EP. 3B: Factors Affecting Therapeutic Selection for NTRK Fusion-positive Thyroid Cancer

In this Precision Medicine Perspectives series, “Advancements in the Treatment of NTRK Fusion-positive Cancers,” experts share insights into the evolving treatment landscape for NTRK fusion-positive cancers by surveilling key advancements in the field, reflecting on areas of unmet need and highlighting potential improvements on the horizon.

For patients with NTRK fusion-positive solid tumors, there are currently 2 United States Food and Drug Administration (FDA)-approved agents available, larotrectinib and entrectinib. Larotrectinib’s 2018 approval was supported by key findings from the LOXO-TRK-14001 (NCT02122913), NAVIGATE (NCT02576431) and SCOUT (NCT02637687) clinical trials. In 2019, entrectinib was approved for patients with NTRK fusions following the ALKA-372-001 (EudraCT 2012–000148–88), STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267) clinical trials.

In the interview ahead, Marcia Brose, MD, PhD, from the Sidney Kimmel Cancer Center – Jefferson Health comments on the current treatment landscape for NTRK fusion-positive cancers and emphasizes key considerations affecting treatment decision-making.

Targeted Oncology™: What methods are currently available for the detection of NTRK fusions, and what are the advantages and limitations associated with each method?

BROSE: There are currently many ways to detect NTRK fusions, but only a couple that we would use. There are ways to detect NTRK fusion cancers by using standard immunohistochemistry; however, they do not work very well. We do not have a standardized scoring system, and in a way, it requires that we would have a high expectation that TRK would be positive. It's not generally a good way to screen a large number of tumors. We use instead the best testing method: RNA-based next-generation sequencing. The benefit of this approach is that if we're looking for either point mutations or gene fusions, we're likely to find them no matter what the gene involved is and with one test we can uncover multiple different possible targets. The limitation is that we tend to need a good high-quality sample. That means that, if it's in paraffin, it should be no more than about 2 years old, or sometimes we just need to send a fresh biopsy sample.

Targeted Oncology™: What does the current treatment landscape look like for NTRK fusion-positive thyroid cancer? How do you approach therapy selection among the currently available treatments?

BROSE: Patients who have NTRK fusion-positive cancer have a couple of treatment options. They have 2 treatment options that target TRK selectively. The first of these is called larotrectinib, and the second that was approved is called entrectinib. These are both highly selective TRK inhibitors. The second way we can target all thyroid cancers, regardless of their genotype, is to use lenvatinib, sorafenib, or cabozantinib, which was the most recently approved. Right now, the treatment landscape includes 5 different agents.

When I have a patient who has an NTRK fusion cancer, I will normally pick an NTRK fusion-targeted agent first: a selective TRK inhibitor. This means that I'll usually have the option of picking either larotrectinib or entrectinib. In my experience, for thyroid cancer, the responses were a little higher in the studies with larotrectinib than the studies that included entrectinib. For that reason, I tend to pick larotrectinib as my go-to for NTRK fusion thyroid cancer. In addition to the highly selective inhibitors, remember that those patients would still be eligible for the lenvatinib, sorafenib, or cabozantinib because the multikinase inhibitors are good for all types of cancer, including NTRK fusion cancers.

Targeted Oncology™: Are there any clinical considerations that should be made prior to treatment selection? Are there certain thyroid tumor types or clinical scenarios in which a particular TRK inhibitor may be more advantageous than another?

BROSE: We tend to always think about the patient first when we're picking what treatment options we're going to provide. We have to consider what are the patient’s comorbidities. Do they have issues with high blood pressure? Do they have issues where they're extra thin? All of these kinase inhibitors can have adverse effects (AEs) of different kinds. The one thing I'll say is that when we pick a selective TRK inhibitor, we have the benefit of usually a very tolerable agent that usually goes pretty well with most comorbidities. The reason I say that is that all of the multikinase inhibitors tend to cause side effects such as increasing blood pressure. For that reason, a patient who has extremely high blood pressure that's hard to control would not be as good a candidate for a multikinase inhibitor. If they had the option to be on a TRK inhibitor, I would always choose that. That's why we always consider what the clinical situation is that we're facing.

