In the second video of the series, Marcia Brose, MD, PhD, from the Sidney Kimmel Cancer Center – Jefferson Health shares key insights into factors affecting treatment decisions for patients with TRK fusion-positive cancers including the consideration of comorbidities and adverse event profiles.
When I have a patient who has a TRK fusion cancer, I will normally pick a TRK 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 TRK 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 TRK fusion cancers.
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 their 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 side effects 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 do things like elevate 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 adverse events 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 a TRK fusion cancer, I will always offer that as my first line of therapy because they tend to get as good or better responses with less toxicity.
The main adverse event that I have to deal with [for] larotrectinib is basically 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 kind of muscle achiness that can happen often as they get closer to their next dose. 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 adverse events were really what we call grade 1 and grade 2, meaning these are usually very manageable. There are extremely few grade 3 or grade 4 [adverse events], which are either clinically significant or life-threatening. The good news is that these are things that I can deal with, and they don't tend to be inhibitory. And very rarely would I ever have to stop the drug because of them.
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. 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, I would say, 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 side effects, 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. Well, that's a good problem to have, but the question we then have is 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 where it's 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 we can't stop there. We still need to know more, and I'm looking forward to the next era for TRK fusion cancers.