Latest Advances in Tumor-Agnostic Strategies for NTRK Fusion-Positive Cancer

Speaker 1 Welcome back to the Oncology Brothers podcast. I'm Rahul Gosain, here as always with my brother and Co host Rohit Gosain as practicing community oncologist. Our goal is to keep you, our fellow community oncologist, up to date with the latest in oncology. Today, we're diving into our key takeaways from a session on Entrek Fusion positive solid malignancies, a topic that we had a chance to moderate during a satellite event of ASCO 2025 organized in partnership with Medscape Global Oncology. Rohit, this is a little different than what we've done in the past. There's no panelists, it's just you and I. So let's get started. Speaker 2 Absolutely, Rahul. Let's do this. So over the next few minutes, let's touch on what we walked away from our panel discussion on entrefusion positive solid malignancies. We had a fun panel representation from US and Europe, Doctor David Hong, a medical oncologist from MD Anderson, Dr. Jerushka Naidu, a thoracic medical oncologist from the Ireland Cancer Center, and Doctor Theodore Lech, a pediatric medical oncologist from Children's Hospital of Philadelphia. We got a decent bit to cover here, ranging from how common ENTREC fusions are, then diving into how to detect them are available treatment options. They're CNS activity and side effects, which is extremely important because of the quality of life. So let's dive right in, Rahul. How prevalent are ENTREC fusions and why should a community on call just even care about them? Speaker 1 Yeah, Rohat. One line around this is they're common in rare tumors and rare in common tumors. Speaker 2 That's a very good way to sum it up, Rahul. Entergy infusions frequency varies quite a bit depending on the cancer type. For example, they're rather very common in mammary analog secretory carcinoma or even an infantile fibrous sarcoma. We see them about 90% of the cases. But when talking about the cancers which a community oncologist see, that is colorectal cancer or lung cancer, we see them about 1 to 3%. Speaker 1 And again, what you want to walk away with is if you've not seen this one yet in your practice, let's make sure we keep looking for these mutations. Rohit. Another take away from Doctor Hong's talk was that comprehensive NGS next gene sequencing is critical because these fusions are scattered across diverse histologies, from sarcomas to thyroid cancers to gliomas. Missing them means we are missing a chance for an highly effective therapy. Speaker 2 Exactly, Rahul, with regards to the topic of NGS, comprehensive NGS testing is in fact the way to go and this was rather stressed by all panelists. That was Doctor Lash, Dr. Hong and Doctor Naidu, where we have to make sure that we are checking DNA along with RNA testing as looking for these fusions in RNA does increase sensitivity and now a lot of commercial partners are already doing that. That is full NGS does include DNA as well as RNA testing. With regards to testing we also touched on AZMO algorithm for Antrex fusion testing which is an IHC test which can be used for screening tool. But again it is tied up to a lot of false positives. So if IHC is +1 needs to make sure you do a confirmatory testing which can be Phish, RTPCR or NGS. Even though this was a little later during our discussion, but important to bring it up now. That is we did a poll around what are the barriers for testing keeping in mind the global community oncology participation, limited access to NGS was mentioned. The overall would expect things to change as NGS platforms are reaching out to the masses and in fact rural settings. Speaker 1 And when we were on the topic of NGS, another thing that came up was these dense reports that we see when it comes to NGS and Rohit, we see this day in, day out in our practice, the concern around making sense once you have that report, we. Speaker 2 See this all day long in our clinical settings. OK, so now we know how to test where the gold standard in fact is targeted RNA based NGS which captures this specific fusion. Rahul, So what are the treatment options available once we know the patient does have this mutation? Speaker 1 Right now we have 2 first generation tract inhibitors, Lerotrectinib and Entrectinib. During our discussion, Doctor Naidu shared real world data from Victoria study comparing Lerotrectinib to standard of care therapies where Lerotrectinib showed significant improvement in overall and progression free survival. And some data continues to support overall response rate close to 75% here. This is very impressive. And then we also had a chance to touch on Entrectonab, which is also an active agent with very similar efficacy profile, showing response rate close to 60%. And Roy, besides these first generation track inhibitors, we touched on the second generation track inhibitors like repotractinib, which is often reserved for times when the disease has progressed or there's resistance to 1st generation track inhibitors. Speaker 2 Right. And this was discussed that all these agents are active, but let's not forget the CNS activity because these type of malignancies have high incidence of CNS involvement, which was yet another big focus during our talk which was covered by Doctor Naidu. We don't have head to head trial comparisons, but we all the track inhibitors that we have in place. But overall when doing cross trial comparison, they're attracted Neb seem to have a little high response rate in the setting. A few things to keep in mind, there are side effects