However, I will say that when I look at the number of grade 3 and grade 4 AEs that were seen in the clinical trials, there were far fewer of these in patients who had TRK inhibitors. For that reason, again, if somebody is eligible for a TRK inhibitor, meaning they have an NTRK fusion cancer, I will always offer a TRK inhibitor as my first line of therapy because my patients will get as good or better response with less toxicity.

Right now, there are 2 FDA-approved TRK inhibitors. One is larotrectinib, and the other is entrectinib. In thyroid cancer, the numbers for larotrectinib were a little bit superior when it comes to response rates. It also was a very well-tolerated drug because of its specificity. It's a little bit more specific for TRK A, B, and C. For that reason, for thyroid cancers, I would always pick larotrectinib over entrectinib. In other cancers, they tend to be a little bit more equal, so because I know of larotrectinib, I tend to continue picking larotrectinib at this point. We do have other options. Of course, if somebody had some sort of a reaction to larotrectinib, entrectinib would always be something that we could try to see if they were able to tolerate that instead.

Targeted Oncology™: What are the most concerning AEs associated with treatment with TRK inhibitors, and how do you currently approach management of these AEs?

BROSE: The main AE that I have to deal with for larotrectinib is dizziness, and that can sometimes limit the dose I can provide. If a patient is on the normal starting dose of 100 mg twice daily, and they have severe dizziness, I have had to, on occasion, decrease their dose to 75 mg twice daily. Happily, they still did very well, and have responded and continue to respond to this day.

I have occasionally had issues with patients developing a generalized muscle achiness that can often happen as they get closer to their next dose. I suspect that this may have something to do with the levels of the TRK inhibitor in their bloodstream, and maybe when it goes lower, it's creating this effect.

Whatever the reason is, that can be a little bit difficult for me to treat. Again, I play a little bit with those patients with exactly what time I do the dosing. Sometimes moving up the next dose can help a little bit with that discomfort, or I might try a lower dose as well.

Interestingly, for the most part, the vast majority of the AEs were what we call grade 1 and grade 2, meaning these are usually very manageable. There are extremely few grade 3 or grade 4 AEs that are either clinically significant or life-threatening. The good news is that these are things that I can deal with and very rarely have I ever had to stop the drug because of them.

Targeted Oncology™: What is the biggest area of unmet need in NTRK fusion thyroid cancers?

BROSE: I love the idea that we have a question that says, “What is the unmet need for an NTRK fusion thyroid cancer?” What's amazing is that this is even a question because this is such a rare disease that historically we would've said because there are no therapies whatsoever. You've just asked me what the unmet need is of a rare subpopulation of many cancers that until recently we had no therapies for. We didn't even understand how NTRK fusion cancers across the spectrum, whether it's in lung cancer or gynecologic cancers, could all respond so well to these TRK inhibitors. It's amazing because now that we have these TRK inhibitors, some of these patients will now do well for years. It's a really wonderful time, for this rare group of cancers.

That said, the drug itself will work for quite a long time, but we will still need to understand how we can improve those AEs, especially the dizziness and the muscle aches, because they're not ones that I have a direct, good answer for on how to manage them other than dropping the dose. The other thing is that some of our patients now are getting complete responses. This leads to the question: how do we know whether they have to stay on the drug forever? Or maybe after 5 years, would they be able to have a drug holiday? We need to know more about these patients, especially what happens as they get out longer and longer from the time they start.

Finally, what's an unmet need in every cancer case where a treatment is not curative, is that we need to understand what to do if the drug stops working. We already know that there's a certain mutation that's associated many times with resistance to larotrectinib or entrectinib. Now there are already second-generation TRK inhibitors that are in clinical trials. I'll be looking forward to hearing what the outcome was of these trials. Did they work better? Did they provide additional long periods of response for our patients? We have patients literally who were referred to me with only 3 months to live and now it's 5 or 6 years later, which is a miracle in itself, but not all patients do so well so we can't stop there. We still need to know more and I'm looking forward to the next era for NTRK fusion cancers.