Updates on Biomarker-Directed Therapy for Solid Tumors: Focus on NTRK, RET, and NRG-1 - Episode 6

NRTK Fusions in Oncology 

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Dr Lori Wirth describes the importance and implications of testing for NRTK fusions in patients with solid tumors.

Mark Socinski, MD: Let’s transition to a different topic. We are going to focus on NRTK-directed therapy and talk a little about it. I am going to ask Lori to give us just a brief overview of what we know about NRTK therapy and cancer. We alluded to this issue of fusions and point mutations and so on. Then I’ll ask the group how often we see this and so on. Lori, your thoughts?

Lori Wirth, MD: We have talked a little about the difference between fusions and point mutations. We do see oncogenic fusions involving NRTK1 and NRTK3. This is less commonly seen in NRTK2 with multiple prime fusion partners across different solid tumors, even in hematologic malignancies. It is that fusion with the 5 prime fusion partners that is often a homodimerization domain, like a coil domain, that leads to the expression and activation of the kinase. NRTK would not be expressed in normal lung tissue, so if there is a point mutation, it is not going to be expressed or active outside the setting of those oncogenic fusions. It is the fusion that is really the mechanism that leads to the carcinogenesis with NRTK.

The other thing to think about—the basic biology of it, which is what we’ve mentioned a bunch of times—is that there are multiple 5 prime fusion partners. The more we look, the more we find. In addition to RNA-based assays, if an assay is used that is agnostic to the 5 prime fusion partners, then you are going to happen upon fusion partners that probably are driver-fusion partners that have not been described in rare cases. Across solid tumors, NRTK fusions are pretty uncommon. There are a few diagnoses. We’ve talked about a few of them already that are enriched for NRTK fusions, like infantile sarcomas. Then there is head and neck cancer.

Things that occur above the clavicle are poster children for NRTK -fusion cancer in adult solid tumors. Secret carcinomas that are salivary gland cancers almost invariably harbor ETV6-NRTK3 fusions. Then we also mentioned the papillary thyroid cancer, poorly differentiated thyroid cancer, and even anaplastic thyroid cancer can harbor NRTK fusions. In larotrectinib testing, for example, if you lump together all the adult patients who were enrolled, the most frequent adult patient population had tumors above the clavicles.

Mark Socinski, MD: Fusion partners are certainly important in testing, as you mentioned, but is there any evidence that the fusion partner makes a difference from a clinical outcome point of view?

Lori Wirth, MD: I am glad you raised that. As far as I know, no. We’ve seen that with NRTK and with RET. I can’t really speak to the ALK and ROS1 experience in lung cancer so much, but one would think that the 5 prime fusion partners would matter more than it seems to matter. The kinase that gets activated by that fusion, and that probably explains why. Generally, that kinase will be wild type, at least early on before acquired resistance develops.

Mark Socinski, MD: Jonathan, you live in a world with more frequent NRTK fusions. What are your comments about how common they are in your discipline?

Jonathan Trent, MD, PhD: We do see them, but even in sarcoma these are rare entities. This is estimated to occur in less than 1% of all our sarcoma patients. However, there was a poster presentation at CTOS [Connective Tissue Oncology Society Annual Meeting] a couple of years ago that showed that, in subsets of spindle cell or unclassified pleomorphic sarcoma, the incidents could be as high as 6%. We do see it, but it is still rare. I agree with Lori completely on the fusion partners. We have a lot to learn in that space.

Mark Socinski, MD: My lung cancer colleagues, can you offer commentary on how common they are? Jyoti, have you seen 1 in lung cancer?

Jyoti Patel, MD, FASCO: Yes, actually. I have seen several, but it is uncommon. They are found in 1% of patients. It is an enriched patient population. They tend to be people who have never smoked. They tend to be a little younger. Lung cancer is common. If it is less than 1%, you are still seeing almost 2000 patients a year who could potentially have an NRTK fusion. Histologically, there are also variants. I just took care of a patient recently who had 1 with more neuroendocrine differentiation. Others I’ve seen tend to be a little more adeno or adeno with a fair bit of mucin. It stands to bear that you do not know the results based on histology unless you test.

Mark Socinski, MD: Ben?

Benjamin Levy, MD: We have seen 1, but the identification of this is a reflection of how bad our testing was internally at Hopkins [Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University]. We were not routinely testing for NRTK fusions until about a year ago with an RNA-based platform. We probably missed a few. For a lot of those patients who have never smoked, if they have tissue left over, we’ll send it to a commercially available RNA-based platform to protect these. They are uncommon, but that does not mean they should not be tested, so my experience has been limited to 1 patient.

Mark Socinski, MD: Can I crystalize the feeling of the panel and say that everyone agrees that testing for NRTK fusions should be part of your comprehensive panel across tumors? These do happen across a wide range of tumors, even though it is very uncommon or rare in some circumstances. Would we all agree with that statement? Any dissenters?

Lori Wirth, MD: I certainly agree, and that is the beauty of these panels: We are doing it to find not just the 1% or 2% of patients with lung cancer who harbor NRTK fusions, but we are looking for the other uncommon fusions as well. Even if this testing was just for identifying that 1% or 2% of patients with lung cancer, for those patients it makes a really big difference. It is 1 of the challenges we have: wrapping our heads around testing all patients for these rare entities and the expense involved. If we had cost-benefit analysis, we would see that the treatment options that are unveiled for that smaller percentage of patients makes such a large difference in their therapy that, in the end, the cost-benefit analysis would end up being favorable.

Jyoti Patel, MD, FASCO: To add to what Lori is saying, it is not a zero sum game. It is not to get NRTK or RET. You get both with NGS [next-generation sequencing], so it truly is offering a broad number of options to our patients with full testing.

Mark Socinski, MD: It is like going fishing with a big net, right? You want to catch everything you possibly can.