Characterization of on-target adverse events caused by TRK inhibitor therapy
| Autor: | Mrinal M. Gounder, Alexander Drilon, David M. Hyman, Yonina R. Murciano-Goroff, M. Offin, J. Flory, S.S. Roberts, A. Lin, Ezra Y. Rosen, L. Kaplanis, James J. Harding, Bob T. Li, G. Iyer, Komal Jhaveri, Robin Guo, Ellen M. Basu, Christina Falcon, Dazhi Liu, Julia Glade-Bender, Alison M. Schram, Neerav Shukla |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty animal structures Ataxia 03 medical and health sciences Drug withdrawal 0302 clinical medicine Weight loss Internal medicine Proto-Oncogene Proteins medicine Humans Receptor trkA Adverse effect Retrospective Studies business.industry Cancer Hematology Protein-Tyrosine Kinases medicine.disease Metformin Discontinuation enzymes and coenzymes (carbohydrates) 030104 developmental biology Pyrimidines nervous system 030220 oncology & carcinogenesis Trk receptor embryonic structures Pyrazoles medicine.symptom business medicine.drug |
| Zdroj: | Annals of oncology : official journal of the European Society for Medical Oncology. 31(9) |
| ISSN: | 1569-8041 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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