High prevalence of NTRK fusions in sporadic dMMR/MSI mCRC RAS/RAF wild-type: an opportunity for a post-immune checkpoint inhibitors progression rescue strategy

Abstract

Background: Currently, mismatch repair deficient/microsatellite instable (dMMR/MSI) status constitutes a validated predictive marker of response to immune checkpoint inhibitors (ICIs) in patients with metastatic colorectal cancer (mCRC). Unfortunately, some of these patients do not benefit from ICIs. Very limited therapeutic options for patients with dMMR/MSI mCRC after progression on ICI(s) exist. These patients show poor outcomes with conventional chemotherapy. Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic tropomyosin receptor kinase (NTRK) fusion-driven cancers. NTRK gene fusions are rare (<1%) in CRC and data regarding their prevalence in patients with dMMR/MSI CRC are increased but limited, especially in patients with metastatic disease. Materials and methods: A total of 187 dMMR/MSI mCRC patients, including 120 immune ICI-treated, were screened for NTRK gene fusions. Results: Tumor samples of 10 (5.3%) patients harbored NTRK gene fusions confirmed by FISH (NTRK1 = 8; NTRK3 = 2) including two cases with Lynch syndrome and height sporadic cases with MLH1 promoter hypermethylation and RAS wild-type (wt), out of which only five were positive by pan-TRK immunohistochemistry. One patient with primary resistance to nivolumab received a TRK inhibitor (larotrectinib) and showed a complete response. Conclusions: These results underline the importance of screening for NTRK gene fusions in dMMR/MSI mCRC in sporadic cases with MLH1 promoter hypermethylation RAS/BRAFV600E wt. We highlight several key technical aspects of NTRK fusion testing and interpretation of reports that remain to be explored.

Keywords

• tropomyosin receptor kinase
• mismatch repair deficient
• metastatic colorectal cancer
• immune checkpoint inhibitors