Tumour response to TRK inhibition in a patient with pancreatic adenocarcinoma harbouring an NTRK gene fusion

Ann Oncol. 2019 Nov 1;30(Suppl_8):viii36-viii40. doi: 10.1093/annonc/mdz385. Epub 2019 Dec 24.


Background: Although rare, NTRK gene fusions are known to be oncogenic drivers in pancreatic ductal adenocarcinoma (PDAC). We report the response of a metastatic CTRC-NTRK1 gene fusion-positive PDAC to targeted treatment with the oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib and the eventual development of resistance to treatment.

Patient, methods and results: A 61-year-old woman presented with a 2.5-cm mass in the body of the pancreas and a 1.2-cm liver lesion on routine follow-up for endometrial cancer that was in complete remission. Liver biopsy confirmed a primary PDAC unrelated to the endometrial cancer. The patient was treated with gemcitabine, nab-paclitaxel and ADI-PEG 20 for 12 months until disease progression and toxicity emerged [best overall response (BOR): partial response (PR)]. The patient switched to a modified regimen of folinic acid, fluorouracil, irinotecan and oxaliplatin for 4 months until neuropathy occurred. Oxaliplatin was withheld until disease progression 6 months later (BOR: stable disease). Despite recommencing oxaliplatin, the disease continued to progress. At this time, somatic profiling of the liver lesion revealed a CTRC-NTRK1 gene fusion. Treatment with larotrectinib 100 mg twice daily was commenced with BOR of PR at 2 months. The patient progressed after 6 months and was re-biopsied. Treatment was switched to the investigational next-generation TRK inhibitor selitrectinib (BAY 2731954, LOXO-195) 100 mg twice daily. After 2 months, the disease progressed and dabrafenibtrametinib combination therapy was initiated due to existence of a BRAF-V600E mutation. However, the cancer continued to progress and the patient died 2 months later.

Conclusions: Targeted TRK inhibition with larotrectinib in PDAC harbouring a CTRC-NTRK1 gene fusion is well tolerated and can improve quality of life for the patient. However, acquired resistance to therapy can emerge in some patients. Next-generation TRK inhibitors such as selitrectinib are currently in development to overcome this resistance (NCT02576431; NCT03215511).

Keywords: NTRK gene fusion; larotrectinib; TRK fusion cancer; pancreatic adenocarcinoma; selitrectinib; tropomyosin receptor kinase inhibition.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Aza Compounds / administration & dosage
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / genetics
  • Chymotrypsin / genetics*
  • Chymotrypsin / metabolism
  • Female
  • Humans
  • Imidazoles / administration & dosage
  • Middle Aged
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Oximes / administration & dosage
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinases / metabolism
  • Pyrazoles / administration & dosage
  • Pyridones / administration & dosage
  • Pyrimidines / administration & dosage
  • Pyrimidinones / administration & dosage
  • Receptor, trkA / genetics*
  • Receptor, trkA / metabolism


  • Aza Compounds
  • Imidazoles
  • Oncogene Proteins, Fusion
  • Oximes
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridones
  • Pyrimidines
  • Pyrimidinones
  • selitrectinib
  • trametinib
  • Protein Kinases
  • Receptor, trkA
  • tropomyosin kinase
  • Chymotrypsin
  • chymotrypsin C
  • larotrectinib
  • dabrafenib

Associated data

  • ClinicalTrials.gov/NCT02576431
  • ClinicalTrials.gov/NCT03215511