Prevalence, treatment response, and survival in a real-world NTRK gene fusion-positive microsatellite instability-high metastatic colorectal cancer cohort

Background: Tropomyosin receptor kinase (TRK) inhibitors are approved for patients with neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumors, but clinical benefit in metastatic colorectal cancer (mCRC) is uncertain. We aimed to determine the prevalence, treatment response, and overall survival of NTRK fusion-positive, microsatellite instability-high (MSI-H), or mismatch repair-deficient (dMMR) mCRC patients in a real-world cohort. Materials and methods: Tumor tissue was collected for all patients diagnosed with MSI-H/dMMR mCRC between 2015 and 2021 in the Netherlands. Pan-TRK immunohistochemistry was carried out, and positive cases were assessed for NTRK fusions by RNA-based next-generation sequencing. Clinical data on treatment duration and overall survival were obtained from the Netherlands Cancer Registry. Results: Nine out of 268 MSI-H/dMMR colorectal tumors (3.4%) harbored an NTRK fusion. All NTRK fusion-positive tumors were RAS/BRAF^V600E wild-type. In the subgroup of RAS/BRAF^V600E wild-type MSI-H/dMMR patients, the prevalence of NTRK fusions was 22%. The benefit of chemotherapy (2/7) and anti-epidermal growth factor receptor (EGFR) therapy (0/2) in NTRK fusion-positive patients was limited. All four patients treated with programmed death-(ligand) 1 [PD-(L)1] inhibitors had sustained responses and a minimum overall survival of 36 months. Conclusions: In this real-world cohort study, NTRK fusions are most prevalent in RAS/BRAF^V600E wild-type MSI-H/dMMR 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, PD-(L)1 inhibitors seem effective in this population. Therapeutic strategies regarding TRK inhibitors versus PD-(L)1 inhibitors need investigation. We recommend early testing for NTRK fusions in RAS and BRAF^V600E wild-type MSI-H/dMMR mCRC patients.