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Third-Line Treatment in Refractory CRC

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Cathy Eng, MD, FACP, The University of Texas MD Anderson Cancer Center; John L. Marshall, MD, The Ruesch Center for the Cure of GI Cancers ; Michael A. Morse, MD, Duke Cancer Institute; Dale R. Shepard, MD, PhD, FACP, Taussig Cancer Institute, Cleveland Clinic
Published: Monday, Apr 23, 2018



Transcript: 

John L. Marshall, MD: A patient is microsatellite stable, has a good performance status, is asymptomatic from their metastatic disease, has had oxaliplatin-based therapy, and has had irinotecan-based therapy. It’s 2 years later. We’ve had our discussion. We may send the patient to supportive care, to get that initiated. We’ve got approved medicines in this space. We have regorafenib. We have trifluridine/tipiracil (TAS-102). Johanna, can you talk about your thinking on those medicines? How do you describe those to patients? What is their value, in this space?

Johanna C. Bendell, MD: So, just remembering that this would be for the RAS-mutant patient who doesn’t have an EGFR...

John L. Marshall, MD: Fair enough.

Johanna C. Bendell, MD: There is an interesting abstract at this year’s meeting. This is a Japanese study with 50 patients per arm. So, it is small. They gave patients cetuximab, and then regorafenib; or, regorafenib, and then cetuximab. Interestingly, the patients who got the regorafenib followed by cetuximab had an improved overall survival, compared to the reverse. What’s even more interesting is, when you look at the progression-free survival, the first progression from cetuximab versus regorafenib is the same. The difference happens in the second progression. So, there has been this discussion about regorafenib. Is this a drug that’s going to work better if you use it earlier, before the patient is so sick?

John L. Marshall, MD: This is sort of my shift in practice.

Cathy Eng, MD, FACP: Who’s the sponsor of the trial? We have to be very careful, correct?

Johanna C. Bendell, MD: Pharmaceutical companies sponsor most of the clinical trials that are done, worldwide.

Cathy Eng, MD, FACP: It’s a very interesting study. It is a small study. They would probably have the most information just because both drugs were created…I mean, TAS-102 is created in Japan.

Michael A. Morse, MD: I think the reason that we continue bevacizumab or other antiangiogenics in the second-line setting is because they have activity. It wouldn’t be surprising, into the third-line setting, to continue some antiangiogenic approach. Cetuximab still has activity in later lines. It seems like no matter how late you give it, you can still get activity. Making sure that the antiangiogenic is still maintained early—even though there wasn’t a difference between the regorafenib and cetuximab, initially— may have a longer-term effect.

John L. Marshall, MD: If you wait too long, if the patient’s performance status is declining, neither of these medicines will catch.

Johanna C. Bendell, MD: Right.

John L. Marshall, MD: These are not sort of catching drugs. They’re sort of stabilizing, prolonging drugs. Is that where you all are, with this, too?

Dale R. Shepard, MD, PhD, FACP: Yes. I kind of favor holidays, sometimes. But, I don’t let people get far before I would start something like regorafenib. And then, my choice between the 2 is really about prior experience. If they’ve had cytopenia problems, I will more likely stay away from TAS-102. If they have a lot of fatigue issues, I’m more likely going to stay away from regorafenib.

John L. Marshall, MD: How do you talk about what potential benefit the patient may have from the therapy? A lot of them have been online. They’ve heard. We tend to bring a bias of lack of responses. How do you describe that to a patient?

Dale R. Shepard, MD, PhD, FACP: The response rates are not going to be high. And so, at that level, I’m less worried about what the scans are going to look like, in terms of response. I’m treating them, more clinically, in terms of, if they get clinical benefit, then I’m OK with that. Then, I’ll continue treatment. But, if they start having a lot of toxicity, at that line, and I’m not expecting a lot of response, I move to the next thing.

John L. Marshall, MD: I’m going to put you on the hot seat, a little bit. All of us have clinical trials. We get sent a patient from a community setting. What have you got? You’ve got approved drugs with surgical benefit on the table, and you’ve got some good phase I data that you think is the best thing since sliced bread. So far, you’re 0 for 10, but you’ve got accrual issues. This is our world, right? This is what our pressures are. The patient is interested in something new. What do you do? Do you send that patient back and put them on your waitlist? Or, do you keep them and put them on that trial?

Michael A. Morse, MD: I think that for a good performance status person, who would be a clinical trial candidate, they are likely to maintain that performance status. Most clinical trials are now performing scans at 8 weeks. And so, it’s very unlikely that the person is going to become untreatable. It’s an opportunity, or a window to try to see if something novel will work.

John L. Marshall, MD: What you’re saying is that you could afford to be wrong and they would still be a candidate?

Michael A. Morse, MD: I find that. For people that are clinical trial candidates, they generally will still be in adequate performance status, to be treated.

John L. Marshall, MD: What about in Nashville?

Johanna C. Bendell, MD: A lot of the people that come to us for clinical trials come to us for clinical trials. And so, we have the discussion. We talk to them about the other options that are available. Most of the time, the patients are like, “Nah, I heard that’s not going to work. I would like a study.” So, a lot of those folks have also self-selected, in a way.

John L. Marshall, MD: Is anything different, in your practice?

Cathy Eng, MD, FACP: No, I totally agree.

Dale R. Shepard, MD, PhD, FACP: My biggest frustration is that a lot of the trials are not allowing colorectal patients.

John L. Marshall, MD: The cohorts are full.

Dale R. Shepard, MD, PhD, FACP: Cohorts are full, or they don’t even exist. A lot of the trials that are coming through are immuno-based something, or other. They’re looking for lung. They’re looking for bladder. They’re looking for kidney. They’re looking for things that we already know that immunotherapy works for. And so, it’s hard to find some of these trials.

John L. Marshall, MD: So many of our trials have slots, but not for 6 or 8 weeks. And so, you go and try regorafenib, and go from there, right?

Transcript Edited for Clarity

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Transcript: 

John L. Marshall, MD: A patient is microsatellite stable, has a good performance status, is asymptomatic from their metastatic disease, has had oxaliplatin-based therapy, and has had irinotecan-based therapy. It’s 2 years later. We’ve had our discussion. We may send the patient to supportive care, to get that initiated. We’ve got approved medicines in this space. We have regorafenib. We have trifluridine/tipiracil (TAS-102). Johanna, can you talk about your thinking on those medicines? How do you describe those to patients? What is their value, in this space?

Johanna C. Bendell, MD: So, just remembering that this would be for the RAS-mutant patient who doesn’t have an EGFR...

John L. Marshall, MD: Fair enough.

Johanna C. Bendell, MD: There is an interesting abstract at this year’s meeting. This is a Japanese study with 50 patients per arm. So, it is small. They gave patients cetuximab, and then regorafenib; or, regorafenib, and then cetuximab. Interestingly, the patients who got the regorafenib followed by cetuximab had an improved overall survival, compared to the reverse. What’s even more interesting is, when you look at the progression-free survival, the first progression from cetuximab versus regorafenib is the same. The difference happens in the second progression. So, there has been this discussion about regorafenib. Is this a drug that’s going to work better if you use it earlier, before the patient is so sick?

John L. Marshall, MD: This is sort of my shift in practice.

Cathy Eng, MD, FACP: Who’s the sponsor of the trial? We have to be very careful, correct?

Johanna C. Bendell, MD: Pharmaceutical companies sponsor most of the clinical trials that are done, worldwide.

Cathy Eng, MD, FACP: It’s a very interesting study. It is a small study. They would probably have the most information just because both drugs were created…I mean, TAS-102 is created in Japan.

Michael A. Morse, MD: I think the reason that we continue bevacizumab or other antiangiogenics in the second-line setting is because they have activity. It wouldn’t be surprising, into the third-line setting, to continue some antiangiogenic approach. Cetuximab still has activity in later lines. It seems like no matter how late you give it, you can still get activity. Making sure that the antiangiogenic is still maintained early—even though there wasn’t a difference between the regorafenib and cetuximab, initially— may have a longer-term effect.

John L. Marshall, MD: If you wait too long, if the patient’s performance status is declining, neither of these medicines will catch.

Johanna C. Bendell, MD: Right.

John L. Marshall, MD: These are not sort of catching drugs. They’re sort of stabilizing, prolonging drugs. Is that where you all are, with this, too?

Dale R. Shepard, MD, PhD, FACP: Yes. I kind of favor holidays, sometimes. But, I don’t let people get far before I would start something like regorafenib. And then, my choice between the 2 is really about prior experience. If they’ve had cytopenia problems, I will more likely stay away from TAS-102. If they have a lot of fatigue issues, I’m more likely going to stay away from regorafenib.

John L. Marshall, MD: How do you talk about what potential benefit the patient may have from the therapy? A lot of them have been online. They’ve heard. We tend to bring a bias of lack of responses. How do you describe that to a patient?

Dale R. Shepard, MD, PhD, FACP: The response rates are not going to be high. And so, at that level, I’m less worried about what the scans are going to look like, in terms of response. I’m treating them, more clinically, in terms of, if they get clinical benefit, then I’m OK with that. Then, I’ll continue treatment. But, if they start having a lot of toxicity, at that line, and I’m not expecting a lot of response, I move to the next thing.

John L. Marshall, MD: I’m going to put you on the hot seat, a little bit. All of us have clinical trials. We get sent a patient from a community setting. What have you got? You’ve got approved drugs with surgical benefit on the table, and you’ve got some good phase I data that you think is the best thing since sliced bread. So far, you’re 0 for 10, but you’ve got accrual issues. This is our world, right? This is what our pressures are. The patient is interested in something new. What do you do? Do you send that patient back and put them on your waitlist? Or, do you keep them and put them on that trial?

Michael A. Morse, MD: I think that for a good performance status person, who would be a clinical trial candidate, they are likely to maintain that performance status. Most clinical trials are now performing scans at 8 weeks. And so, it’s very unlikely that the person is going to become untreatable. It’s an opportunity, or a window to try to see if something novel will work.

John L. Marshall, MD: What you’re saying is that you could afford to be wrong and they would still be a candidate?

Michael A. Morse, MD: I find that. For people that are clinical trial candidates, they generally will still be in adequate performance status, to be treated.

John L. Marshall, MD: What about in Nashville?

Johanna C. Bendell, MD: A lot of the people that come to us for clinical trials come to us for clinical trials. And so, we have the discussion. We talk to them about the other options that are available. Most of the time, the patients are like, “Nah, I heard that’s not going to work. I would like a study.” So, a lot of those folks have also self-selected, in a way.

John L. Marshall, MD: Is anything different, in your practice?

Cathy Eng, MD, FACP: No, I totally agree.

Dale R. Shepard, MD, PhD, FACP: My biggest frustration is that a lot of the trials are not allowing colorectal patients.

John L. Marshall, MD: The cohorts are full.

Dale R. Shepard, MD, PhD, FACP: Cohorts are full, or they don’t even exist. A lot of the trials that are coming through are immuno-based something, or other. They’re looking for lung. They’re looking for bladder. They’re looking for kidney. They’re looking for things that we already know that immunotherapy works for. And so, it’s hard to find some of these trials.

John L. Marshall, MD: So many of our trials have slots, but not for 6 or 8 weeks. And so, you go and try regorafenib, and go from there, right?

Transcript Edited for Clarity
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