associated with it and of course especially when we are trying to treat these patients with palliative intent. The common one that we see is dizziness or fatigue. Majority of patients did have lower grade side effects, but it is important for us to keep that in mind. Educating patients around these side effects is extremely important so they are aware what to expect. Rahul, this is a good segue to pediatric population which was touched on by Doctor Lesh. Speaker 1 Yeah, Rohit, this one was an eye opener. We had a lot to learn here because both you and I are adult hematologist. Oncologist. Speaker 2 Right, exactly. Especially the example that he brought up was about a six month old. As we all know, that particular kid won't be able to tell us if one is feeling fatigue or dizzy at all. Speaker 1 And also one thing that we don't often worry about in adult population ends up being formulation, but this was a big concern in our Pete's patients. Speaker 2 That's right because in tractinib is available as capsules that can be given as an oral suspension or oral pellets. While on the other hand lyrotrectinib has capsules and oral solution as well. But ribotrectinib at this time does not have pediatric puff formulation available before we close the pediatric aspect. Rahul, anything that I missed out here? Speaker 1 I do want to bring up that during our panel discussion, Doctor Latch touched on his real case of a 7 month old with unresectable soft tissue sarcoma who had limited disease and this patient received tract inhibitor. The patient had good response to that local disease. But an important question here is how long do you keep on these agents for rest of their lives? We're talking about a seven month old being on something forever. Well, clearly that's a long, long time. So from PEDs we do have small data on stopping and re challenging and this strategy in certain cases actually looks very promising. These are again small studies, but SCOUT trials showed close to 70% overall response rate when truck inhibitors were reintroduced after drug holiday. And another small study ADVL trial showed close to 80% overall response rate when patients were rechallenged. This is exactly what was done with doctor Latch's patient family have decided to stop the treatment after a period of time. But then the disease recurred and track inhibitor was restarted and thankfully they did see ongoing response for this patient. Rohat, you mentioned this already. Often treatment here is with palliative intent. For us out in the community, what should we do in our clinical practice if there is progressive disease? Speaker 2 Right, Rahul, these treatments are in fact the palliative intent. So keeping the side effect profile in mind is extremely critical. But also if the disease was to progress as you asked, what to do next. In fact, the next step is rebiopsy and repeating NGS to ensure that we are not missing out on any resistant mutation that can be in fact attacked with a targeted therapy if disease was in fact progressing. In that if one has used the first generation tract inhibitor, then one can consider ripotrectinib and then relying on chemotherapy options if there was a gross progression or rather leaning on radiation colleagues, if there is in fact oligo metastatic progression. Speaker 1 Yes. Another thing to keep in mind or on our radar should be the response rate to immunotherapy. If you have Entraq fusion, it might not be that robust. Not to say I'm not going to use immunotherapy if indicated, it's just that we might not expect a significant response here. Speaker 2 Exactly, and the other important thing that Doctor David Hung mentioned was that entrect fusions are not commonly seen with other commutations either. SO1 doesn't have to worry about tying in with other targeted therapies here. Our job is to ensure we are looking for all alterations and administering the right targeted therapy and then managing side effects, effects that come along with these medications. Over the last few minutes, we have summarized close to 100 slide deck presentation. So, Rahul, before we close, let's do a quick recap for our listeners. Speaker 1 In this episode, we share our takeaways from moderating the INTRAC Fusion Positive Cancer session at a satellite event during ASCO 2025 in partnership with Metscape Global Oncology. Intracfusions are rare and are seen roughly in about 1 to 3% of solid tumors, but they can be enriched in certain cancers that are rare, like memory secretory carcinoma and pediatric liomas. But the important thing here is comprehensive NGS, ideally RNA based, is essential for detection. Speaker 2 To close, our treatment options here include first generation track inhibitors such as lyrotrectinib or atrectinib, which offer dramatic benefits with high world response rate and dramatic improvement in progression free survival and also oral survival in these patients. We now also have second generation agents like repotrectinib as part of our treatment options. All of the agents have robust CNS activity as well. Though the majority of the side effects that these agents cause are low grade, but dizziness and fatigue are the common ones that one experiences. To close, I want to emphasize the importance of comprehensive NGS testing for all our adult and pediatric cancers so that we can continue to look for these rare and track fusion positive solid cancers. Thanks for joining us. Please make sure to check out the full accredited enduring program by Medscape Global Oncology in the link below. We are the oncology brothers.