Jochen H. Lorch, MD, MS

There were a number of trials conducted using larotrectinib and similar trials using entrectinib. Those started out as phase 1 trials, which were tissue agnostic. Any tumor with an 

 fusion was included, and in some cases there were also 

 mutations allowed. In the LOXO-101 study that was for larotrectinib, children were also included. This was followed by cohort expansions on this trial. It turns out that the efficacy in general was very good, with radiographic response rates above 70%. That was also true for thyroid cancer. There were cases that did not reach the amount of shrinkage necessary for a partial response. In most cases, there was some shrinkage that was still appreciated, and more than half of all patients were still alive and on treatment at the 1-year mark.

Have these data been practice changing? Well, my feeling is that yes, based on the impressive efficacy and also the general absence of severe adverse effects, especially compared to the standard of care in iodine-refractory thyroid cancer, which is lenvatinib and sorafenib, where numerous cases require dose reductions and dose modifications. All this is much less of a problem with larotrectinib and also entrectinib. So these are good treatment options for patients with an 

In terms of monitoring, I typically get CT scans every 2 months to assess for a response, and otherwise I follow patients pretty closely clinically with routine laboratory tests and physical examinations perhaps 1 week or 10 days after initially starting the treatment, but then spread out the intervals increasingly. I usually end up seeing patients perhaps once per month while on treatment.

What do we know about resistance mechanisms for NTRK-targeted therapy? For larotrectinib, just like with entrectinib and any other tyrosine kinase inhibitor for that matter, eventually resistance occurs, and there are recurring new mutations that are found in these tumors that typically affect the ATP [adenosine triphosphate] binding site, making it impossible for the drug to bind to its target. There are second-generation NTRK inhibitors in development and in early clinical testing that are trying to overcome this resistance.

What is my personal experience with larotrectinib, and entrectinib for that matter, because I consider them very similar? Well, these are very well-tolerated drugs and there’s really no comparison to the old multityrosine kinase inhibitors, such as lenvatinib or sorafenib, and the efficacy has been great. So far I’ve seen responses in all cases. It’s perhaps important to note that not all cases respond, but if you look at these cases more carefully, it often turns out that if there was an 

 fusion detected, it was not one of the clinically meaningfully ones. Also for 

 mutations, not the fusions, but the mutations, it seems that the responses are much lower. I suspect that many of these mutations that are found in next-generation sequencing of 

 are just bystander mutations that have no clinical implications. It’s therefore not surprising that targeting NTRK in that scenario does not work.

A good confirmatory test I think is still immunohistochemistry to look for overexpression of the protein. There’s also a confirmatory testing that’s possible based on RNA sequencing. This is a more specialized test, but it’s frequently and increasingly widely available. Especially for cases where there are questions about whether this is meaningful, then this additional testing may be helpful. In cases where there is no urgent need to have a response because there’s not bulky disease or there’s no disease that’s immediately life threatening, then one could also just try to treat and assess for a response. If there is no response, then it was probably not a meaningful mutation or fusion, and if there is, then use that as a confirmation that the sequencing provided some reasonable data.

What’s often seen in cases that are truly 

 fusion positive and where this is the significant driver of the disease, is that the duration of response can be quite long. From the early trials, there are still numerous patients who are being treated beyond the 2-year mark with responses still ongoing, which speaks to the efficacy of larotrectinib, also entrectinib I think, but also to the significance of 

 fusions as a driver mutation of this disease.

As a medical oncologist who sees a lot of iodine-refractory thyroid cancer, it’s been very gratifying to see the emergence of these targeted therapies that really have made thyroid cancer a treatable disease, which it was not back in 2005, before the advent of sorafenib, for example. Now we have sorafenib and lenvatinib for the vast majority of cases, but then we also increasingly have these targeted therapies such as larotrectinib and also entrectinib for, say, 

 fusion positive cases. We have the BRAF inhibitors for those cases that are 

 V600E mutated, which also has good efficiency and also with a slightly more favorable adverse effect profile compared to multityrosine kinase inhibitors. Also, with the recent approval of selpercatinib and the anticipated approval of pralsetinib, we have 2 RET inhibitors that are highly effective in 

 fusion-positive, iodine-refractory thyroid cancer.

