Role of NTRK Inhibitors


John L. Marshall, MD: Hello, and welcome to this OncLive® Peer Exchange® titled “TRK Inhibitors in Lung and GI cancers.” I’m Dr John Marshall from Medstar Georgetown University Hospital, and I’m joined by an amazing faculty. Normally we’re all together, but this time we’re all around the United States, and they’re joining me today on this virtual discussion. First, Dr Tanios Bekaii-Saab, Tony Saab, from the Mayo Clinic. Dr Shubham Pant from The University of Texas MD Anderson Cancer Center.

Shubham Pant, MD: Thank you for having me.

John L. Marshall, MD: Dr Jyoti Patel from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, welcome.

Jyoti D. Patel, MD: Thank you.

John L. Marshall, MD: Dr Luis E. Raez from Memorial Healthcare System.

Luis E. Raez, MD: Thank you for having me.

John L. Marshall, MD: And Dr Mark Socinski from AdventHealth Cancer Institution. Mark, welcome.

Mark A. Socinski, MD: Thanks, John.

John L. Marshall, MD: Today we’re going to discuss a number of topics pertaining to the use of TRK inhibitors in lung and GI [gastrointestinal] cancers. Let’s get started. Jyoti, Dr Patel, we’re going to start with you. If you could set the stage for us, what is a TRK inhibitor? And specifically for you, what is neurotrophic tropomyosin receptor kinase [NTRK] inhibitor? What are they, and what are they all about?

Jyoti D. Patel, MD: It’s a mouthful, but this is a class of transmembrane proteins that have been found to be oncogenic drivers. These genes are fusion events that are quite rare but across a wide variety of tumors. When we detect these, we find that they are the sentinel event for a tumor to become cancerous and to really grow. What’s exciting about this is it’s a bona fide target for cancer therapy across a multitude of tumors.

John L. Marshall, MD: I think it’s also fascinating biology about these cell receptors and the discovery of these receptors from another field to turn this into a cancer target. Dr Pant, talk a little about that whole biology and what we as oncologists were forced to learn as we have been discovering this new therapy. Take us through that a bit.

Shubham Pant, MD: The TRK inhibitors—the TRKs—of course play a pivotal role in the physiology development and function of the peripheral and the central nervous system. That’s 1 of the main roles, physiological roles in the human body. We have 3 NTRK genes—NTRK1, NTRK2, and NTRK3—and they give rise to the proteins, which are TRKA, TRKB, and TRKC. Essentially most of the ones we see are fusions in NTRK1, NTRK2, and NTRK3 genes, which lead to this activated protein kinase of TRKA, TRKB, and TRKC.

That’s the oncogenic driver for the growth of the tumors, and as Dr Patel said, there are different tumors. Some are rare like infantile fibrosarcoma, typically breast cancer, which we can talk about later. That’s common with rare tumors and the common tumors where it’s more rare. That’s how we’re seeing it currently.

John L. Marshall, MD: That’s a clever way to put it. There are receptor tyrosine kinases in some way. They’re transmembrane receptors that are ligand dependent in the normal state, and with the fusions that occur that we’re going to talk about, they become independent. It’s a signaling pathway. Tony? Anybody else? Mark, do you want to chime in on your thoughts on the biology of this pathway?

Mark A. Socinski, MD: To me, it’s fascinating when you think about the role that these proteins play in the normal state in neurological development. It’s interesting, as we’ll talk about a bit later, to look at the adverse effects profile of the drugs. But similar to what we’ve seen in what I think is 1 of the poster children of genomic tumor, lung adenocarcinoma, a number of these fusions—not only NTRK but things like ALK, ROS1, and RET fusions—and all these things create an oncogenic pathway. And as John said, it’s really a growth pathway.

These are what we used to call “stupid” cancers—they’re very simple from a mutational burden load. It typically is dominated by 1 pathway. These small-molecule drugs that are orally absorbed are highly effective, as we’ll talk about, not only in NTRK fusions but in a number of different fusion situations that we have in solid tumors, with obviously lung cancer having a number of them.

John L. Marshall, MD: Yeah. We have a merger of lung and GI, so we’re going to have to fight it out for above and below the diaphragm for a discussion.

Transcript Edited for Clarity

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