TRK Inhibitor Therapy Shows ‘Unique’ Adverse Event Profile

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: A study of US cancer patients using TRK inhibitors suggests that “a substantial proportion” may experience on-target adverse events (AEs) including weight gain, dizziness and pain on withdrawal of treatment. 

“This safety profile is unique relative to other anticancer therapies and warrants careful monitoring”, the researchers write in the Annals of Oncology. 

Nevertheless, they believe that the “on-target toxicities are manageable with pharmacologic intervention and dose modification.” 

Medical records were collated for 96 patients who received at least one dose of a first-generation (84%) or later-generation (31%) TRK inhibitor between 2013 and 2019 at the Memorial Sloan Kettering Cancer Center in New York, USA. Sixteen percent of patients received two and 1% received three TRK inhibitors in sequence. 

The patients were aged a median 52 years and 51% were female. There were 15 different types of tumour represented, most commonly lung (45%), gastrointestinal (10%) and salivary (8%) cancers and sarcoma (8%). NTRK fusions were detected in 41% of patients, ROS1 fusions in 25% and other alterations in 30%, most commonly ALK fusions or mutations. 

Overall, 53% of the patients gained weight during treatment, and both the frequency and severity of weight gain increased with the duration of treatment, report Alexander Drilon and co-workers from the institution. 

“This finding is not unexpected as the TRKB pathway regulates appetite centers”, they comment. 

The majority (86%) of patients who gained weight had a higher than ideal bodyweight at baseline but an obese body mass index did not predict a significantly incidence of weight gain. Ten patients were given pharmacological agents for weight loss, such as a glucagon-like peptide-1 analogue or metformin, and 80% of these individuals stopped gaining or lost a “modest” amount of weight. 

A further 41% of patients experienced dizziness, most commonly grade 1 (32%) and 2 (8%), with six patients reporting moderate to severe dizziness with ataxia. Dizziness was described as positional light headedness, imbalance, vertigo or mixed symptoms, and was associated with orthostatic hypotension in 21% of the group. 

Dizziness lasted for a median of 5 months; dose modification resolved symptoms in seven of nine patients but 12 patients were given pharmacological interventions, which the investigators say “resulted in modest benefit.” 

And 18% of patients experienced paresthesia, most commonly described as a mild, “perioral” and/or a “sunburn” sensation that did not require dose modification or treatment. 

Overall, 34% of the 81 patients who discontinued TRK inhibitor therapy reported withdrawal pain after a median of 2 days, consisting of “full-body ache, muscle pain, and/or allodynia”, sometimes with a headache.

Withdrawal pain lasted a median of 14 days in patients who permanently discontinued treatment and 3 days for those who temporarily stopped therapy. Almost half (46%) of patients required pharmacological intervention for their pain, but the pain was only ameliorated by a return to treatment.

Alexander Drilon et al explored a tapering TRK inhibitor dose in two patients discontinuing treatment who had previously experienced TRK inhibitor withdrawal pain; a 25% reduction every 7 days in one patient achieved “a much lower severity of withdrawal pain” compared with an earlier treatment interruption (grade 1 vs 3).

The researchers note that pain was significantly more common in patients who had used their TRK inhibitor for over 6 months (63 vs 13%) and that use of opioids for cancer pain did not affect the likelihood of withdrawal pain.

“We thus recommend (1) avoiding or minimizing TRK inhibitor interruption, (2) adjunctively managing pain when discontinuation is necessary, and (3) considering a slow tapering dose schedule for patients who need to permanently discontinue therapy”, the team concludes. 

Reference  

Liu D, Flory J, Lin A, et al. Characterization of on-target adverse events caused by TRK inhibitor therapy. Ann Oncol; Advance online publication 15 May 2020. https://doi.org/10.1016/j.annonc.2020.05.006