Challenges for TRK Fusion–Targeting Agents

John L. Marshall, MD: Let’s wrap up our whole discussion. What a great discussion, and everything that you all have brought to this will be valuable to all who listen in. Tony, give me a sense of what you think are the challenges going forward for TRK fusion–targeting agents.

Tanios S. Bekaii-Saab, MD, FACP: The biggest challenge is the obvious. These are rare, incredibly rare, and the rarity becomes even more problematic when you’re not consistent in looking for them. This means for something that’s 1 in 100 or 1 in 1000, if you just randomly pick every other patient that comes to your clinic and send for testing, then you are 1 in 100,000 just by randomness alone.

One thing we have to keep in mind is that if you a have a fusion, you’re going to have a great response, for a patient who may not do as well on chemotherapy. For some patients, this is 1 of the longest reported responses so far. There are many that are ongoing. It is now almost 4 years. We know that if patients respond, they can respond pretty well. So we want to find them.

This is the same thing with MSI [microsatellite instability] high and the same thing, frankly, with a lot of these alterations that are at the level of 1% or 2%. We have to be consistent. We have to look for them consistently—that’s the biggest challenge.

Luis was talking about how these next-generation agents that are looking, essentially, at patients who fail because of the development of the mutation. Now we’re looking at even a smaller subgroup of patients and how to salvage them and make a difference in those patients. That also brings the question of those who are intrinsically resistant because they have the core mutation, and how do we actually put all these together? Frankly, it’s not just multidisciplinary collaboration, it’s also multispecialty collaboration.

We can’t do it in the GI [gastrointestinal] space or in just the lung or saliva. So how do we bring everyone together to essentially work on this? That’s 1 of the challenges. The other challenge is, of course, testing.

We heard a little about IHC [immunohistochemistry], FISH [fluorescence in situ hybridization], RNA for fusions. DNA-based testing is problematic because it may miss 25% or 30%, and we know that the most commonly used 1 in clinic is actually DNA-based genomic testing. You’re missing on some of these patients—30% of a very small percentage is problematic, so the DNA-RNA hybrid assay is probably the best, but at the same time it’s the most costly and takes a long time.

IHC and FISH are useful, but again, how many patients are you going to test for IHC and FISH to find 1 patient? They’re not costly. IHC is highly sensitive and specific and requires 1 unstained slide, but you’re wasting a slide, and you may be wasting time when you need to find a lot of other alterations.

If we can find a better way to do this DNA-RNA, have sequencing more efficient or faster so we can give the answer to our patients, and rely more on these liquid-based biopsies to find them better, that would actually be the best bet to continue to move these things forward and eliminate some of these barriers that are prohibiting us from finding these patients, because they do better.

John L. Marshall, MD: Jyoti, maybe you could comment for me. I hear so many comments from community oncologists and the like who are frustrated by the concept of raw molecular profiling, and they’re like, “I never find anything.” They get tired of looking because they don’t see much value in it. What’s your counsel to somebody who’s having that feeling?

Jyoti D. Patel, MD: Sure. These drugs and these targets certainly feel like unicorns, but if you don’t look, you’ll never find them. They radically change the outcome for these patients, their ability to get back to life, the improvements in performance status, and the rapid diminution of symptoms. It’s really remarkable.

Certainly just at the beginning of this COVID-19 [coronavirus disease 2019] crisis, we believe we just had a patient with what looked like horrific disease, and we found out she had an NTRK fusion before we all went in to hunker down. The entire team was ecstatic and so happy for her. She’s already feeling a lot better.

The point is, even if it’s 1% in common cancers, that adds up to a lot of people every year. These uncommon cancers in which the fusions are pathognomonic, certainly that’s easy, that’s knee-jerk. But taking the time to individualize for each patient, developing the right plan, takes discipline, as you mentioned, but it also takes moving away from what we think a patient with an NTRK fusion should look like. It can occur sporadically in anyone with colon cancer, pancreatic cancer, or lung cancer. You just need to look.

As the cost of testing goes down, that barrier is changing. The ability for us to look across multiple fusions and multiple mutations is now backed by better and better evidence. Again, that barrier should be less, and we should really push our systems to make that cleaner, to rely on less tissue, and to get answers faster for our patients.

John L. Marshall, MD: Yeah, and I know this whole wave of precision medicine has got it to where most insurance is covering these tests with CMS [Centers for Medicare & Medicaid Services] support. I think about how many Chem-20 tests and how many screening CT [computed tomography] scans I’ve done over my career where I got nothing back. It’s normal, or it’s negative, yet that hasn’t slowed me down from ordering those Chem-20s and the CT scans. I wonder if that’s the way we should be thinking about this.

Shubham, why don’t you give us your thoughts on this issue of testing and impact on patients?

Shubham Pant, MD: As Tony and Jyoti said, if we don’t test them, we won’t find them. So testing is important, especially where you can really find it. Right now, at least for these fusions, you really want to find these fusions, otherwise you might miss them. You might get false negatives. So RNA-Seq is a very important factor in this. As Tony was saying, we don’t catch all these on DNA or RNA-Seq.

It’s still the missing part that can really make it robust. This is because the sensitivity and specificity of RNA-Seq is far better, and we can really find that. When you’re looking at a needle in the haystack, you want to find that needle; you don’t want to miss it.

The second thing is, once you pick out in these patients, especially with these rare tumors—as I said, the responses and everything are very gratifying, obviously for patients but also for the treating physicians when you see these patients do better for a long period of time.

John L. Marshall, MD: Yeah, and to add to what you just said, RNA-Seq is important. It’s important for you to understand where your test is going, where your sample is going, and that your shop is doing the appropriate testing in support of that. Is that fair enough?

Shubham Pant, MD: Absolutely.

Transcript edited for clarity.