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Relapsed/Refractory mCRC: Treatment Dosing Strategies

Panelists: Howard Hochster, MD, FACP, Rutgers Cancer Institute; Joleen Hubbard, MD, Mayo Clinic; Christopher Lieu, MD, University of Colorado School of Medicine; John Marshall, MD, Georgetown University Hospital; Tony Saab, MD, Mayo Clinic
Published: Thursday, Mar 14, 2019



Transcript: 

John L. Marshall, MD:
So I’m going to let Tony talk about dosing for regorafenib. Is anybody fiddling with TAS-102 dosing? So we’ve got this funky 2-week on, 2-week off, a lot of myelosuppression. Is anybody going with every other week?

Howard S. Hochster, MD, FACP: Well, there are data in combination. We did a study of TAS-IRI [irinotecan] and bev [bevacizumab], in which you give 5 days every 14. And also, at this GI ASCO [Gastrointestinal Cancers Symposium] meeting, there’s a poster from a study that I started at Yale University that Mike Cecchini is presenting of TAS with oxaliplatin. And that is also given on a 2-week schedule, like that with just 5 days. And I think that does improve the tolerance a little bit better, and it’s the same dose intensity. But I don’t know for sure that it wouldn’t, given it’s equivalent.

John L. Marshall, MD: Right. Is anybody else fiddling? Is anybody adding a little bev in this setting?

Joleen M. Hubbard, MD: We’ve tried that at Mayo Clinic, adding some bevacizumab. Sometimes there are issues with coverage for that. We don’t have great data to suggest that we’re benefiting, but from some anecdotal reports, we’ve had some good responses.

John L. Marshall, MD: It’s that sort of bev beyond progression theory, right?

Howard S. Hochster, MD, FACP: Well, there are data from Japan. Ushino did a study with TAS and bev that looks pretty positive. And then in Europe they did a first-line study for patients who weren’t eligible for combination chemotherapy in the eyes of their providers. And in Europe, I guess they’re a little bit more reluctant in some patients to give combination chemotherapy. Mostly they were elderly but still with good performance status. But TAS and bev was better than cape [capecitabine] and bev, and that’s the TASCO1 trial. I think that today, if they’re a good performance status patient, I tend to give people TAS and bev.

John L. Marshall, MD: Tony?

Tanios S. Bekaii-Saab, MD: To an original point, really for fluoropyrimidines overall, you need 5 days every 7 days. So that goes back to the maintenance question, maybe perhaps to answer your original question that it’s OK to give 5 days of cape and give 2 days off and continue with that. But that’s a good proof of principle. Now, going back to the dosing with regorafenib…

John L. Marshall, MD: Give us the quick summary of what the gang out there really needs to know about dosing this drug.

Tanios S. Bekaii-Saab, MD: We’ve always toyed with the drug with dosing in the clinic because we have issues with certainly cumulative toxicity and early toxicity in the first 2 weeks. So this study, the ReDOS trial, was trying to find a clinical way, an optimized way to essentially figure out the best dose for the patient, the right dose for the patient as close as possible. So it had 2 arms. One arm was what we call the “dose escalation strategy.” It went from 80 to 120 to 160 on a weekly basis, increased by 40 as the patient tolerated. And the other one was a very standard 160. The primary outcome was essentially an outcome that measures both efficacy and tolerability, and it was the capacity for the patients to be able to make it to the third cycle. So go into 2 cycles, and get a scan, and if they’re tolerating the drug, of course they continue through a third cycle. And we’re hoping for 15% improvement with a dose escalation strategy versus the standard 160 dose, and we actually got 16%. This was statistically significant. It was positive. There were 120 patients, so it’s not a small study by all the standards that go into the NCCN [National Comprehensive Cancer Network] guidelines. In fact, this actually went into the NCCN guidelines.

John L. Marshall, MD: And I think this is going to result in a label change, right?

