TRK Inhibitor in GI Cancers: Adverse Effect Profile

John L. Marshall, MD:Tony, our friend Jordan Berlin published some work at ASCO GI [American Society of Clinical Oncology/The Gastrointestinal Cancers Symposium] or has an abstract for this ASCO about TRK fusions in GI [gastrointestinal] cancers. Have you had a chance to take a peek at that, or have any sense of what that’s going to show?

Tanios S. Bekaii-Saab, MD, FACP:I think it was presented at ASCO GI. There may be an update coming at ASCO [American Society for Clinical Oncology Annual Meeting] 2020 as well. There were very few patients with GI cancers, primarily colorectal cancer. There were a couple of cholangiocarcinoma, pancreas, and appendix cases. I think there was 1 liver, as well. Overall, what was seen in the general population both in terms of efficacy as well as toxicity data were some remarkable responses.

You see some durable responses, again, very similar. The median overall survival was around 2.5 years or so. But with a small sample size it’s very difficult to have a very heterogenous group and a very small subgroup of patients. It’s very difficult to say whether it’s standard, individually, for the different tumors. Those patients respond, and they respond deep. The responses tend to be durable.

I think that’s the main message. So when you separate the gastrointestinal cancers from the overall group, you still see about the same. It is possible that there is a differential response, if you have salivary gland or maybe a lung cancer, or perhaps a less pretreated tumor, that you may actually see a deeper and more prolonged response. Of course, I think for the experience, as Luis put it, it’s too early to tell at this point of time whether there may be variations dependent on the site of origin.

But overall, I think for the GI cancers, we’re seeing very similar trends in terms of the responses, the durability, and their depth.

John L. Marshall, MD:Mark, maybe let’s drill down on the all-important toxicity. We really haven’t focused on that at all. I think you mentioned earlier in the program about some of the specific toxicities. Can you give us a high-level look? Then I’ll ask others to chime in about toxicity.

Mark A. Socinski, MD: With these very targeted agents, we’re all getting used to looking at the grade 3 or 4 columns with the 0s or 1s, which is great. When you look at this particular agent, actually the most common toxicity—all of which was grade 3 or less—was an alteration in either ALT [alanine aminotransferase] or AST [aspartate aminotransferase], with most of them being grade 1, to be honest. Fatigue, some GI toxicities, as well as dizziness, are common. But surprisingly there can also be some anemia, so some myelosuppression there.

Other GI toxicities include diarrhea, which we can see with many of the TKIs [tyrosine kinase inhibitors]. There can also be a low rate of fever, or some arthralgias. Weight gain was another one that stood out to me, as well as headache. But again, if you start to look at the grade 3 or 4 columns, it’s very uncommon to be either severe or life-threatening. Most of these end up in the grade 1 column and are manageable.

John L. Marshall, MD:The one I come back to all the time is neurotoxicity, and I think you mentioned that as well. When you think about chronic therapy, cumulative toxicities, have others experienced patients with the neurotoxicity or have any issues that you think should be brought out during this discussion?

Shubham Pant, MD: Normally, just as Mark said, these patients tolerate this drug well, even with chronic therapy. They’re not like some of the other drugs that, when you go to chronic therapy, grade 2 diarrhea is not grade 2 diarrhea. If you’re getting consistent grade 2 diarrhea, that’s not good—that’s impeding the quality of life. Grade 2 fatigue is impeding of quality of life. It’s pretty bad.

So what I’m saying is we’re trying to really look at these chronic toxicities, but as far as it comes to these drugs, in my experience they have been mostly fairly mild. So for toxicity, just as Mark said, there can be some fatigue. But normally for even the chronic therapy patients, they have done fairly well.

Some diarrhea has been easily controlled. The neurotoxicities are very interesting. It’s actually dizziness. In most of the studies we’ve done a neuro exam and everything, but that’s what we see. It’s more a loss of balance than the classic neuropathy. Some patients do experience dizziness, and it could be sometimes bad enough that they might need to use something to walk, such as a cane or something, especially if they’re older.

Transcript edited for clarity.

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