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Role of TAS-102 (Trifluridine/tipiracil) in Advanced Colorectal Cancer

Panelists:John L. Marshall, MD, Georgetown University Hospital;Tanios Bekaii-Saab, MD, Mayo Clinic;Cathy Eng, MD, FACP, MD Anderson Cancer Center;Daniel G. Haller, MD,FACP,FRCP, University of Pennsylvania;Tara E. Seery, MD, UC Irvine
Published: Wednesday, Sep 14, 2016



Transcript:

John L. Marshall, MD:
What are you doing with the dosing schedule for TAS-102?

Daniel G. Haller, MD: I think people should start at the full dose.

John L. Marshall, MD: Is it fancy capecitabine or is it a different drug?

Daniel G. Haller, MD: No. It’s a totally different drug; 5-FU-resistant cell lines can respond to this drug. It’s an old drug, but it had such a short half-life. Trifluridine was not a drug that was pragmatic, so it sat on the shelves until tipiracil came along and inhibited thymidine phosphorylase—like an infusional drug.

John L. Marshall, MD: Can you give it in DPD (dihydropyrimidine dehydrogenase) deficiency?

Daniel G. Haller, MD: Yes. And the other part of it is, whether you like it or not, it only has one toxicity to speak of, and that’s neutropenia.

John L. Marshall, MD: I have a few low level…

Daniel G. Haller, MD: Fatigue.

John L. Marshall, MD: And a bit of nausea. There’s 10% to 15% that have some degree of nausea.

Cathy Eng, MD: Myelosuppression.

Daniel G. Haller, MD: There are some.

John L. Marshall, MD: Myelosuppression is big. Is it 2 weeks in a row, 1 week off, don’t give it on weekends…

Daniel G. Haller, MD: It’s actually 5 days: Monday to Friday, Monday to Friday.

Cathy Eng, MD: Yes, it’s a unique schedule.

John L. Marshall, MD: Has anybody gone to every other week yet? Have you fiddled with this—full dose, but every other week—or no?

Daniel G. Haller, MD: The Japanese may have because they’ve had it for a long time.

John L. Marshall, MD: They’ve had it for a while, yes.

Daniel G. Haller, MD: It seems like neutropenia is more sensitive to whether you have food in your stomach, which you really need to do. If a patient has unexpected neutropenia, we ask, “Did you eat?” And then the other thing is the scheduling. It really seems like that little break is very important.

Cathy Eng, MD: You really have to be careful with the schedule because some patients don’t think about just taking it days 1 through 5. Sometimes they forget, and then will come in severely neutropenic.

Daniel G. Haller, MD: Well, the company developed a pill box, which they give out. It has 10 days, or 2 weeks, but the weekend is blocked off so that you can’t fill it.

Cathy Eng, MD: Somehow, one of my patients still took it.

Daniel G. Haller, MD: Although the patients in trials are always age 60 and male, in practice, they’re age 75 and not always male. It’s hard for people to keep track of things because they’re taking 8 other drugs. What we started doing is having the nurse practitioner fill the pill box with them in the room. You could talk to the patient about it while you’re doing it, and that way they can’t accidentally overdose on the drug.

John L. Marshall, MD: Tara, I’m going to ask a little bit of this from everybody, but I’m going to give you the floor first. You’ve gone through first-line and second-line, and let’s say what’s left is the recycling of oxaliplatin. You’ve got TAS-102 and you’ve got regorafenib. How do you pick among those?

Tara E. Seery, MD: I really discourage people from recycling oxaliplatin if they have neuropathy. We love to recycle it, but then patients have a miserable life. I prefer to give Stivarga first, followed by TAS-102. When you look at the trial for TAS-102, 20% had Stivarga. When you look at the Stivarga trial, of course, no one had it. So, I like to try Stivarga first. Granted, when I look at the different side effects that patients have, if they’ve had horrendous hand-foot syndrome, I’m not going to give Stivarga first. I’m going to let their hands recover before I give them something that will cause issues. I won’t give Stivarga if they have uncontrolled high blood pressure, but that really shouldn’t be an issue these days. But, if their bone marrow has been really wiped out, then I really have to be careful giving the TAS-102.