Tanios S. Bekaii-Saab, MD: It’s actually already added some level to the label. When we publish the paper, it may change the label. The most intriguing finding was actually a survival advantage, although it was, for secondary endpoints, statistically a wash, but it was—now with the updated data—a 4-month difference in survival between the dose escalation strategy—80, 120, 160—versus the 160 dose. And what’s interesting is that when we looked at arm B, which is the 160 dose, the survival was 6 months. This is similar to what you see in CORRECT. So your arm A, the dose escalation arm, had a 10-month survival, and that’s in a very refractory patient population.

John L. Marshall, MD: Is everybody doing this?

Joleen M. Hubbard, MD: Yeah. We’ve been doing this at Mayo Clinic for a long time, and it works quite well. We need to get the message out to our community colleagues. I commonly will get referrals, and they’ll say right in the referral from the community oncologist, “I refuse to give that drug. It’s a horrible drug.” I think if we give it in the right way, if we dose escalate, we can keep patients on it for a longer period of time. And we do have data to suggest that the initial toxicities actually lessen over time. I actually had a patient who was mad at me because she initially lost weight; she wanted to lose weight. And then after a couple of months on the drug, that adverse effect went away, and she started gaining weight again. I think you can give it in a humane and safe way. It’s a great strategy.

John L. Marshall, MD: How important do you think it is to do the dose escalation? I hear a lot of doctors saying, “Well, I’ll just split the difference. I’ll start at 120, and I’ll see them in a month.” Are you seeing them every week and managing them that way?

Joleen M. Hubbard, MD: We see them every 2 weeks, and we definitely just go ahead and start with the 80. I think it is a more tolerable approach to do a gradual ramp-up.

John L. Marshall, MD: Do I need to push to toxicity? So if there’s zero toxicity, I go all the way to 160? Is that what you do?

Christopher Lieu, MD: Well, I would. I think you try to get to the FDA-approved dosing of 160 mg, but sometimes, in some patients, you just can’t get there, which is OK.

John L. Marshall, MD: Is hand-foot good?

Tanios S. Bekaii-Saab, MD: Hand-foot is improved.

John L. Marshall, MD: No, does hand-foot improve my outcome?

Tanios S. Bekaii-Saab, MD: The answer is, yes, but I’d be careful because, again, it goes back to the whole concept. Do I need to improve a month and just punish the patient? The answer is no. I think it’s important to understand that in this study the goal was to reach 160. In fact, half the patients who stayed on beyond 2 cycles were on 160 mg. And some of the best performers were on 160 mg. So it should remain the goal, and I think you have to do it in a measured fashion. The other very important point to make is that the understanding of the dosage is important because essentially, even across all TKIs [tyrosine kinase inhibitors], we have difficulties with dosage. The other point is that when we’re starting to think about moving perhaps regorafenib, if we think about REVERCE or other trials, earlier on, you want to make sure even more that you have a great dosing strategy under the belt because this agent seems to work better if you move it up the line.

John L. Marshall, MD: Howard, quick close.

Howard S. Hochster, MD, FACP: I was going to agree with that. I think a lot of patients end up on 120 mg. I mean, that’s probably the most common dose with it, and they can tolerate that pretty well. But I agree, you should try to get to 160 mg. But if they’re not really tolerating 120 mg perfectly, there’s probably no reason to make them miserable and push it higher. And the other point I wanted to say, even going back to the CORRECT study, there are about 20% of patients who have 6 to 12 months of benefit. So I think that’s what we’re really looking for: the people who really get a benefit from it. And some of these people have lung metastases that hollow out, and they have really interesting responses.

John L. Marshall, MD: Yeah, and a really important message we need to share with our patients and with our referring doctors. This drug does have value with that nice tail of the curve. Last point.

Tanios S. Bekaii-Saab, MD: So on that point, and very quickly, regardless of the arm they were on, when they actually went to the third cycle, the median survival was 12 months.

John L. Marshall, MD: From then.

Tanios S. Bekaii-Saab, MD: From then. But I think that’s an important point because we always think about these agents, and it probably applies the same to TAS-102 and others, we always think about these agents as an average survival of maybe 6 months, and then we add maybe a month or 2. But for those patients who benefit, the median survival is actually pretty significant. It’s, on average, 1 year. That’s a lot of time for a patient in the refractory setting.


