Characterization of on-target adverse events caused by TRK inhibitor therapy
1Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, USA.
Background:
The tropomyosin receptor kinase (TRK) pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse events (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.
Patients And 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% confidence interval (CI), 43%-62%] of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with glucagon-like peptide 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 reinitiation 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.
Insights
Tropomyosin receptor kinase (TRK) inhibitors can cause weight gain, dizziness, and withdrawal pain in cancer patients. These manageable on-target adverse events require careful monitoring and intervention strategies for optimal patient care.
Area of Science:
- Oncology
- Pharmacology
- Translational Medicine
Background:
- The tropomyosin receptor kinase (TRK) pathway regulates appetite, balance, and pain.
- TRK inhibitors are approved for TRK or ROS1 fusion-positive cancers.
- On-target adverse events (AEs) of TRK inhibition are under-recognized, including withdrawal pain.
Purpose of the Study:
- To characterize the frequency, severity, duration, and management of AEs associated with TRK inhibitors.
- To identify specific AEs such as weight gain, dizziness, and withdrawal pain.
- To inform clinical management strategies for TRK inhibitor-related toxicities.
Main Methods:
- Retrospective analysis of patients with advanced solid tumors treated with TRK inhibitors.
- Identification and characterization of AEs including weight gain, dizziness, and withdrawal pain.
- Evaluation of management strategies and outcomes for observed AEs.
Main Results:
- Weight gain occurred in 53% of patients, often managed with GLP-1 analogs or metformin.
- Dizziness (with or without ataxia) affected 41% of patients, with dose reduction being effective.
- Withdrawal pain was observed in 35% of patients, effectively managed by TRK inhibitor reinitiation.
Conclusions:
- TRK inhibitors are associated with significant on-target AEs: weight gain, dizziness, and withdrawal pain.
- These toxicities are distinct from other anticancer therapies and necessitate monitoring.
- Management involves pharmacologic interventions and dose modifications for AEs related to TRK inhibition.
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