Background
Oncogenic fusions within Neurotrophic Tyrosine Receptor Kinase (NTRK) 1, 2, or 3 drive constitutive hyperproliferative activity of (TRK) A, B, and C, respectively. Two TRK inhibitors have been approved for patients with advanced solid tumors bearing oncogenic fusions in NTRK1-3. We sought to describe the prevalence of NTRK fusions and rearrangements and to evaluate treatment outcomes among veterans treated with TRK inhibitors.
Methods
Patients with NTRK1-3 gene fusions or rearrangements were identified from the VA National Precision Oncology Program (NPOP) database. Separately, patients with orders for larotrectinib or entrectinib were identified from the Corporate Data Warehouse (CDW) and associated patient demographics and vital status were obtained. The prevalence of NTRK1-3 gene fusions and rearrangements was computed for all patients who had testing within NPOP. For patients who received either larotrectinib or entrectinib, duration of drug use, tumor response, reasons for drug discontinuation and toxicities were abstracted from medical records. For patients not treated with either drug, medical records were used to identify the reason for no drug use.
Results
Among 14,515 samples sequenced through NPOP (11,714 tissue DNA ,176 tissue DNA/RNA and 2625 liquid biopsy DNA tests), 14 (0.096%) had NTRK1-3 gene fusions or rearrangements (6 canonical fusions, 2 non-canonical fusions and 6 non-fusion gene rearrangements). Two patients tested outside of NPOP had canonical fusions. Among the 16 patients, 5 had prostate, 4 lung, 2 thyroid, 2 sarcoma, 1 bladder, 1 gastric, and 1 colorectal cancer. Twelve patients had metastatic disease, and 4 had early-stage disease. Eight patients were prescribed a TRK inhibitor (larotrectinib 5, entrectinib 3). Median duration of treatment was 59 (29 – 88) days. No responses were observed in the 7 evaluable patients. One patient developed neurotoxicity requiring temporary cessation of larotrectinib, and one patient treated with entrectinib developed volume overload requiring hospitalization leading to drug discontinuation.
Conclusion
Among veterans tested in NPOP, oncogenic NTRK fusions and rearrangements are very uncommon, and no patient had a response to treatment with a TRK inhibitor. Reconsideration of NTRK1-3 testing methodology and recommendations is warranted.