Transcript Edited for Clarity

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Transcript: 

John L. Marshall, MD:
So I’m going to let Tony talk about dosing for regorafenib. Is anybody fiddling with TAS-102 dosing? So we’ve got this funky 2-week on, 2-week off, a lot of myelosuppression. Is anybody going with every other week?

Howard S. Hochster, MD, FACP: Well, there are data in combination. We did a study of TAS-IRI [irinotecan] and bev [bevacizumab], in which you give 5 days every 14. And also, at this GI ASCO [Gastrointestinal Cancers Symposium] meeting, there’s a poster from a study that I started at Yale University that Mike Cecchini is presenting of TAS with oxaliplatin. And that is also given on a 2-week schedule, like that with just 5 days. And I think that does improve the tolerance a little bit better, and it’s the same dose intensity. But I don’t know for sure that it wouldn’t, given it’s equivalent.

John L. Marshall, MD: Right. Is anybody else fiddling? Is anybody adding a little bev in this setting?

Joleen M. Hubbard, MD: We’ve tried that at Mayo Clinic, adding some bevacizumab. Sometimes there are issues with coverage for that. We don’t have great data to suggest that we’re benefiting, but from some anecdotal reports, we’ve had some good responses.

John L. Marshall, MD: It’s that sort of bev beyond progression theory, right?

Howard S. Hochster, MD, FACP: Well, there are data from Japan. Ushino did a study with TAS and bev that looks pretty positive. And then in Europe they did a first-line study for patients who weren’t eligible for combination chemotherapy in the eyes of their providers. And in Europe, I guess they’re a little bit more reluctant in some patients to give combination chemotherapy. Mostly they were elderly but still with good performance status. But TAS and bev was better than cape [capecitabine] and bev, and that’s the TASCO1 trial. I think that today, if they’re a good performance status patient, I tend to give people TAS and bev.

John L. Marshall, MD: Tony?

Tanios S. Bekaii-Saab, MD: To an original point, really for fluoropyrimidines overall, you need 5 days every 7 days. So that goes back to the maintenance question, maybe perhaps to answer your original question that it’s OK to give 5 days of cape and give 2 days off and continue with that. But that’s a good proof of principle. Now, going back to the dosing with regorafenib…

John L. Marshall, MD: Give us the quick summary of what the gang out there really needs to know about dosing this drug.

Tanios S. Bekaii-Saab, MD: We’ve always toyed with the drug with dosing in the clinic because we have issues with certainly cumulative toxicity and early toxicity in the first 2 weeks. So this study, the ReDOS trial, was trying to find a clinical way, an optimized way to essentially figure out the best dose for the patient, the right dose for the patient as close as possible. So it had 2 arms. One arm was what we call the “dose escalation strategy.” It went from 80 to 120 to 160 on a weekly basis, increased by 40 as the patient tolerated. And the other one was a very standard 160. The primary outcome was essentially an outcome that measures both efficacy and tolerability, and it was the capacity for the patients to be able to make it to the third cycle. So go into 2 cycles, and get a scan, and if they’re tolerating the drug, of course they continue through a third cycle. And we’re hoping for 15% improvement with a dose escalation strategy versus the standard 160 dose, and we actually got 16%. This was statistically significant. It was positive. There were 120 patients, so it’s not a small study by all the standards that go into the NCCN [National Comprehensive Cancer Network] guidelines. In fact, this actually went into the NCCN guidelines.

John L. Marshall, MD: And I think this is going to result in a label change, right?

Tanios S. Bekaii-Saab, MD: It’s actually already added some level to the label. When we publish the paper, it may change the label. The most intriguing finding was actually a survival advantage, although it was, for secondary endpoints, statistically a wash, but it was—now with the updated data—a 4-month difference in survival between the dose escalation strategy—80, 120, 160—versus the 160 dose. And what’s interesting is that when we looked at arm B, which is the 160 dose, the survival was 6 months. This is similar to what you see in CORRECT. So your arm A, the dose escalation arm, had a 10-month survival, and that’s in a very refractory patient population.

