Characterization of on-target adverse events caused by TRK inhibitor therapy Journal Article
| Authors: | Liu, D.; Flory, J.; Lin, A.; Offin, M.; Falcon, C. J.; Murciano-Goroff, Y. R.; Rosen, E.; Guo, R.; Basu, E.; Li, B. T.; Harding, J. J.; Iyer, G.; Jhaveri, K.; Gounder, M. M.; Shukla, N. N.; Roberts, S. S.; Glade-Bender, J.; Kaplanis, L.; Schram, A.; Hyman, D. M.; Drilon, A. |
| Article Title: | Characterization of on-target adverse events caused by TRK inhibitor therapy |
| Abstract: | 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. © 2020 European Society for Medical Oncology |
| Keywords: | ntrk fusion; toxicity management; trk inhibitors |
| Journal Title: | Annals of Oncology |
| Volume: | 31 |
| Issue: | 9 |
| ISSN: | 0923-7534 |
| Publisher: | Oxford University Press |
| Date Published: | 2020-09-01 |
| Start Page: | 1207 |
| End Page: | 1215 |
| Language: | English |
| DOI: | 10.1016/j.annonc.2020.05.006 |
| PUBMED: | 32422171 |
| PROVIDER: | scopus |
| PMCID: | PMC8341080 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2020 -- Source: Scopus |
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