Addressing the Presence of NTRK Gene Fusions in Thyroid Cancer

Marcia S. Brose, MD, PhD, FASCO

NTRK gene fusions are key molecular markers in thyroid cancer. Knowledge of the presence of NTRK gene fusions in patients with thyroid cancer can help with diagnosis, determining prognosis, and selecting the optimal treatment plan for the patient.¹

Since 2019, the FDA has granted approval to 2 agents for the treatment TRK fusion-positive cancer. First, larotrectinib (Vitrakvi) was approved in 2018 for the treatment of adult and pediatric patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity. This also applies to patients who have no satisfactory alternative treatments or whose cancer has progressed following treatment. More data around the efficacy and safety of larotrectinib have been reported since its approval which further confirm its benefit in thyroid cancer, specifically.²

Entrectinib (Rozlytrek) was granted FDA approval in 2019, for the treatment of adults and pediatric patients 12 years of age and older with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy. Like larotrectinib, the drug is very active and has improved outcomes in patients with thyroid cancer.³

In the future, there may be additional opportunities with larotrectinib and entrectinib, including moving the use of the drug to the frontline setting for select patient subgroups.

“At this point, what's interesting is that I don't think we're going to have additional trials that are going to say to us, we should put this in first-, second- or third-line. Both larotrectinib and entrectinib previously have achieved a tumor agnostic indication, meaning that they are indicated anytime that you have a gene fusion, and thyroid cancer again, we wouldn't treat people who are not otherwise curable. If somebody is being cured, there's no need to be testing or even treating. But in the case of patients who have RAI-refractory disease, that's progressing, we would be moving this upfront, said Marcia S. Brose, MD, PhD, FASCO in an interview with Targeted Oncology™.

In the interview, Brose, professor, Department of Medical Oncology, Sidney Kimmel Medical College Thomas Jefferson University, vice chair, Department of Medical Oncology Jefferson Northeast, chief of Cancer Services, Sidney Kimmel Cancer Center-Jefferson Northeast, associate director of Community Based Clinical Research, SKCC chair of Hematolog/Oncology, Jefferson Torresdale Hospital, discussed treatment of TRK fusion-positive thyroid cancer based on the most recent data from ASCO 2022 and ongoing studies.

TARGETED ONCOLOGY: Once an NTRK fusion is identified in a patient with thyroid cancer, what does that tell you about their diagnosis and prognosis?

Brose: We don't really use it so much for the diagnosis and prognosis in thyroid cancer as much as we do it as part of the treatment planning. It's predictive of a response to a TRK inhibitor, and therefore, if somebody has that molecular marker, it identifies them as being a candidate for an additional therapy that a patient without that marker would not be eligible for. We tend to check for and TRK fusions, when we find a patient who needs systemic therapy. In thyroid cancer, particularly in differentiated thyroid cancer, that tends to be once a patient is deemed not curable by either surgery or radioactive iodine alone.

What are the commonly found NTRK gene fusions, and what disease or prognostic characteristics do you see with NTRK1-rearranged carcinoma vs NTRK2 or NTRK3?

We don't really discriminate that much between them. Mostly, patients who have NTRK fusions will have either 1 or 3, and there are a few that have NTRK2. All of them result in upregulation of the NTRK domain, the active domain. As a result, those patients are all eligible for treatment with and NTRK inhibitors. What is true is that there are certain ones that we find more commonly in different cancers. I would say NTRK3 ETB6 is one of the most common that we see in papillary thyroid cancer, but there are other binding partners and they have been seen. Most importantly, you just want to have a test that will be very comprehensive and checking for NTRK fusions in all 3.

I'll point out that while we don't see a lot of NTRK fusions in medullary thyroid cancer, they have been reported. Even when we're doing in medullary thyroid cancer, we would still do a full point mutation and gene fusion panel.

