From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis.

The discovery of neurotrophic tyrosine receptor kinase () gene fusions has facilitated the development of precision oncology. Two first-generation inhibitors (larotrectinib and entrectinib) are currently approved for the treatment of patients with solid tumors harboring gene fusions. Nevertheless, comprehensive profiling at the pan-cancer genomic level and real-world studies pertaining to the adverse events of inhibitors are lacking. We characterize the genome of at the pan-cancer level through multi-omics databases such as The Cancer Genome Atlas (TCGA). Through the FDA Adverse Event Reporting System (FAERS) database, we collect reports of entrectinib and larotrectinib-induced adverse events and perform a pharmacovigilance analysis using various disproportionality methods. expression is lower in most tumor tissues, while they have higher methylation levels. gene expression has prognostic value in some cancer types, such as breast invasive carcinoma (BRCA). The cancer type with highest alteration frequency is skin cutaneous melanoma (SKCM) (31.98%). Thyroid carcinoma (THCA) has the largest number of fusion cases, and the most common fusion pair is . Adverse drug events (ADEs) obtained from the FAERS database for larotrectinib and entrectinib are 524 and 563, respectively. At the System Organ Class (SOC) level, both drugs have positive signal value for "nervous system disorder". Other positive signals for entrectinib include "cardiac disorders", "metabolism and nutrition disorders", while for larotrectinib, it is "hepatobiliary disorders". The unexpected signals are also listed in detail. ADEs of the two inhibitors mainly occur in the first month. The median onset time of ADEs for entrectinib and larotrectinib was 16 days (interquartile range [IQR] 6-86.5) and 44 days ([IQR] 7-136), respectively. Our analysis provides a broad molecular view of the family. The real-world adverse drug event analysis of entrectinib and larotrectinib contributes to more refined medication management.