Now we’re seeing this broad spectrum of targeted therapies, and my hope is that this will continue and that we’ll be able to personalize targeted therapies more and more based on the genetic profile in thyroid cancer, just as in most other cancers as well.

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

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

She was treated with radioactive iodine 150 millicuries

Whole body scan showed uptake in neck only consistent with thyroid remnant

Follow-up at 2 months TSH 0.2 mU/L; thyroglobulin 26 ng/mL

MRI of the brain revealed multiple small lesions

Initiated treatment with larotrectinib 100 mg PO BID

Videos

LOXO-101 Trial Regimen Overview

 is part of next-generation sequencing, which at least in this day and age does capture 

 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 

 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 

 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 

 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.

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.

Preferred Testing Methods and Treatment Options 

This is a little bit of an odd case. To have a presentation with a thyroid nodule that’s palpable is very typical, and for this to be papillary thyroid cancer is also completely unremarkable. That is frequently the case. Where this case is a little bit unusual is that, first, the papillary thyroid cancer, which was 3.8 cm in diameter, had already metastasized to several lymph nodes in the central neck compartment. That can happen. But the brain metastases were definitely unusual. We only see brain metastases in about 15% of all patients with papillary thyroid cancer or with iodine-refractory thyroid cancer, which is not necessarily what this patient has. So this is definitely an unusually aggressive thyroid cancer.

Having brain metastases obviously raises the stakes of treatment in this considerably, since the prognosis for cancer in general that has spread to the brain is generally much less favorable than without brain metastases. The classical treatment for this would be evaluation by neurosurgery. It sounds like there were multiple brain lesions, so it’s likely not a case that would be amenable to resection of these multiple nodules. But whole brain radiation or stereotactic radiation to these individual brain lesions is also something that could classically be considered.

fusion positive obviously gives us another option to treat with larotrectinib or a similar drug, which is entrectinib, and has a very similar profile. The incidence of 

 fusion positive thyroid cancer is relatively high compared to other types of cancers. Across the board of all cancer types, the incidence is roughly 1%. But with thyroid cancer, it’s in the order of 10% to 15%. There also seem to be some geographical variations; for example, in Japan, the incidence seems to be a little bit higher. There’s also a higher incidence of fusion 

, which is related to radiation exposure and has been described in people who were exposed to radioactive iodine and radiation during the Chernobyl disaster in Ukraine.

NTRK Gene Fusion Thyroid Cancer: Incidence and Prognosis 

I would like to present a case today of a 71-year-old woman who presented with a painless ball on her neck. She otherwise has a history of hypercholesterolemia, which is well controlled medically. On examination, there is a palpable, nontender, solitary left-to-the-midline neck mass, otherwise unremarkable. The clinical work-up and initial treatment, including laboratory tests, including TSH [thyrotropin] and thyroid globulin antibodies, all of those were normal. An ultrasound of the neck was then performed, which showed a 3.8-cm suspicious mass arising from the left thyroid lobe, and 4 suspicious submandibular lymph nodes, the largest one was 2.2 cm in size. She then had an ultrasound-guided fine needle aspiration, and that confirmed papillary thyroid cancer. A CT scan of the chest, abdomen, and pelvis showed no evidence of distant metastatic disease.

The patient then underwent a total thyroidectomy, with a central compartment neck dissection and left selective neck dissection, which showed a 3.8-cm papillary thyroid cancer rising from the left lobe of the thyroid, with 2 out of 7 positive central compartment lymph nodes, with tumor foci up to 1.3 cm in diameter. There was no external extension, and the stage was thus T2N1M0. She also had a good performance status, which was felt to be a 0.

After this, she underwent treatment with radioactive iodine and received 150 mCi. The whole body scan showed uptake in the neck only, consistent with thyroid remnant, and she was then continued on levothyroxine as is standard of care.

At follow-up at 2 months, her TSH was adequately suppressed at 0.2 mU/L, and thyroglobulin was still elevated at 26 ng/mL. The patient, since she also had some headaches, had an MRI of the brain, which actually revealed multiple small lesions. She then underwent biomarker testing through next-generation sequencing, which revealed an 

. Treatment with larotrectinib, 100 mg orally twice a day, was initiated.

Jochen H. Lorch, MD, MS | Authors

Articles

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Preferred Testing Methods and Treatment Options

NTRK Gene Fusion Thyroid Cancer: Incidence and Prognosis

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