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%e62%] 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%e51%) 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%e46%) 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.

Tropomyosin Receptor Kinase Inhibitors for the Treatment of TRK Fusion Cancer

“…In addition to these prospective analyses, Liu and colleagues carried out a retrospective analysis of adverse events in 96 patients who had received a TRK inhibitor for the treatment of advanced cancer (53). The focus of this study was on-target adverse events likely to have arisen secondary to TRK inhibition, including weight gain (53% of patients at any grade), dizziness (41%; 6% of patient concurrently with ataxia), paresthesia (18%), and pain associated with treatment withdrawal (34%).…”

“…This on-target safety profile was deemed to be unique relative to other anticancer agents. While warranting careful monitoring, these adverse events were found to be manageable either with pharmacologic intervention and/or dose modification, or TRK inhibitor re-initiation (53).…”

Pursuing Precision: Receptor Tyrosine Kinase Inhibitors for Treatment of Pediatric Solid Tumors

“…For example, agents targeting VEGFR are commonly associated with hypertension, diarrhea, proteinuria, poor wound healing, and thyroid dysfunction, while those targeting ALK or MET may cause vomiting or pancreatic inflammation. The scope of toxicities can affect a wide range of organ systems and can include weight gain, dizziness, and pain upon withdrawal of therapy [ 123 ]. The incidence of toxicities may be related to the extent of various kinases inhibited.…”

TRK Inhibitors: Tissue-Agnostic Anti-Cancer Drugs

“…Trk signaling is known to play a role in nerve growth during the fetal period, while NGF function is reported to induce pain in adulthood [ 55 ]. From the beginning of Trk inhibitor development, there was a concern for adverse CNS effects, and thus, adverse events were closely observed and characterized [ 56 ]. Representative adverse events related to neurological systems include withdrawal pain, weight gain, and dizziness [ 48 , 52 ].…”

“…Patients who discontinued Trk inhibitor therapy experienced symptoms of pain. Full-body ache, muscle pain, allodynia, and concurrent flares of pre-existing pain are described as withdrawal symptoms [ 56 ]. The mechanisms of withdrawal pain are not clear, but it is presumed to be caused by increased expression of transient receptor potential vanilloid I, a nociceptive mediator [ 57 ].…”