Since NTRK is not as common in thyroid cancer as a biomarker like BRAF V600E, do you find these tumors difficult to treat. Why or why not?

In general, they are less common than BRAF, but they can be anywhere from 10% to 20%. If someone was a pediatrician, and were looking at papillary thyroid cancer in kids say up to 10 years old, you would probably find NTRK gene fusion 60% of the time, or maybe even higher, then the other ones would probably have RET fusions.

It really depends a little bit on the age group, but NTRK gene fusion can be even more common than BRAF. So that's number one, when it’s a younger person, I definitely will be checking it from that perspective. But interestingly, if they're RAI-refractory, they still might be up to 10% or even 15% or 20%, which is not a nothing number. If you treat a lot of thyroid cancer, you'll find them frequently. Again, it’s not as frequent as BRAF, but you do find them.

If you do find them, it is good news for the patient because those patients will tend to do much better. They'll have an opportunity to have an agent that will be much more successful. We do have agents that will target BRAF tumors, but I will say that the response rate significantly lower. If I were to rate them hierarchically, the agents for papillary thyroid cancer, the first is TRK inhibitors, then RET inhibitors for those people who have RET fusions or TRK fusions. The next is lenvatinib [Lenvima], which has a response rate in the 60s and then following that is something like vemurafenib [Zelboraf] or dabrafenib [Tafinlar], both of which have response rates of about 30%.

Can you discuss the targeted therapies that have shown the most promise for the treatment of TRK fusion-positive thyroid cancer?

The 2 agents that are the most positive in TRK fusion positive cancers are larotrectinib and entrectinib. In lung cancer, when you're treating TRK fusions, they can be kind of similar as far as the response rates in the high 60% to 70%. In papillary thyroid cancer, there seems to be a little bit of more of a difference. With larotrectinib, the response rate is in the 80s for papillary thyroid cancer, whereas for entrectinib, it is in the 60s.

For papillary thyroid cancer, I do think that larotrectinib appears to be the better or more active agent, as far as response rates go. Patients also do very well with progression-free survival. We're looking at 3 to 4 years at this point. Many of the overall survival numbers haven't even been reached. There has been updated data, because we keep on updating it, and we continue to see significantly long durations of response with larotrectinib and entrectinib. Both seem to be active in patients who've had CNS metastasis. In both of the trials, most of the CNS metastases have been treated prior to the therapy, but these were not negative markers.

For instance, if somebody had a CNS metastasis, they seem to do very well with these agents just as much as if they didn't have a CNS metastasis. Both of these agents were very active, but in papillary thyroid cancer, I think larotrectinib has a little bit of an edge over and entrectinib based on the most updated numbers. They've had updates even as recently as ASCO 2022.

Can you discuss some of the data presented at ASCO 2022?

At ASCO 2022, we had updated datasets, which basically had some of the data cuts going all the way through 2021. With that, we've seen continued prolonged responses to both larotrectinib and entrectinib. As I pointed out, the papillary thyroid cancer subset has shown that it's probably around 86% responsive for larotrectinib and in the 66% to 69% range for entrectinib.

Both of these agents have had pretty good tolerability. The adverse event profiles were also updated and for the most part they are comparable. It should be known that entrectinib as a little bit less specific for NTRK. It was developed as a ROS1 inhibitor. Probably because of the additional targets within entrectinib, ROS1 and ALK, it tends to also lead to more side effects. Maybe that's part of the reason why larotrectinib is getting better efficacy, because it has fewer side effects and safety can be maintained at a higher dose.

With the other drugs, you're seeing a little bit more neutropenia, there's a little bit more other inhibition of say JAK1, and that can cause suppression of the bone marrow. There's a little bit more neutropenia and other side effects with entrectinib, whereas with larotrectinib, the main side effects are going to be things like dizziness, and weight gain. But what's significant about these drugs is the lack of grade 3 and grade 4 toxicities in general. Overall, compared to say, the multikinase inhibitors like lenvatinib, we are seeing significantly less adverse events and therefore patients tolerate larotrectinib well.

