Larotrectinib and The Risk of Fracture in TRK Fusion Thyroid Cancer

Between 75% and 80% of patients treated with larotrectinib have an objective response, and many of those responses are durable. The agent has also been shown to be both age and histologically agnostic and has shown activity in a number of tumor types, including thyroid cancer.

To determine whether larotrectinib increased the risk of fractures, researchers looked at data from 3 studies, the Phase 1 adult study (NCT02122913) of larotrectinib in generalized patients, with or without the presence of a TRK fusion, the pediatric SCOUT- study (NCT02637687), and the phase 2 NAVIGATE study (NCT02576431) for adults and adolescents.

Theodore W. Laetsch, MD, an attending physician at the Cancer Center at the Children’s Hospital of Philadelphia, discusses whether there is an increased risk of fractures with larotrectinib in patients with TRK fusion-positive thyroid cancer.

TARGETED ONCOLOGY: What efficacy has been shown with larotrectinib and what impact has it had since it was approved by the FDA?

LAST: We will continue to update the efficacy data for larotrectinib. But it has been very consistent that between 75% and 80% of larotrectinib-treated patients who have TRK fusion cancer have objective responses. And those reactions are quite durable. In pediatric patients, I am a pediatric oncologist, the median duration of response has still not been reached. Most patients are still being treated. So I think the really exciting nature of the efficacy of larotrectinib that we’ve seen is that it’s both age-independent, so there were children and adults involved in the studies very early on, and also histologically agnostic, meaning we had an activity see all over the world. a very large number of different tumor types with TRK gene fusions in a very profound and durable way. What is the general side effect profile of this drug and solid tumors? Larotrectinib is thus a TRK inhibitor. And so, some of the side effects that we see are part of this class of drugs and related to TRK inhibition, and those include some neurological side effects like fatigue and dizziness. We will also occasionally see patients when we stop this therapy will have some pain at the time of withdrawal which can last for several days but this is due to inhibition of the TRK receptor. Dizziness will also occur in some patients. We see some potential off-target effects, meaning they are not clearly related to TRK receptor inhibition. In children. The most common of these are mild elevations in liver function tests and mild cytopenias, most commonly neutropenia.

Can you provide some background information on your fracture analysis? How did this come about?

There has been concern about an increased fracture rate in patients treated with other less specific TRK inhibitors, specifically entrectinib. And so we decided to look at the larotrectinib data from patients treated in one of the ongoing clinical trials and led to the FDA approval of larotrectinib to evaluate the fracture rate to see if that was common or not in this group of patients. .

From which studies does this data come? And what can you tell me about the patient population you assessed?

It comes from 3 different trials. So the Phase 1 adult study of larotrectinib with generalized patients, with or without the presence of a TRK fusion, and then the pediatric SCOUT study that enrolled patients, again initially with or without the presence of a TRK fusion, but was subsequently changed to enroll only patients with TRK fusions for the phase two portion. And then the phase 2 study for adults and adolescents called NAVIGATE. The latter two studies are still ongoing with patients. And so this included a group of patients that ranged from very young, less than a month old, to older adults, and with a wide variety of different histologies. Looking at the safety results, it did not limit the analysis to patients with TRK fusions and included patients with or without TRK fusions, all patients enrolled in those studies.

What results have you seen so far?

We evaluated the fracture rate in patients treated in those 3 clinical trials and found that the fracture rate was really quite low, about 7% for the whole cohort of patients, which is in line with expectations for patients with advanced cancer who participated. to such studies, and there is no clear evidence that fracture rates increase with larotrectinib treatment.

I think it is important to emphasize that we are continuing to collect additional safety data and that these investigations are ongoing. And especially in growing children, it’s important to continue collecting this data, but we were certainly happy to see these results.

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