Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor for the treatment of TRK fusion cancer

Abstract

Introduction: Detecting oncogenic drivers across multiple cancers has brought about a shift toward a more targeted therapeutic approach. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are genomic rearrangements containing the kinase domain of one of three tropomyosin receptor kinases (TRK) and a dimerization domain contributed by another gene, generating fusion proteins, which are oncogenic drivers, targetable with TRK inhibitors. Larotrectinib is a first-in-class TRK inhibitor, granted accelerated FDA approval for treating TRK fusion cancer. This breakthrough indication across cancer subtypes and ages, from infancy through adulthood, highlights the need to understand the heterogeneous patient population and cancer types studied in larotrectinib clinical trials. Areas covered: We provide a narrative review of preclinical, pharmacokinetic, efficacy, and safety data for larotrectinib from three clinical trials that led to regulatory approval. Expert opinion: Larotrectinib elicits impressive responses in most patients with TRK fusion cancer, regardless of tumor type and age. Treatment is well tolerated with a low rate of treatment-emergent grade 3-4 adverse events, dose reductions and discontinuations due to adverse events, and recent findings indicate patient-reported improvement in quality of life. This highlights the importance of early testing for NTRK gene fusions in cancers that may harbor them, even if rare. ARTICLE HISTORY

Larotrectinib versus Prior Therapies in Tropomyosin Receptor Kinase Fusion Cancer: An Intra-Patient Comparative Analysis

“…However, the marked improvement in GMI seen with larotrectinib, especially as the majority of patients were free of progression at the data cut-off, together with the high ORR and long durability of disease control previously reported [4], is very promising. Larotrectinib has demonstrated clinically meaningful, tumor-agnostic efficacy and a favorable safety profile irrespective of age, NTRK gene, or fusion partner, showing great potential as a targeted therapy [4,5]. Another limit of the GMI assessment is the potential heterogeneity of a tumor over time that may result in variable tumor cell growth dynamics.…”

“…Larotrectinib is a specific tropomyosin receptor kinase (TRK) inhibitor that is approved by the US Food and Drug Administration and European Medicines Agency (EMA) to treat patients with TRK fusion cancer [2,3]. In three phase I/II clinical trials (adult phase I, NCT02122913; SCOUT, NCT02637687; NAVIGATE, NCT02576431) evaluating the efficacy and safety of larotrectinib in patients with TRK fusion cancer, larotrectinib demonstrated tumor-agnostic efficacy (objective response rate (ORR), 79%) and a favorable safety profile in patients with TRK fusion cancer, irrespective of age, the NTRK gene, or fusion partner [4,5].…”

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

“…Remarkably, both larotrectinib and entrectinib displayed activity against CNS tumors with NTRK fusions, indicating the ability for BBB penetration. 231,232 When referring to the adverse events of first-generation TRK inhibitors, it should be noted that both agents have favorable overall safety profiles compared to other small-molecule TKIs. These drugs are generally well-tolerated in patients, with low incidences of dose reductions, discontinuations, and grade 3-4 adverse events.…”

Targeting Epidermal Growth Factor Receptor (EGFR) in Pediatric Colorectal Cancer

“…These are oncogenic drivers induced by genomic rearrangements between the kinase domain of one of three tropomyosin receptor kinases (TRK) and a dimerization domain by another gene. The resulting fusion proteins are targetable with TRK inhibitors whose efficacy has also been proved on many childhood patients [40].…”