectinib were identified from three clinical trials (NCT02122913, NCT02576431, and NCT02637687). NTRK gene fusion data were determined by local molecular testing. The testing method, NTRK gene fusions, and exon structure were extracted from the molecular pathology reports from 212 patients. The data cut-off was July 20, 2020.
Results: TRK fusion exon junction data were available for 80 patients from 14 different tumor types. Median age was 47 years (range 0.5-84 years). The ORR for these patients was 82.5% (95% confidence interval [CI] 72.4-90.1). Patients had gene fusions involving NTRK1 (40%), NTRK2 (4%), or NTRK3 (56%), a pattern similar to that seen in the larger dataset. We detected 20 different NTRK gene fusions; the most common were ETV6-NTRK3, TPM3-NTRK1, and LMNA-NTRK1 detected in 39 (49%), ten (13%), and seven (9%) patients, respectively. There were 12, three, and five different fusion partners associated with NTRK1, NTRK2, and NTRK3, respectively. The majority (12/20; 60%) of fusions were intrachromosomal rearrangement events: 8/12 (67%) related to NTRK1, 2/3 (67%) related to NTRK2, and 2/5 (40%) related to NTRK3. There were 35 different 5’/3’ gene breakpoint combinations: 3’ fusion points were located at NTRK1 exon 8 (n = 2), NTRK1 exon 9 (n = 5), NTRK1 exon 10 (n = 15), NTRK1 exon 11 (n = 6), NTRK1 exon 12 (n = 3), NTRK1 exon 13 (n = 1), NTRK2 exon 15 (n = 2), NTRK2 exon 16 (n = 1), NTRK3 exon 14 (n = 21), and NTRK3 exon 15 (n = 24). For ETV6-NTRK3 fusions, the NTRK3 fusion point was at exon 14 in ten of 11 thyroid carcinomas, but in only three of 13 salivary gland tumors.
Conclusions: Among 80 patients with TRK fusion cancer, we detected 20 different NTRK gene fusions, of which 55% occurred in only one patient each. There were 36 different fusion variants. Despite the variability of the fusion structure, larotrectinib was equally efficacious. The large number of potential different fusion partners and involvement of various breakpoints highlight the need for validated and appropriate testing methodologies that are agnostic of 5’ partners and breakpoints.
Citation Format: Marc Ladanyi, Sinchita Roy-Chowdhuri, Lauren Ritterhouse, Felix Sahm, Ricarda Norenberg, Kui Shen, Chi Chen, Marc Fellous, Nicoletta Brega, Cornelis M. van Tilburg, Jessica J. Lin, Marcia S. Brose, Ulrik N. Lassen, Ray McDermott, Theodore W. Laetsch, David S. Hong, Alexander Drilon, Erin R. Rudzinski. Variability in NTRK gene fusions does not appear to impact response to larotrectinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT545.