RET and NTRK Inhibitors for Differentiated Thyroid Cancer

The rationale for targeting actionable mutations in differentiated thyroid cancer with RET and NTRK inhibitors.

Lori Wirth, MD: Speaking of NTRK fusions, we have some great data to talk about with NTRK fusion-driven disease, RET fusion-driven disease. Maria, do you want to lead off on that discussion?

Maria E. Cabanillas, MD: Sure. I think we could probably start with mentioning the different other fusions that we can see in papillary thyroid cancer. The majority again are going to be mutations and fusions in papillary. We do see some actionable mutations and fusions in follicular and Hurthle cell, but they’re very rare, so we’re talking about mostly in papillary and poorly differentiated cases, BRAF mutations, RET fusions, NTRK fusions. But we also do see ALK fusions, and there has been a ROS1 fusion reported. Actually, I think Lori you reported it, in a patient with papillary thyroid cancer. So, those are things to think about. But starting out with the RET inhibitors, just because RET fusions are the most common of the fusions in papillary thyroid cancer, we’re going to see those in about 8% to 10% of papillary thyroid cancers, whereas NTRK fusions we see in about 3%. You’ll encounter the RET fusion much more often.

Selpercatinib is an approved drug for RET fusion differentiated thyroid cancer [DTC], also for RET mutated medullary thyroid cancer and lung cancer. In the trial that was published in the New England Journal of Medicine, there were 17 patients who had RET fusion DTC, and these were patients taken from the phase 1 and 2 trials, so it was data that were put together from the different studies. Fifteen patients were evaluable for response, and of those 15 patients, there was an overall response rate of 80%, which is really fantastic.

Median progression-free survival wasn’t reached, but at 1 year, 64% were progression free. In terms of adverse events, there were some adverse events of hypertension, increased liver function tests. There was some hyponatremia and diarrhea. And if you look at the whole cohort of the 531 patients with RET-aberrant cancer treated on these trials, it was only a 2% discontinuation rate with selpercatinib for treatment-emergent adverse events.

Pralsetinib is also a selective RET inhibitor and is also approved for RET mutation and RET fusion thyroid cancers. They enrolled 20 patients with RET fusion-positive thyroid cancer, but only 9 were evaluable for response, so there are less data with pralsetinib. But the overall response rate was again phenomenal. It was 89% who had partial responses, and the median progression-free survival and overall survival were not reached. But at 1 year, 81% of patients were progression free, and in terms of overall survival, the estimated 1-year overall survival was 91%. The adverse event profile is similar but not really the same. It’s interesting that pralsetinib tends to cause more anemia. They also reported more musculoskeletal pain and constipation. Both drugs cause increased liver function tests, but I have changed from one or the other because of increased liver function tests, and it’s been OK on the opposite drug, so that is worth trying. Also, the RET inhibitors can cause hypertension, so this drug did cause hypertension. The discontinuation rate in these patients was 4%, so it’s pretty good.

In terms of the TRK inhibitors, larotrectinib is the one that we have the most data with, but there is also entrectinib, which is approved in NTRK fusion-positive solid tumors. For larotrectinib, according to the update of the American Thyroid Association this year [2021], we had data on 29 patients with TRK fusion thyroid cancer. This is compiled from 3 different trials, including a pediatric larotrectinib trial. There were 22 patients with differentiated thyroid cancer enrolled, and 21 were evaluable for response. The overall response rate was 86%, and that included 2 complete responses. There was no best response at progression, so again, really stellar outcomes. The median follow-up time was 22 months, and with that, we had a median progression-free survival of 51 months, and overall survival was not reached. But at 2 years, 92% of patients were alive.

The adverse event profile includes anemia, low lymphocytes. Those were the higher-grade adverse events, and these drugs can cause some dizziness and nausea. Patients tend to adjust to that dizziness and it does resolve. There were no patients discontinued from the trial due to treatment-emergent adverse events. In terms of entrectinib, there is a publication for the 54 patients with advanced cancer who had TRK fusions, but it only included 5 patients with thyroid cancer. We don’t really know what their subtypes were, and there was 1 partial response out of 5. But almost nothing is known about that thyroid cancer population, so it’s hard to talk about entrectinib in the context of thyroid cancer. We think it’s probably a similar drug, but it does have other targets and so may lead to some off-target effects.

Lori Wirth, MD: One of the things that I was surprised about initially with the larotrectinib integrated data sets is that if you take out the children with infantile fibrosarcoma driven by ETV6-NTRK fusions and look at the adult patients with solid tumors who were enrolled across the 3 trials, the most common diagnosis is thyroid cancer. In the most updated data, the adults with soft tissue sarcomas and adults with thyroid cancers were the 2 most common adult diagnoses across the larotrectinib experience. I think that’s an underappreciated fact that I like to highlight every chance I get.

Transcript edited for clarity.

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