John L. Marshall, MD: Is everybody doing this?

Joleen M. Hubbard, MD: Yeah. We’ve been doing this at Mayo Clinic for a long time, and it works quite well. We need to get the message out to our community colleagues. I commonly will get referrals, and they’ll say right in the referral from the community oncologist, “I refuse to give that drug. It’s a horrible drug.” I think if we give it in the right way, if we dose escalate, we can keep patients on it for a longer period of time. And we do have data to suggest that the initial toxicities actually lessen over time. I actually had a patient who was mad at me because she initially lost weight; she wanted to lose weight. And then after a couple of months on the drug, that adverse effect went away, and she started gaining weight again. I think you can give it in a humane and safe way. It’s a great strategy.

John L. Marshall, MD: How important do you think it is to do the dose escalation? I hear a lot of doctors saying, “Well, I’ll just split the difference. I’ll start at 120, and I’ll see them in a month.” Are you seeing them every week and managing them that way?

Joleen M. Hubbard, MD: We see them every 2 weeks, and we definitely just go ahead and start with the 80. I think it is a more tolerable approach to do a gradual ramp-up.

John L. Marshall, MD: Do I need to push to toxicity? So if there’s zero toxicity, I go all the way to 160? Is that what you do?

Christopher Lieu, MD: Well, I would. I think you try to get to the FDA-approved dosing of 160 mg, but sometimes, in some patients, you just can’t get there, which is OK.

John L. Marshall, MD: Is hand-foot good?

Tanios S. Bekaii-Saab, MD: Hand-foot is improved.

John L. Marshall, MD: No, does hand-foot improve my outcome?

Tanios S. Bekaii-Saab, MD: The answer is, yes, but I’d be careful because, again, it goes back to the whole concept. Do I need to improve a month and just punish the patient? The answer is no. I think it’s important to understand that in this study the goal was to reach 160. In fact, half the patients who stayed on beyond 2 cycles were on 160 mg. And some of the best performers were on 160 mg. So it should remain the goal, and I think you have to do it in a measured fashion. The other very important point to make is that the understanding of the dosage is important because essentially, even across all TKIs [tyrosine kinase inhibitors], we have difficulties with dosage. The other point is that when we’re starting to think about moving perhaps regorafenib, if we think about REVERCE or other trials, earlier on, you want to make sure even more that you have a great dosing strategy under the belt because this agent seems to work better if you move it up the line.

John L. Marshall, MD: Howard, quick close.

Howard S. Hochster, MD, FACP: I was going to agree with that. I think a lot of patients end up on 120 mg. I mean, that’s probably the most common dose with it, and they can tolerate that pretty well. But I agree, you should try to get to 160 mg. But if they’re not really tolerating 120 mg perfectly, there’s probably no reason to make them miserable and push it higher. And the other point I wanted to say, even going back to the CORRECT study, there are about 20% of patients who have 6 to 12 months of benefit. So I think that’s what we’re really looking for: the people who really get a benefit from it. And some of these people have lung metastases that hollow out, and they have really interesting responses.

John L. Marshall, MD: Yeah, and a really important message we need to share with our patients and with our referring doctors. This drug does have value with that nice tail of the curve. Last point.

Tanios S. Bekaii-Saab, MD: So on that point, and very quickly, regardless of the arm they were on, when they actually went to the third cycle, the median survival was 12 months.

John L. Marshall, MD: From then.

Tanios S. Bekaii-Saab, MD: From then. But I think that’s an important point because we always think about these agents, and it probably applies the same to TAS-102 and others, we always think about these agents as an average survival of maybe 6 months, and then we add maybe a month or 2. But for those patients who benefit, the median survival is actually pretty significant. It’s, on average, 1 year. That’s a lot of time for a patient in the refractory setting.


Transcript Edited for Clarity
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