Driver Mutations in NTRK Fusion-Positive Cancers

John L. Marshall, MD: Dr Pant, I want you to take us through this issue of when more than 1 target is found. As we talked about this, this is more common in the GI [gastrointestinal] cancer space. But how do you prioritize this? I'll be very interested to get some feedback from our lung cancer colleagues after your comments. How do you decide when you hit the gold mine, and you have a bunch of different targets to play with?

Shubham Pant, MD: First, I wanted to add onto Tony's comment about when we are looking at somatic mutations. My patients say, “Of all these mutations, why can't you target it? I've got this thing called KRAS, so why can't you target it?”

Some of them are drivers, but then you get on these NGS [next-generation sequencing] reports, and you get a whole host of passenger mutations, which are not the driver mutations. That's exactly how I explain it to my patients. You have the driver and you have the passengers. If you take out the passengers, that's not going to stop the bus. That's one of the ways to look at how to interpret these NGS reports because we get a lot of referrals about NTRK mutations and everything in the early days of NTRK inhibitors when we had it in clinical trials.

We used to get all these NTRK mutations, and there was nothing we could do about it. Some of the folks used to send us patients who were upset about it because the physician had talked it up on their 1 patient who had an NTRK fusion who got a great response.

Coming back specifically to NTRK fusions, when staining studies have been done in pathology, about 25% of patients could be PD-L1 positive with NTRK fusions, and a smaller amount with MSI [microsatellite instability] or MSI-high. I think the NTRK fusion is such an oncogenic driver. I've seen in the early days some patients with sarcoma, who couldn't get out of bed with a PS [performance status] of 3. If you give them this NTRK inhibitor, the PS improves. It's fairly dramatic, there’s a difference in a couple of weeks, and I think Mark said this before. The PS improves for these patients, and they are dramatically improved. I think it just depends on the response patients get.

I have a patient who still comes to me from New Jersey, one of the first patients that I put on one of the NTRK inhibitors and had multiple lung lesions. The lesions disappeared, they just melted away like magic. This has been sustained now for 3+ years. I think in this context of NTRK fusions, behind the NTRK fusion, I'm going to go after it first with an NTRK inhibitor, because I think it's a very powerful oncogenic driver.

John L. Marshall, MD: If you had both MSI and an NTRK fusion, you would treat the NTRK first?

Shubham Pant, MD: NTRK fusion first, with an NTRK inhibitor first, yes.

John L. Marshall, MD: All right. Any of the lung cancer specialists want to chime in? Do you guys ever see multiple targets at the same time? Mark?

Mark A. Socinski, MD: It's very uncommon to rare. In the original lung cancer mutation consortium study that had about 800 adenocarcinomas in it, I believe it was 2% or 3% that had more than 1 mutation. Most of the co-mutations were more of PI3-kinase, BRAF, and so forth that at the time were not particularly targetable. So it's not a common occurrence in lung cancer.

Jyoti D. Patel, MD: Although, that definitely changes after treatment. It's an acquired resistance that develops. That's really where these co-mutations now have become more interesting, right, as we're starting to develop trials around them, but not at diagnosis.

Mark A. Socinski, MD: Yes. My comments were restricted to the patients with driver mutations. Shub made this point, that you start looking at the average patient with lung cancer who has a 50-pack-year history of smoking, you send off to somewhere like Foundation Medicine for genomic testing, and 14 different alterations come back. It's a lot of noise on the report. Everyone doesn't know how to interpret it. At the end of the day you find a lot of mutations, I guess you'd call those co-mutations and such, but we just don't know what to do with it. It's like a genomic mess, so to speak. But in the driver populations, you tend to see the 1 driver that dominates.

Luis E. Raez, MD: I think it’s important because we're learning, as you said at the beginning, but I think until now we're assuming there is only 1 driver. That is why, for example in the lung community, if I remember, there is only a very small number of patients in Japan. They tested more than 3000 people, and it's a very small cohort of patients who may have ALK and EGFR at the same time. I think the researchers want to give more drugs…but until now we are assuming there is 1 driver. When there is resistance, the driver may switch to another driver, but it's always 1.

John L. Marshall, MD: John, I want to add in there that my colleagues and I, in the phase 1 unit at MD Anderson Cancer Center, have treated a number of these patients with sarcoma, secretory cancers, or some others such as one of the rare tumors, or the common ones. But as I said, the response is so dramatic with NTRK inhibitors when you have the NTRK fusion. You see the tumor change and the patients’ PS is dramatically improved. If you inhibit that, it's really powerful.

Transcript edited for clarity.