Remembering that lenvatinib’s response rate is in the 60% to 63% range, and larotrectinib is 86%, we really have justification for moving that ahead of what has been sort of the first-line preferred, 1 of the 2 first-line preferred therapies, by the NCCN guidelines. Now we have 4 preferred therapies. We have larotrectinib and entrectinib for TRK fusions, we have selpercatinib [Retevmo] and pralsetinib [Gavreto] RET fusion, and we have lenvatinib and sorafenib [Gleevec] for non-fusion cancer in the frontline setting.

What has recent research taught us about managing TRK fusion-positive thyroid cancer?

The one thing I think that we all need to be on the lookout for is for any patient who has RAI-refractory disease, I would say we now have a new standard of care, which is to do RNA-based next-generation sequencing. We get all of the gene fusions and then we actually get this result prior to starting systemic therapy. Prior to the data on larotrectinib and entrectinib, and it was okay to start with lenvatinib and then find out later if someone had a BRAF mutation, for the reasons that BRAF mutation efficacy was lower. It was fine to start with a multikinase inhibitor like lenvatinib with a response rate of 60% and then move to the BRAF inhibitor in the second- or third-line.

At this point, I think we have justification for moving the NGS testing upfront. I think that also means that we need our endocrinal colleagues to be sending the patients to us a little earlier and not holding on to them until the patients have either very bulky disease or symptoms. It's important for them to identify these patients at the time of RAI-refractory or non-avid disease, and refer them to an oncologist who knows how to treat thyroid cancer so that they can do the proper workup and education for these therapies.

What new strategies are being explored for TRK fusion-positive thyroid cancers?

I think that at this point, what's interesting is that I don't think we're going to have additional trials that are going to say to us, we should put this in first-, second-, or third-line. Both larotrectinib and entrectinib previously have achieved a tumor agnostic indication, meaning that they are indicated anytime that you have a gene fusion, and thyroid cancer again, we wouldn't treat people who are not otherwise curable. If somebody is being cured, there's no need to be testing or even treating. But in the case of patients who have RAI-refractory disease, that's progressing, we would be moving this upfront. This is based more on clinical data and experience than it's ever going to be on actual data, because we probably will never get a head-to-head trial.

There is a trial ongoing at Children's Hospital of Philadelphia, looking at whether or not giving larotrectinib might also help with radioactive iodine uptake, and therefore help patients to have full cures with radioactive iodine. That's in development. It's not clear if it's going to be additive because already surgery radioactive iodine is curative in the vast majority of cases. I think it may be hard to prove that adding larotrectinib is going to improve on that, but we'll hopefully get some information about that in the next few years.

As research continues for NTRK fusions in general and for TRK fusion-positive thyroid cancer, what clinical questions to you hope to see answered?

I hope that we get to know how long these drugs work. I think that it's nice to be able to tell patient, you are going to get 5 years from this drug. Until now, we really haven't been able to say that with any other drugs.

It will also be important for us to follow every single patient that has resistance, because these are the kinds of drugs that many times will have a single point mutation as resistance. As we've seen with Gleevec [Imatinib], and all these other targeted therapies, many times if we can identify the resistant mutations, and there are second-generation agents that target the resistance mutations, we have the opportunity then to extend efficacy for even longer periods of time. We can also pinpoint the well-tolerated agents.

_REFERENCES:

_{1. Pekova B, SykorovaV, Mastiknova K, et al. NTRK fusion genes in thyroid carcinomas: clinicopathological characteristics and their impacts on prognosis. Cancers (Basel). 2021;13(8):1932. Published online April 16, 2021. doi: 10.3390/cancers13081932}

_{2. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA.gov. November 26, 2018. Accessed July 11, 2022. https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions}

_{3. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. FDA.gov. August 15, 2019. Accessed July 11, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc}