Preferred Testing Methods and Treatment Options

EP: 1.A 71-Year-Old Woman With NTRK Gene Fusion Thyroid Cancer

EP: 2.NTRK Gene Fusion Thyroid Cancer: Incidence and Prognosis

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EP: 3.Preferred Testing Methods and Treatment Options

EP: 4.LOXO-101 Trial Regimen Overview

Jochen H. Lorch, MD, MS: What is my preferred way of testing for NTRK fusions? Clearly, NTRK is part of next-generation sequencing, which at least in this day and age does capture NTRK fusions in general, 1 through 3, although not all assays do. There has to be a specific set of baits that are used to be able to call fusions accurately. There is, however, also the possibility to use just immunohistochemistry, which checks for NTRK kinase expression. This test is actually quite highly sensitive and specific for NTRK fusions, with sensitivity and specificity beyond 90%. So this is a lower-cost alternative and is also frequently used as a procedure to screen all these thyroid cancers, which usually do not have an NTRK fusion. The more definitive test, as I said, is next-generation sequencing.

What are the treatment options for this patient? I think the most important question always with thyroid cancer, especially with differentiated thyroid cancer as in this case, is whether to treat a patient at all following radioactive iodine. Typically, after a dose of radioactive iodine in a case like this, without brain metastases, the appropriate next step would be to wait and see if there is any structural disease that can be detected at any point. Again, the somewhat unusual feature of multiple brain metastases is different in this case than in most, and obviously she does require some treatment. Again, should there be radiation such as whole brain radiation or stereotactic radiation as a next step, or, because of the NTRK fusion positivity, one of the new NTRK inhibitors, is really up for debate.

There are good data for larotrectinib, but also for entrectinib, that it passes the blood-brain barrier in sufficient quantities, so that in this case, especially since the brain metastases are small, one could make a case for treatment with 1 of these drugs. Without the brain metastases, my recommendation would be to wait, monitor thyroglobulin levels, keep TSH [thyrotropin] fully suppressed, and wait. In many cases, no treatment is required for a long period.

For this case, let’s assume that there is structural disease that returned, aside from the brain metastases, and that she does require treatment. In this case, the standard of care is the multityrosine kinase inhibitor lenvatinib, which is FDA approved, or another one, sorafenib, which is also FDA approved for RAI [radioactive iodine]-refractory thyroid cancer. There are other options also that are available such as mTOR inhibitors, everolimus, for example, which also has considerable activity in iodine-refractory thyroid cancer.

In iodine-refractory thyroid cancer, the standard of care is lenvatinib and sorafenib. Both are FDA approved. They’re multityrosine kinase inhibitors that primarily target VEGF, and they’re typically fraught with lots of [adverse] effects. There’s a significant amount of fatigue, hypertension, and chronic use can also result in a number of cardiovascular problems: bleeding, clotting, heart attacks, strokes also. So these are generally difficult drugs to take, but they are the FDA-approved first-line treatment in this disease.

Now, for NTRK fusion positive cases, I think it’s reasonable to consider them a standard of care also for first-line treatment based on the fact that these drugs are generally very well tolerated in contrast to the multityrosine kinase inhibitors that are FDA approved. The efficacy is also outstanding.

What would be the next line of therapy for this patient? Well, as I mentioned, I think it would be entirely reasonable to consider larotrectinib or entrectinib in this situation, primarily for the treatment of the multiple small brain metastases.

Transcript edited for clarity.

Case: A 71-Year-Old Woman With Thyroid NTRK Gene Fusion Cancer

Initial Presentation

• A 71-year-old woman presents with a painless “ball on his neck”
• PMH: hypercholesterolemia, medically controlled
• PE: palpable, non-tender solitary left-of-the midline neck mass; otherwise unremarkable

Clinical Workup and Initial Treatment

• Labs: including TSH, anti-Tg antibodies WNL
• Ultrasound of the neck revealed a 3.8 cm suspicious mass arising from the left thyroid; 4 suspicious submandibular lymph nodes, largest 2.2 cm in size
• Ultrasound-guided FNAB of the thyroid mass and the largest lymph node confirmed undifferentiated papillary thyroid carcinoma
• Chest/abdominal/pelvic CT showed no evidence of distant metastases
• Patient underwent total thyroidectomy with therapeutic central compartment and left selective neck dissection
  • Pathology: 3.8 cm undifferentiated papillary thyroid cancer arising in left lobe of thyroid, 2 of 7 positive central compartment lymph nodes, largest 1.3 cm, no extra nodal extension
• StageT2N1M1; ECOG PS 0
  
  

Follow-Up and Additional Treatment

• She was treated with radioactive iodine 150 millicuries
  • Whole body scan showed uptake in neck only consistent with thyroid remnant
  • Added levothyroxine to regimen
• Follow-up at 2 months TSH 0.2 mU/L; thyroglobulin 26 ng/mL
  • MRI of the brain revealed multiple small lesions
• Biomarkers testing:NTRK fusion+, RET-, BRAF-, NRAS-,KRAS-
• Initiated treatment with larotrectinib 100 mg PO BID