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

Abstract

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.

Figure 1.

Computed tomography imaging. Computed tomography taken at (A) baseline before initiation of larotrectinib and (B) showing the best overall response of partial response to treatment with larotrectinib.

Figure 2.

[¹⁸F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) imaging. (A) FDG-PET imaging taken at baseline before initiation of larotrectinib. 2-fluoro-2-deoxy-D-glucose (FDG)-avidity is visible in the primary pancreatic tumour and liver metastases. (B) FDG-PET imaging showing the best overall response of partial response to treatment with larotrectinib. FDG-avidity in previously hypermetabolic pancreatic and liver lesions is resolved.

Figure 3.

Liver biopsy analysis. (A) Haemotoxylin and eosin (H&E): A core biopsy of the patient’s liver mass demonstrated a moderately differentiated adenocarcinoma, morphologically compatible with pancreatobiliary origin (H&E, 100× original magnification). (B) TrkA immunohistochemistry (IHC): Immunohistochemical staining for TrkA (NTRK1) demonstrated diffuse, strong cytoplasmic expression (TrkA IHC, clone EP1058Y, Abcam, Cambridge, UK, 100× original magnification). (C) Archer^® software: Fusion analysis was carried out on the tumoral RNA with the MSK-IMPACT™ panel and demonstrated an in-frame fusion between CTRC (NM_007272) exon1 and NTRK1 (NM_002529) exon8, including the kinase domain of NTRK1 (JBrowse software).