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Maintenance Therapy for mCRC

Panelists: John Marshall, MD, Georgetown University; Cathy Eng, MD, Vanderbilt University; Tanios Bekaii-Saab, MD, Mayo Clinic; Dustin Deming, MD, University of Wisconsin; Michael Morse, MD, Duke Cancer Institute
Published: Tuesday, Aug 13, 2019



Transcript: 

John Marshall, MD: Let’s quickly shift to this concept of lines of therapy. Tony, you already brought up earlier maintenance therapy. Very quickly, I don’t need a big discussion, 3 to 4 months of whatever your induction therapy is. Then what does maintenance look like for you?

Tanios Bekaii-Saab, MD: Maintenance can look 2 ways. One, you always have a discussion about whether we give a holiday.

John Marshall, MD: Total holiday.

Tanios Bekaii-Saab, MD: It’s less preferable, but it could be reasonable, beyond a certain point. Maintenance therapy is preferable. Primarily, it has been shown to prolong disease-free survival, but perhaps even a hint of overall survival.

John Marshall, MD: A nudge of overall?

Tanios Bekaii-Saab, MD: Yes.

John Marshall, MD: What do you give? What do you do?

Tanios Bekaii-Saab, MD: I do capecitabine, like CAIRO3, but a little different. Capecitabine plus bevacizumab; bevacizumab every 3 weeks. Capecitabine, in all frankness, to give daily all the time for our patients, at least in the United States, is an impossible task. I’ve simplified it to 5 days, say Monday to Friday, because of all the concerns raised about oral therapy, and try not to confuse the patients about taking this and that. Monday to Friday, you take your pills, weekends off, at a low dose.

John Marshall, MD: I always joke, if radiation doesn’t work on the weekends, neither does chemotherapy.

Tanios Bekaii-Saab, MD: They need that. Even that couple of days break in between the 5 days actually makes it reasonable.

John Marshall, MD: I hear a lot of folks…I agree with what Tony just said.

Cathy Eng, MD: I think that’s personal preference.

Tanios Bekaii-Saab, MD: John just agreed with me.

John Marshall, MD: A couple of us. But what I hear a lot….

Tanios Bekaii-Saab, MD: It makes it more than personal.

Cathy Eng, MD: That is not in the literature.

John Marshall, MD: I hear from our community friends that giving capecitabine can sometimes be an issue. The co-pay is a barrier, and so they tend to keep pumps going. Dustin, what’s your strategy?

Dustin Deming, MD: I also tend to keep pumps going because I think the patients tolerate it better. When I do use capecitabine for a patient’s preference, I prefer an every-other-week regimen, which is reasonable.

John Marshall, MD: Just chronic exposure, Mike? What are you doing?

Michael Morse, MD: Agreed. Capecitabine where people would prefer an oral agent, intravenous if that’s….

John Marshall, MD: You keep maintaining it?

Michael Morse, MD: Yes.

John Marshall, MD: Cathy, I’ll give you 1 vote, too.

Cathy Eng, MD: It depends on the patient. I either do IV [intravenous] 5-FU [fluorouracil] or capecitabine. With the capecitabine dosing, I’m very careful to evaluate the patient to see what I believe he can tolerate.

John Marshall, MD: Yes.

Cathy Eng, MD: I don’t maximize the dose, by any means. I actually cap the doses.

Tanios Bekaii-Saab, MD: We always round down. That’s the general rule with capecitabine. We always round down.

Cathy Eng, MD: Definitely.

John Marshall, MD: Let me make it a year later. It’s going well. They’ve been coming in every 2 weeks dutifully. You gave them 1 extra week off for summer vacation. Do you make any changes, or do you just let it ride? Do you keep both drugs going? Do you drop your bevacizumab? What’s your longer-term strategy, because this does happen, right?

Dustin Deming, MD: Depending on the patient, this is where I start getting creative. If this is a patient who now looks to have a really favorable biology, I start looking at their CT [computed tomography] scans a little differently. I start thinking, is it time to start whittling away at some things in the liver? Is this the time where getting their primary out…because at least in my experience, those patients who have the best benefit from bevacizumab-containing regimens are also the ones who seem to be at higher risk for perforation. If you’re going to be on bevacizumab for a couple years, that’s probably something to consider, though not necessarily a standard that I would do for everybody.

John Marshall, MD: Mike, let me shift gears a little bit to second line and beyond. I think of colorectal cancer and metastatic disease like a chess game. You make one move, then you have some other pieces on the board, and you decide when to move the other pieces. I’m asking you your overall chess strategy in deciding to move to second line and third line. What are some of the variables that you put it on?

Michael Morse, MD: In terms of choice of therapy, I’m motivated by the idea of preserving as many lines of therapy possible for people. We believe that the more lines you can receive, each of which has a couple of months or more survival benefit associated with them, people might do the best longest, so I try not to discard drugs too early. That would get into second line. If you’ve given bevacizumab first line, whether you continue bevacizumab, I’d definitely do that.

John Marshall, MD: If we argued that at first line, we needed to be more intensive initially, is that true in subsequent lines, or can I be a little gentler through second line?

Michael Morse, MD: There are going to be limitations, first of all, on what people can tolerate after they’ve already had a very aggressive chemotherapy approach. I don’t think the data are as strong about giving aggressive therapy later on. If you’ve chosen for a person who has progressive disease to receive the most aggressive therapy, it probably doesn’t make sense to continue to be aggressive.

John Marshall, MD: Cathy?

Cathy Eng, MD: The TRIBE2 did that, though. They reintroduced that.

Michael Morse, MD: They did, but you know, people….

Cathy Eng, MD: I’m not saying that it applies to every patient; the data are there.

Michael Morse, MD: I would argue that’s a reintroduction and not technically a second-line therapy, so I agree with where you’re going.

Cathy Eng, MD: I just wanted to make sure that we were clarifying that correctly.

Tanios Bekaii-Saab, MD: Here’s the other point about TRIBE2 that’s important to keep in mind. The majority of the patients were right-sided. The majority of the patients were RAS-mutated. Again, that argument continues to hold, for those patients where you think you’re going to run out of options fairly quickly, to intensify. For those patients who have favorable outcomes, which is a good chunk of our patients, you don’t need to go that intense.

Cathy Eng, MD: Don’t forget that the original TRIBE data reported one of the highest 5-year overall survival rates at 25%.

Tanios Bekaii-Saab, MD: It was much less than CALGB 80405. Historically, I’m not convinced 100% that this applies to all patients, and I still think we really need to be selective.

Cathy Eng, MD: I fully agree with that. As mentioned earlier, I wouldn’t give it to everybody, but it’s an option.

Dustin Deming, MD: In the TRIBE study, it’s important to notice, especially for this question about when we’re reinitiating or going to second-line therapy, that the triplet combination didn’t have a better progression-free survival than just FOLFIRI-BEV [folinic acid/fluorouracil/irinotecan plus bevacizumab]. Coming back with the triplet regimen isn’t necessarily better, based on that TRIBE2 data.

John Marshall, MD: Just the idea of biologics beyond progression—we’ve talked about EGFR, but in all of the other patients, we have second-line indications for 3 VEGF [vascular endothelial growth factor] inhibitors. Cathy, what do you do in this space in a patient when you want to continue some VEGF therapy?

Cathy Eng, MD: In regard to refractory settings such as multitargeted…?

John Marshall, MD: Secondary. No, more in the, you have 3 monoclonal antibodies.

Cathy Eng, MD: Oh, for the second line? I think most of us traditionally do continue bevacizumab, as Mike mentioned earlier. Most of us are comfortable with that, and obviously, some of the other drugs are a bit more costly, financially, so that’s another thing to take into account. Historically, many of us will continue bevacizumab, initiating first line.

John Marshall, MD: Are there patients where you might change drugs in that setting? We see a lot of our community partners using the other monoclonals.

Cathy Eng, MD: You do?

John Marshall, MD: Yes, in our space.

Cathy Eng, MD: I’ve not seen that.

Michael Morse, MD: There’s not any reason. You can’t compare the studies totally with each other, because there are slight differences in the patient populations. In 1 study, they didn’t all have bevacizumab in the first line. I think it’s certainly a choice of the oncologists and patient.

Transcript Edited for Clarity

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Transcript: 

John Marshall, MD: Let’s quickly shift to this concept of lines of therapy. Tony, you already brought up earlier maintenance therapy. Very quickly, I don’t need a big discussion, 3 to 4 months of whatever your induction therapy is. Then what does maintenance look like for you?

Tanios Bekaii-Saab, MD: Maintenance can look 2 ways. One, you always have a discussion about whether we give a holiday.

John Marshall, MD: Total holiday.

Tanios Bekaii-Saab, MD: It’s less preferable, but it could be reasonable, beyond a certain point. Maintenance therapy is preferable. Primarily, it has been shown to prolong disease-free survival, but perhaps even a hint of overall survival.

John Marshall, MD: A nudge of overall?

Tanios Bekaii-Saab, MD: Yes.

John Marshall, MD: What do you give? What do you do?

Tanios Bekaii-Saab, MD: I do capecitabine, like CAIRO3, but a little different. Capecitabine plus bevacizumab; bevacizumab every 3 weeks. Capecitabine, in all frankness, to give daily all the time for our patients, at least in the United States, is an impossible task. I’ve simplified it to 5 days, say Monday to Friday, because of all the concerns raised about oral therapy, and try not to confuse the patients about taking this and that. Monday to Friday, you take your pills, weekends off, at a low dose.

John Marshall, MD: I always joke, if radiation doesn’t work on the weekends, neither does chemotherapy.

Tanios Bekaii-Saab, MD: They need that. Even that couple of days break in between the 5 days actually makes it reasonable.

John Marshall, MD: I hear a lot of folks…I agree with what Tony just said.

Cathy Eng, MD: I think that’s personal preference.

Tanios Bekaii-Saab, MD: John just agreed with me.

John Marshall, MD: A couple of us. But what I hear a lot….

Tanios Bekaii-Saab, MD: It makes it more than personal.

Cathy Eng, MD: That is not in the literature.

John Marshall, MD: I hear from our community friends that giving capecitabine can sometimes be an issue. The co-pay is a barrier, and so they tend to keep pumps going. Dustin, what’s your strategy?

Dustin Deming, MD: I also tend to keep pumps going because I think the patients tolerate it better. When I do use capecitabine for a patient’s preference, I prefer an every-other-week regimen, which is reasonable.

John Marshall, MD: Just chronic exposure, Mike? What are you doing?

Michael Morse, MD: Agreed. Capecitabine where people would prefer an oral agent, intravenous if that’s….

John Marshall, MD: You keep maintaining it?

Michael Morse, MD: Yes.

John Marshall, MD: Cathy, I’ll give you 1 vote, too.

Cathy Eng, MD: It depends on the patient. I either do IV [intravenous] 5-FU [fluorouracil] or capecitabine. With the capecitabine dosing, I’m very careful to evaluate the patient to see what I believe he can tolerate.

John Marshall, MD: Yes.

Cathy Eng, MD: I don’t maximize the dose, by any means. I actually cap the doses.

Tanios Bekaii-Saab, MD: We always round down. That’s the general rule with capecitabine. We always round down.

Cathy Eng, MD: Definitely.

John Marshall, MD: Let me make it a year later. It’s going well. They’ve been coming in every 2 weeks dutifully. You gave them 1 extra week off for summer vacation. Do you make any changes, or do you just let it ride? Do you keep both drugs going? Do you drop your bevacizumab? What’s your longer-term strategy, because this does happen, right?

Dustin Deming, MD: Depending on the patient, this is where I start getting creative. If this is a patient who now looks to have a really favorable biology, I start looking at their CT [computed tomography] scans a little differently. I start thinking, is it time to start whittling away at some things in the liver? Is this the time where getting their primary out…because at least in my experience, those patients who have the best benefit from bevacizumab-containing regimens are also the ones who seem to be at higher risk for perforation. If you’re going to be on bevacizumab for a couple years, that’s probably something to consider, though not necessarily a standard that I would do for everybody.

John Marshall, MD: Mike, let me shift gears a little bit to second line and beyond. I think of colorectal cancer and metastatic disease like a chess game. You make one move, then you have some other pieces on the board, and you decide when to move the other pieces. I’m asking you your overall chess strategy in deciding to move to second line and third line. What are some of the variables that you put it on?

Michael Morse, MD: In terms of choice of therapy, I’m motivated by the idea of preserving as many lines of therapy possible for people. We believe that the more lines you can receive, each of which has a couple of months or more survival benefit associated with them, people might do the best longest, so I try not to discard drugs too early. That would get into second line. If you’ve given bevacizumab first line, whether you continue bevacizumab, I’d definitely do that.

John Marshall, MD: If we argued that at first line, we needed to be more intensive initially, is that true in subsequent lines, or can I be a little gentler through second line?

Michael Morse, MD: There are going to be limitations, first of all, on what people can tolerate after they’ve already had a very aggressive chemotherapy approach. I don’t think the data are as strong about giving aggressive therapy later on. If you’ve chosen for a person who has progressive disease to receive the most aggressive therapy, it probably doesn’t make sense to continue to be aggressive.

John Marshall, MD: Cathy?

Cathy Eng, MD: The TRIBE2 did that, though. They reintroduced that.

Michael Morse, MD: They did, but you know, people….

Cathy Eng, MD: I’m not saying that it applies to every patient; the data are there.

Michael Morse, MD: I would argue that’s a reintroduction and not technically a second-line therapy, so I agree with where you’re going.

Cathy Eng, MD: I just wanted to make sure that we were clarifying that correctly.

Tanios Bekaii-Saab, MD: Here’s the other point about TRIBE2 that’s important to keep in mind. The majority of the patients were right-sided. The majority of the patients were RAS-mutated. Again, that argument continues to hold, for those patients where you think you’re going to run out of options fairly quickly, to intensify. For those patients who have favorable outcomes, which is a good chunk of our patients, you don’t need to go that intense.

Cathy Eng, MD: Don’t forget that the original TRIBE data reported one of the highest 5-year overall survival rates at 25%.

Tanios Bekaii-Saab, MD: It was much less than CALGB 80405. Historically, I’m not convinced 100% that this applies to all patients, and I still think we really need to be selective.

Cathy Eng, MD: I fully agree with that. As mentioned earlier, I wouldn’t give it to everybody, but it’s an option.

Dustin Deming, MD: In the TRIBE study, it’s important to notice, especially for this question about when we’re reinitiating or going to second-line therapy, that the triplet combination didn’t have a better progression-free survival than just FOLFIRI-BEV [folinic acid/fluorouracil/irinotecan plus bevacizumab]. Coming back with the triplet regimen isn’t necessarily better, based on that TRIBE2 data.

John Marshall, MD: Just the idea of biologics beyond progression—we’ve talked about EGFR, but in all of the other patients, we have second-line indications for 3 VEGF [vascular endothelial growth factor] inhibitors. Cathy, what do you do in this space in a patient when you want to continue some VEGF therapy?

Cathy Eng, MD: In regard to refractory settings such as multitargeted…?

John Marshall, MD: Secondary. No, more in the, you have 3 monoclonal antibodies.

Cathy Eng, MD: Oh, for the second line? I think most of us traditionally do continue bevacizumab, as Mike mentioned earlier. Most of us are comfortable with that, and obviously, some of the other drugs are a bit more costly, financially, so that’s another thing to take into account. Historically, many of us will continue bevacizumab, initiating first line.

John Marshall, MD: Are there patients where you might change drugs in that setting? We see a lot of our community partners using the other monoclonals.

Cathy Eng, MD: You do?

John Marshall, MD: Yes, in our space.

Cathy Eng, MD: I’ve not seen that.

Michael Morse, MD: There’s not any reason. You can’t compare the studies totally with each other, because there are slight differences in the patient populations. In 1 study, they didn’t all have bevacizumab in the first line. I think it’s certainly a choice of the oncologists and patient.

Transcript Edited for Clarity
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