Daniel G. Haller, MD: But, you probably will anyway.

Tara E. Seery, MD: I will.

Daniel G. Haller, MD: We’re not going to go back to the FOLFOX/FOLFIRI thing. They’ll never be directly compared. I think most patients who are usually 0’s and 1’s—in the TAS-102 trial, 40% of people got another line of therapy after, and only 20% of those were regorafenib—are recycling and going back to EGFR agents, or whatever they responded to before.

John L. Marshall, MD: What would you quote a patient on response to recycling oxaliplatin in this setting? They came off in 3 months because it was working and haven’t had it in 18 months.

Cathy Eng, MD: I would reutilize it.

John L. Marshall, MD: But, what would you tell that patient about the odds of their cancer responding?

Cathy Eng, MD: I would say they may not be as high as they were when we originally provided it to them.

John L. Marshall, MD: I’ll give you that. Is it above 10%?

Cathy Eng, MD: I suspect it’s going to be. If they had a very, very nice response originally, yes.

John L. Marshall, MD: And they still got it on the table. How do you sequence these things?

Tanios Bekaii-Saab, MD: Very similar to Tara. First of all, the recycling is my least favorite option. It’s the desperate option. It’s the one that has not been tested, so I leave it to the end of the line beyond even a clinical trial.

John L. Marshall, MD: There’s no OS shown with that, or you’ve got two drugs that have at least OS?

Tanios Bekaii-Saab, MD: We don’t know anything about it, so I wouldn’t put it ahead of regorafenib or TAS-102.

John L. Marshall, MD: Make it a symptomatic liver metastatic patient who you’d like to respond. Does that change your bias a little bit?

Tanios Bekaii-Saab, MD: There’s something called SBRT (stereotactic body radiation therapy) that may actually help a little bit more.

John L. Marshall, MD: I’ll make it paravertebral. I saw some nods.

Tanios Bekaii-Saab, MD: You have to have a response rate of at least 25%-30% to convince me that it’s worth recycling. I don’t believe you can get to that.

John L. Marshall, MD: Fair enough.

Transcript Edited for Clarity

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Transcript:

John L. Marshall, MD:
What are you doing with the dosing schedule for TAS-102?

Daniel G. Haller, MD: I think people should start at the full dose.

John L. Marshall, MD: Is it fancy capecitabine or is it a different drug?

Daniel G. Haller, MD: No. It’s a totally different drug; 5-FU-resistant cell lines can respond to this drug. It’s an old drug, but it had such a short half-life. Trifluridine was not a drug that was pragmatic, so it sat on the shelves until tipiracil came along and inhibited thymidine phosphorylase—like an infusional drug.

John L. Marshall, MD: Can you give it in DPD (dihydropyrimidine dehydrogenase) deficiency?

Daniel G. Haller, MD: Yes. And the other part of it is, whether you like it or not, it only has one toxicity to speak of, and that’s neutropenia.

John L. Marshall, MD: I have a few low level…

Daniel G. Haller, MD: Fatigue.

John L. Marshall, MD: And a bit of nausea. There’s 10% to 15% that have some degree of nausea.

Cathy Eng, MD: Myelosuppression.

Daniel G. Haller, MD: There are some.

John L. Marshall, MD: Myelosuppression is big. Is it 2 weeks in a row, 1 week off, don’t give it on weekends…

Daniel G. Haller, MD: It’s actually 5 days: Monday to Friday, Monday to Friday.

Cathy Eng, MD: Yes, it’s a unique schedule.

John L. Marshall, MD: Has anybody gone to every other week yet? Have you fiddled with this—full dose, but every other week—or no?

Daniel G. Haller, MD: The Japanese may have because they’ve had it for a long time.

John L. Marshall, MD: They’ve had it for a while, yes.

Daniel G. Haller, MD: It seems like neutropenia is more sensitive to whether you have food in your stomach, which you really need to do. If a patient has unexpected neutropenia, we ask, “Did you eat?” And then the other thing is the scheduling. It really seems like that little break is very important.

Cathy Eng, MD: You really have to be careful with the schedule because some patients don’t think about just taking it days 1 through 5. Sometimes they forget, and then will come in severely neutropenic.

Daniel G. Haller, MD: Well, the company developed a pill box, which they give out. It has 10 days, or 2 weeks, but the weekend is blocked off so that you can’t fill it.

Cathy Eng, MD: Somehow, one of my patients still took it.

Daniel G. Haller, MD: Although the patients in trials are always age 60 and male, in practice, they’re age 75 and not always male. It’s hard for people to keep track of things because they’re taking 8 other drugs. What we started doing is having the nurse practitioner fill the pill box with them in the room. You could talk to the patient about it while you’re doing it, and that way they can’t accidentally overdose on the drug.

John L. Marshall, MD: Tara, I’m going to ask a little bit of this from everybody, but I’m going to give you the floor first. You’ve gone through first-line and second-line, and let’s say what’s left is the recycling of oxaliplatin. You’ve got TAS-102 and you’ve got regorafenib. How do you pick among those?

Tara E. Seery, MD: I really discourage people from recycling oxaliplatin if they have neuropathy. We love to recycle it, but then patients have a miserable life. I prefer to give Stivarga first, followed by TAS-102. When you look at the trial for TAS-102, 20% had Stivarga. When you look at the Stivarga trial, of course, no one had it. So, I like to try Stivarga first. Granted, when I look at the different side effects that patients have, if they’ve had horrendous hand-foot syndrome, I’m not going to give Stivarga first. I’m going to let their hands recover before I give them something that will cause issues. I won’t give Stivarga if they have uncontrolled high blood pressure, but that really shouldn’t be an issue these days. But, if their bone marrow has been really wiped out, then I really have to be careful giving the TAS-102.

Daniel G. Haller, MD: But, you probably will anyway.

Tara E. Seery, MD: I will.

Daniel G. Haller, MD: We’re not going to go back to the FOLFOX/FOLFIRI thing. They’ll never be directly compared. I think most patients who are usually 0’s and 1’s—in the TAS-102 trial, 40% of people got another line of therapy after, and only 20% of those were regorafenib—are recycling and going back to EGFR agents, or whatever they responded to before.

John L. Marshall, MD: What would you quote a patient on response to recycling oxaliplatin in this setting? They came off in 3 months because it was working and haven’t had it in 18 months.

Cathy Eng, MD: I would reutilize it.

John L. Marshall, MD: But, what would you tell that patient about the odds of their cancer responding?

Cathy Eng, MD: I would say they may not be as high as they were when we originally provided it to them.

John L. Marshall, MD: I’ll give you that. Is it above 10%?

Cathy Eng, MD: I suspect it’s going to be. If they had a very, very nice response originally, yes.

John L. Marshall, MD: And they still got it on the table. How do you sequence these things?

Tanios Bekaii-Saab, MD: Very similar to Tara. First of all, the recycling is my least favorite option. It’s the desperate option. It’s the one that has not been tested, so I leave it to the end of the line beyond even a clinical trial.

John L. Marshall, MD: There’s no OS shown with that, or you’ve got two drugs that have at least OS?

Tanios Bekaii-Saab, MD: We don’t know anything about it, so I wouldn’t put it ahead of regorafenib or TAS-102.

John L. Marshall, MD: Make it a symptomatic liver metastatic patient who you’d like to respond. Does that change your bias a little bit?

Tanios Bekaii-Saab, MD: There’s something called SBRT (stereotactic body radiation therapy) that may actually help a little bit more.

John L. Marshall, MD: I’ll make it paravertebral. I saw some nods.

Tanios Bekaii-Saab, MD: You have to have a response rate of at least 25%-30% to convince me that it’s worth recycling. I don’t believe you can get to that.

John L. Marshall, MD: Fair enough.

Transcript Edited for Clarity
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