Prevalence, treatment and survival of NTRK gene fusions in microsatellite instable metastatic colorectal cancer patients

TRK inhibitors are a treatment option for patients with NTRK fusions positive tumors, including metastatic colorectal cancer (mCRC). However, the clinical behavior, including response to standard therapy and overall survival, in NTRK fusion positive mCRC is unknown which complicates the interpretation of tumor agnostic basket trials studying TRK inhibitors. We aim to estimate the prevalence of NTRK fusions in microsatellite instable (MSI) mCRC and to determine patient characteristics and clinical behavior of this NTRK fusion subtype. FFPE tissue was requested from all MSI mCRC patients diagnosed between 2015 and 2020 in the Netherlands. Pan-Trk immunohistochemistry was used as screening method. Positive cases were analyzed by RNA-based NGS with Archer or FFPE-targeted locus capture to assess NTRK1, 2, and 3 rearrangements. Clinical data were retrieved from the Netherlands Cancer Registry. In total, 8 out of 203 tumors (3,9%) harbored an NTRK fusion: 7 rearrangements were found in the NTRK1 gene and 1 NTRK3-ETV6 fusion was detected. All NTRK-fusion positive tumors were RAS and BRAF wild-type. In the subgroup (n = 26) of RAS and BRAF wild-type MSI patients, prevalence of NTRK fusions was 23%. All NTRK-fusion positive tumors showed loss of MLH1 and PMS2 and MLH1 promotor hypermethylation was found in 7 out of 8 tumors. Benefit from chemotherapy (1/6) or anti-EGFR therapy (0/2) in NTRK-fusion positive patients was limited, but all four immunotherapy-treated patients had ongoing responses and a minimum overall survival of 470 days. The four patients who did not receive immunotherapy had a short overall survival (range 11-282 days). In this population wide cohort study, NTRK fusions are most prevalent (23%) in RAS and BRAF wild-type MSI mCRC patients. This is the first study to suggest resistance to chemotherapy and anti-EGFR therapy in NTRK-fusion positive tumors leading to impaired overall survival. In contrast, immunotherapy seems to be effective in NTRK-fusion positive patients. The clinical condition of the patient probably dictates the choice of upfront immunotherapy versus TRK inhibitors in this subgroup. We recommend early testing for NTRK fusions in RAS and BRAF wild-type MSI patients.