Characterization of On-Target Adverse Events Caused by TRK Inhibitor Therapy
Menée à partir de données portant sur 96 patients atteints d’un cancer de stade avancé ou non résécable, cette étude rétrospective identifie les symptômes associés à une utilisation d’inhibiteurs de TRK et analyse la sévérité et la durée de ces symptômes
Purpose : The TRK pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse effects (AEs) observed with TRK inhibition, these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial. Methods : Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized. Results : Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% (95% CI, 43%-62%) of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with GLP-1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%-51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%-46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor re-initiation was the most effective intervention for withdrawal pain. Conclusions : TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification.