Corticosteroids for Managing TRK Inhibitor Withdrawal Pain: A Report on Two Cases

TL;DR

Corticosteroids like prednisone or dexamethasone can quickly relieve withdrawal pain caused by stopping TRK inhibitors in cancer patients.

Contribution

This report introduces corticosteroids as a novel therapeutic approach for TRK inhibitor withdrawal pain when tapering is not possible.

Findings

Two patients with TRK inhibitor withdrawal pain experienced rapid relief with corticosteroids.

Pain did not recur after steroids were discontinued, with no unexpected toxicity.

The findings suggest a potential role for corticosteroids in managing this specific withdrawal syndrome.

Abstract

NTRK gene fusions are oncogenic drivers. Targeted TRK inhibitors such as larotrectinib, entrectinib and repotrectinib are effective therapies for tumors harboring these fusions. Abrupt cessation of TRK inhibitors can trigger withdrawal pain. A short course of corticosteroids (prednisone or dexamethasone) may provide rapid and lasting relief from TRK inhibitor withdrawal pain, highlighting a potential therapeutic approach when tapering is not feasible.

Background: Neurotrophin receptor tyrosine kinase (NTRK) fusions are potent oncogenic mutations. Inhibitors such as larotrectinib, entrectinib and repotrectinib are used when cancer cells harbor NTRK1, NTRK2 or NTRK3 fusion. Signal disruption between nerve growth factor (NGF) and its target is thought to impact nociception. Withdrawal pain is reported with larotrectinib and entrectinib. Case presentation: Two male patients aged 37 and 41 years old and treated with, respectively, repotrectinib and larotrectinib for NTRK fusion-positive solid tumors experienced debilitating pain after abrupt cessation of their targeted therapy. Short courses of prednisone for the former and dexamethasone for the latter were initiated after failure of standard analgesia. Both patients improved within 24 h and the pain did not recur after steroids were weaned off. They had improvements in their functional status without unexpected toxicity. Conclusions and relevance: For patients experiencing TRK inhibitor withdrawal pain, especially when tapering down the inhibitor is not an available strategy, a short course of corticosteroids can provide lasting relief. These cases emphasize the importance of better understanding the mechanism underlying the relationship between NRTK, NGF and nociception.