Purpose: Receptor tyrosine kinase fusions in colorectal cancers are rare, but potentially therapeutically relevant. We describe clinical, molecular, and pathologic attributes of RTK fusion–associated colorectal cancer. Experimental Design: We identified all cases with RTK fusions in patients with colorectal cancer seen at Dana-Farber Cancer Institute (Boston, MA) who underwent OncoPanel testing between 2013 and 2018. Clinical, histologic, and molecular features were extracted from the patient charts and molecular testing results. Results: We identified 12 driver oncogenic fusions in various RTKs. These fusions occurred exclusively in BRAF and RAS wild-type tumors and were enriched in right-sided and mismatch repair–deficient (MMR-D) colorectal cancers. All of the MMR-D colorectal cancers with RTK fusions were found in tumors with acquired MMR-D due to MLH1 promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D colorectal cancer with RTK fusions largely resembled BRAF V600E–mutated MMR-D colorectal cancer, rather than those secondary to Lynch syndrome. We describe two patients with fusion-associated microsatellite stable (MSS) colorectal cancer who derived clinical benefit from therapeutic targeting of their translocation. The first harbored an ALK-CAD fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an ALK L1196Q gatekeeper mutation. The second patient, whose tumor contained an ROS1-GOPC fusion, continues to benefit from entrectinib after 9 months of therapy. Conclusions: RTK fusions in colorectal cancer are a rare, but important disease subgroup that occurs in RAS and BRAF wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in MSS colorectal cancer and provide an important therapeutic target.

Background. Trifluridine/tipiracil (FTD/TPI) and regorafenib prolong survival for patients with refractory metastatic colorectal cancer (mCRC); limited comparative effectiveness data exist. Materials and Methods. A retrospective, longitudinal cohort study of patients with mCRC who initiated FTD/TPI or regorafenib (index therapy) between 2012-2017 at a US tertiary oncology center, Dana-Farber Cancer Institute, was conducted. Using best tumor response assessments, realworld overall response rates (rwORR) and disease control rates (rwDCR) were described and analyzed using logistic regression. Survival rate was examined for each month after index therapy using Kaplan-Meier. Overall survival (OS) was assessed using Cox proportional hazards models. Subgroup analyses among patients with index therapy as 2nd-or 3rdline were performed. Results. 126 and 95 patients were treated with FTD/TPI or regorafenib as index therapy, respectively. Patients treated with FTD/TPI versus regorafenib had a better response (rwORR 52.5% vs. 34.2%, adjusted OR=2.6, all p-value<0.05; rwDCR 64.2% vs. 46.1%, adjusted OR=2.5, all p-value<0.05). Similar findings were observed for FTD/TPI versus regorafenib as 2nd-or 3rd-line therapy (rwORR 54.8% vs. 25.9%, adjusted OR=4.1, all p-value<0.05; rwDCR 69.0% vs. 37.0%, adjusted OR=4.9, all p-value<0.05). A greater proportion of patients treated with FTD/TPI versus regorafenib survived at 3 months (86.2% vs. 73.4%, p=0.016) and 4 months (79.6% vs. 65.8%, p=0.017). Adjusted OS hazard ratio for FTD/TPI versus regorafenib was 0.80, p=0.157. Conclusion.Patients treated with FTD/TPI had better tumor response and disease control than patients treated with regorafenib. Subgroup analysis in 2nd-or 3rd-line suggests that early use of FTD/TPI may have clinical benefits.Implications for Practice Statement: This real-world retrospective study compared clinical outcomes and clinical conditions between patients with refractory mCRC treated with FTD/TPI vs. regorafenib. Compared with patients treated with regorafenib, patients treated with FTD/TPI were significantly less likely to have dose modifications and more likely to have higher real-world objective response rate (rwORR) and real-world disease control rate (rwDCR) based on best tumor response while treated. Patients treated with FTD/TPI vs. regorafenib had significantly greater odds of having rwORR or rwDCR in adjusted analyses. Monthly survival rates were higher overall in patients treated with FTD/TPI vs. regorafenib in the first 6 months of follow-up, particularly at months 3 and 4. Adjusted overall survival results were similar between treatment groups. Clinical conditions while on treatment were consistent with the literature. This study offers insight into patients' treatment experience in real-world clinical settings. The Oncologist 2021;9999:• •