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. 2020 Sep;31(9):1207-1215.
doi: 10.1016/j.annonc.2020.05.006. Epub 2020 May 15.

Characterization of on-target adverse events caused by TRK inhibitor therapy

D Liu  1 , J Flory  2 , A Lin  3 , M Offin  2 , C J Falcon  4 , Y R Murciano-Goroff  4 , E Rosen  4 , R Guo  4 , E Basu  5 , B T Li  2 , J J Harding  2 , G Iyer  2 , K Jhaveri  2 , M M Gounder  2 , N N Shukla  6 , S S Roberts  7 , J Glade-Bender  6 , L Kaplanis  8 , A Schram  2 , D M Hyman  2 , A Drilon  9
Affiliations

Characterization of on-target adverse events caused by TRK inhibitor therapy

D Liu et al. Ann Oncol. 2020 Sep.

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.

Keywords: NTRK fusion; TRK inhibitors; toxicity management.

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Conflict of interest statement

Disclosure JF has received honoraria from Genentech. AL has received research funding from Bristol Myers Squibb and NantOmics and holds equity in Sanofi. MO has served on advisory boards for PharmaMar, Novartis, and Targeted Oncology, and received travel expenses from Bristol Myers Squibb and Merck. YRM-G has received travel expenses from AstraZeneca. BTL holds two institutional patents (US62/685,057, US62/514,661), and has served on advisory boards for Genentech (subsidiary of Roche), Eli Lilly, Guardant Health, Hengrui Therapeutics, Mersana Therapeutics, and Thermo Fisher Scientific, received travel expenses from MORE Health and Resolution Bioscience, and received research funding from Amgen, AstraZeneca, BioMedValley Discoveries, Daiichi Sankyo, Genentech, GRAIL, Guardant Health, Eli Lilly, Hengrui Therapeutics, Illumina, and MORE Health. JJH has received consulting fees from Bristol Myers Squibb, Cytomx, Eli Lilly, Eisai, Exelixis, Imvax, QED, and research funding from Bristol Myers Squibb. GI has received research funding from Janssen, Mirati Therapeutics, and Novartis, and consulting fees from Mirati Therapeutics. MMG has received honoraria from Bayer and Flatiron Health, served on advisory boards for Bayer, Boehringer Ingelheim, Epizyme, Daiichi Sankyo, Karyopharm, and Springworks Therapeutics, served on a speakers’ bureau for Amgen, and received travel expenses from Epizyme. AS has received research funding from Eli Lilly, Kura Oncology, Merus, Northern Biologics, and Surface Oncology. DMH owns stock in Fount Therapeutics, has served on advisory boards for ArQule, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharma, CytomX, Debiopharm, Fount Therapeutics, Genentech, Eli Lilly, Janssen, Jazz Pharma, Pfizer, and Puma Biotechnology, received research funding from AstraZeneca, Bayer, Loxo Oncology, and Puma Biotechnology, and received travel expenses from Chugai Pharma and Genentech; he is currently employed by and holds equity in Loxo Oncology, a subsidiary of Eli Lilly. AD has received honoraria and/or served on advisory boards for 14ner/Elevation Oncology, Abbvie, ArcherDX, AstraZeneca, Axis Pharma, Bayer, Beigene, BergenBio, Blueprint Medicines, Exelixis, Helsinn, Hengrui Therapeutics, Loxo Oncology (subsidiary of Eli Lilly), Monopteros, MORE Health, Remedica, Roche (subsidiaries Genentech and Ignyta), Pfizer, Takeda (subsidiaries Ariad and Millennium), TP Therapeutics, Tyra Biosciences, and Verastem; and received research funding from Exelixis, Foundation Medicine GlaxoSmithKline, Pfizer, PharmaMar, Teva, and Taiho. All research funding was provided to the institution. All other authors report no financial relationships.

Figures

Figure 1.
Figure 1.. Neurologic adverse events observed with TRK inhibition.
The frequency of paresthesias, weight gain, dizziness with or without ataxia, and withdrawal pain are summarized. The frequency of each adverse event is shown by the worst grade the patient experienced during therapy. For withdrawal pain, only patients who had dose interruptions and were at risk for this event were included (N = 81); all 96 patients were included in the other analyses. The effects of TRKA, TRKB, or TRKC loss in preclinical models that predict the emergence of these toxicities is summarized below.
Figure 2.
Figure 2.. Weight gain.
A, cumulative frequency of weight gain by worst grade over time on TRK inhibitor therapy. B-D, pattern of weight gain on therapy, separated by severity; B, grade 1; C, grade 2; D, grade 3. Points on the left side of the y-axis represent the patient’s ideal body weight plotted in reference to baseline weight, i.e. points below 0 indicate baseline weight prior to TRK inhibitor therapy is above ideal body weight. Weight trends for patients for whom pharmacologic intervention or dose reduction was recommended are plotted with colored lines, and size of data points indicates duration of treatment with corrective pharmacological intervention. TRK inhibitor dose was reduced in 1 patient with grade 2 weight gain (C).
Figure 3.
Figure 3.. Dizziness.
A. Swimmer’s plot of time to treatment discontinuation for all patients who developed dizziness with or without ataxia on TRK inhibitor therapy (N = 39). Each bar represents an individual patient. The orange box indicates the time of dizziness onset and the orange line indicates ongoing dizziness. B. Pie chart showing the frequency distribution of the categories of dizziness that patients experienced.
Figure 4.
Figure 4.. Withdrawal pain.
Swimmer’s plot of time to treatment discontinuation for all patients who developed withdrawal pain on TRK inhibitor therapy (N = 28). Each bar represents an individual patient.
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