The Biology of Extending Survival in Advanced CRC - Episode 13

Role of Trifluridine/Tipiracil in CRC


John L. Marshall, MD: Let’s switch to the other medicine. Dirk, I’m going to put you on the spot to teach us about TAS-102 and the clinical trial. May you tell us a little bit about the drug?

Dirk Arnold, MD, PhD: TAS-102 is now called trifluridine/tipiracil. It’s a combined drug. Trifluridine means fluoropyrimidine—I’ll explain in a minute—and tipiracil is an enzyme. The trifluridine is the active metabolite. This is administered into the cell and, then, it undergoes activation steps by phosphorylation. Then, it acts like a fluoropyrimidine as an antimetabolite.

John L. Marshall, MD: Do you think it’s 5-FU?

Dirk Arnold, MD, PhD: I’ll come to this in a minute. The enzyme which is, let’s say, coupled with it prevents the degradation of this molecule. So, this molecule stays longer, let’s say, in the cell and is not extracted. We have seen that this drug, trifluridine, which is not 5-FU, is also active in 5-FU—resistant cell clones. Therefore, it’s not exactly 5-FU. It works in a 5-FU–sensitive and 5-FU–resistant setting. Therefore, it is a fluoropyrimidine. It is an antimetabolite, but it’s not 5-FU. It may also be working in 5-FU–refractory patients.

John L. Marshall, MD: Toxicity?

Dirk Arnold, MD, PhD: The toxicity profile is different from regorafenib. There is much less symptomatic toxicity, but much more hematotoxicity. As an antimetabolite, it has to be checked. Neuropathy, thrombocytopenia, and febrile neuropathy are the adverse events.

John L. Marshall, MD: There is some mild nausea in some patients, but I would agree with you that most people feel pretty well while they’re taking this.

Tanios Bekaii-Saab, MD: It is interesting. A study that was a retrospective analysis, that came from Japan, looked at the center’s experience with TAS-102 and regorafenib. A lot of the toxicities are very predictable. There was a toxicity that was very intriguingly the same—fatigue. Fatigue was the same between the 2 agents, which is probably less the status of the disease, and a little bit of the drugs. But, there wasn’t much difference between the 2.

We all think regorafenib means fatigue. But, the fatigue was the same, too. The other thing is, the nausea was worse—much worse—with the TAS-102. Again, this was a retrospective analysis, so we should take it with a grain of salt. The gastrointestinal toxicities do belong to the cytotoxic group, as well, and you do see it a little bit more with them. And, again, the other toxicities are what you expect—hand-foot syndrome, and the liver toxicities were definitely worse than with regorafenib. It’s a very interesting study. Because we don’t have those comparative data, it’s very difficult to distinguish other than through our own recollection and biases, how we remember that patient presenting to us after they got their first week of treatment, or 2 weeks of treatment.

John L. Marshall, MD: Paul, I’m going to pick on you for this. We have 2 drugs that are basically approved in, essentially, the same space. You present them both to patients, I’m assuming, in this. How do you help decide, with the patient, which one of these to go to first?

Paul R. Helft, MD: This is more of an art than a science. We certainly try to get patients, in this setting, on to clinical trials of early agents if possible. For example, for a patient who has had a great deal of hand-foot syndrome throughout the course of their disease because of their fluoropyrimidine, you might steer toward TAS-102. For somebody who’s got marginal counts because they have problems left over from their oxaliplatin, before, you might steer towards regorafenib. So, based on those toxicities, that’s certainly one consideration. Then, patient preference plays an even greater, more important role when the trade-offs are much more marginal.

John L. Marshall, MD: Does anyone have a difference of opinion?

Fortunato Ciardiello, MD, PhD: Not really. Maybe if you want to save potential bone marrow toxicity because bone marrow toxicity was a major problem for the first 2 lines, then you are going to regorafenib. But, these are in patients that experience bone marrow toxicity.

John L. Marshall, MD: This is really an observation for me—we thought that sending patients home with oral therapy would actually be a break for them. But, not only is it the fatigue and the different sets of side effects, but one issue that I was not expecting is that they kind of miss the infusion unit. The infusion unit is a place where they get a little Ativan, they have Wi-Fi, and they watch a movie. They get spoiled. They don’t get a manicure and pedicure, but they get spoiled while they’re there. And then, all of a sudden, they’re not going.

Paul R. Helft, MD: I want to come to your infusion center.

John L. Marshall, MD: It’s really good.

Tanios Bekaii-Saab, MD: No, but I agree with you, John.

John L. Marshall, MD: It’s a support system that we’re removing them from, on some level.

Tanios Bekaii-Saab, MD: Yes. “This is easy.” “This is keeping me home, but I miss my infusion nurses.”

John L. Marshall, MD: “My people.”

Tanios Bekaii-Saab, MD: Yes. “I miss chatting with other patients,” and all that.

John L. Marshall, MD: It’s a subtle thing. It’s just one of those things that you might mention.

Tanios Bekaii-Saab, MD: Occasionally, if fluids are indicated, you bring them in once in a while to give them some fluid if indicated.

John L. Marshall, MD: I tell them, “We’re going to try that chemotherapy again. Don’t worry, we’re going back but, for a while, you’re going to take a break.” It’s also a nice moment for them, if they want to take that 2-week trip someplace. It’s a good window.

Transcript Edited for Clarity