NTRK Gene Fusions in Solid Tumors and TRK Inhibitors: A Systematic Review of Case Reports and Case Series.

The approval of larotrectinib and entrectinib for cancer patients harboring an NTRK gene fusion has represented a milestone in the era of "histology-agnostic" drugs. Among the clinical trials that led to the approval of these two drugs, most of the enrolled patients were affected by soft tissue sarcomas, lung, and salivary gland cancer. However, as next-generation sequencing assays are increasingly available in the clinical setting, health care professionals may be able to detect NTRK gene fusions in patients affected by tumor types under or not represented in the clinical trials. To this aim, we systematically reviewed MEDLINE from its inception to 31 August 2022 for case reports and case series on patients with NTRK gene fusion-positive tumors treated with TRK inhibitors. A virtual cohort of 43 patients was created, excluding those enrolled in the above-mentioned clinical trials. Although our results align with those existing in the literature, various cases of central nervous system tumors were registered in our cohort, confirming the benefit of these agents in this subgroup of patients. Large, multi-institutional registries are needed to provide more information about the efficacy of TRK inhibitors in cancer patients affected by tumor types under or not represented in the clinical trials.

The Role of Histology-Agnostic Drugs in the Treatment of Metastatic Castration-Resistant Prostate Cancer.

Precision medicine has opened up a new era in the development of anti-cancer agents that is focused on identifying biomarkers predictive of treatment response regardless of tumor histology. Since 2017, the Food and Drug Administration has approved six drugs with histology-agnostic indications: pembrolizumab (both for tumors with the mismatch-repair deficiency (dMMR)/high microsatellite instability (MSI-H) phenotype and for those with the high tumor mutational burden (TMB-H) phenotype), dostarlimab (for dMMR tumors), larotrectinib and entrectinib (for tumors harboring neurotrophic tyrosine receptor kinase (NTRK) fusions), and the combination of dabrafenib plus trametinib (for BRAF V600E-mutated tumors). The genomic alterations targeted by these antineoplastic agents are rare in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, only a small number of mCRPC patients were enrolled in the clinical trials that led to the approval of the above-mentioned drugs. Therefore, we critically reviewed the literature on the efficacy of histology-agnostic drugs in mCRPC patients. Although the available evidence derives from retrospective studies and case reports, our results confirmed the efficacy of pembrolizumab in dMMR/MSI-H mCRPC. In contrast, few data are available for dostarlimab, larotrectinib, entrectinib, and dabrafenib-trametinib in this subset of patients. Large, multi-institutional registries aimed at collecting real-world data are needed to better comprehend the role of tissue-agnostic drugs in mCRPC patients.