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TAS-102 Versus Regorafenib for Treating mCRC

Panelists: Johanna C. Bendell,MD, Sarah Cannon Research Institute; Dirk Arnold, MD, PhD, KTB Klinik fur Tumorbiologie GmbH & Co. KG ; Heinz-Josef Lenz, MD, FACP, USC Center for Molecular Pathway and Drug Discovery; Zev A. Wainberg, MD, UCLA Medical Center
Published: Friday, Dec 14, 2018

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Transcript: 

Johanna C. Bendell, MD:
So now we’ve gone through all of the [chemotherapies] and we’re down to TAS-102 versus regorafenib. What is your choice?

Zev A. Wainberg, MD: Right. So no head-to-head data, we all know that, so your choice is based on your particular, for lack of a better term, gestalt. We’re in Germany.

Johanna C. Bendell, MD: Gestalt, very good.

Zev A. Wainberg, MD: How do you feel the patient can tolerate the drug, how do you feel the patient can get through, stay on the therapy? And, certainly, I think the new dosing strategy of regorafenib has helped, in my opinion, make that a much more realistic and practical way to dose the drug and sort of reinforced what a lot of people are doing in practice, which is not jump immediately to the 160 [mg/day] of regorafenib but dose escalate in a slow way and do it carefully. And, if you don’t reach 160, well, maybe that’s not the biggest deal as long as patients are sustained on a tolerable dose. Personally, since that data has been presented and found its way into popular mainstream, I think that’s, in my opinion, a better way to go. I do it now almost uniformly in all my patients who get started on regorafenib.

Johanna C. Bendell, MD: So, Dirk, Zev’s alluding to the ReDOS data. What was the ReDOS study and what did we see?

Dirk Arnold, MD, PhD: Well, it goes to this series of studies which are, let’s say, playing around with the right dosing of drugs like regorafenib. And the question is, does it make sense to start with a lower level and then to escalate [the] dose or does it make sense to de-escalate [the] dose? Well, very likely these escalating dose strategies may be better.

Johanna C. Bendell, MD: Yeah. So it sounds like [they are] if you start at 80 [mg/day] and then escalate up.

Dirk Arnold, MD, PhD: Yeah, to 120 [mg] and then maybe 160 [mg]  but never reaching, nearly never reaching 160 [mg]. However, we really have to acknowledge with these flat-dosing drugs, we have to see the gestalt of the pace and see, since we have a very tiny, slim old lady, I think the optimal dosing lies already in this type, in the phenotype of the patient.

Johanna C. Bendell, MD: So are you a ReDOS person? Do you start at 80 and go up or do you start at 120?

Dirk Arnold, MD, PhD: Well, I personally would; I’m still a believer that we should have a go with 160 [mg] in an average size, an average weight patient and then go down as soon as we have to. So I would start with 120 [mg] if I would go up. I would not go down to 80 [mg].

Johanna C. Bendell, MD: Heinz?

Heinz-Josef Lenz, MD, FACP: I have adopted ReDOS like Zev because when I look at the ReDOS studies, one of the most convincing [things] is not only that more patients went into cycle 3, that the endpoint what I thought was very smart because to continue cycle 3, you had to be ongoing and have no toxicity to get off, and you had at least stable disease. So that didn’t jeopardize efficacy. Actually the survival curve at 6 versus 9 months, so you’re not jeopardizing starting. And I think regorafenib needed to do that because one of the biggest arguments within the clinical setting is you have TAS and you have regorafenib, same efficacy on the phase III level but difference in subjective toxicities, not the ones you see in the [laboratory], but subjective. There’s 7 more. However, with ReDOS, I think we have now a handle on it.

Now, when you look back on the clinical trial, there is documented survival benefit of REGO [regorafenib] over TAS-102 in PO1s, performance status 0 and 1, as well as under the age of 65. So, in this patient population, there is clearly demonstrated benefit of REGO over TAS. And you can use regorafenib and can use TAS-102 after REGO without losing efficacy. It’s the same efficacy after REGO. So I use them in this patient population and move it to third-line, doing the ReDOS and having them still eligible for other treatments. So that’s kind of my take.

Johanna C. Bendell, MD: I think what we’ve learned here is that we, as oncologists, have learned how to dose the drugs better. Because what we’ve seen is dose consistency plays such an important role in terms of dose efficacy, where you give very high doses of an agent and then they have to stop it for a long time to recover from the toxicity, rather than low and slow.


Transcript Edited for Clarity
 

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Transcript: 

Johanna C. Bendell, MD:
So now we’ve gone through all of the [chemotherapies] and we’re down to TAS-102 versus regorafenib. What is your choice?

Zev A. Wainberg, MD: Right. So no head-to-head data, we all know that, so your choice is based on your particular, for lack of a better term, gestalt. We’re in Germany.

Johanna C. Bendell, MD: Gestalt, very good.

Zev A. Wainberg, MD: How do you feel the patient can tolerate the drug, how do you feel the patient can get through, stay on the therapy? And, certainly, I think the new dosing strategy of regorafenib has helped, in my opinion, make that a much more realistic and practical way to dose the drug and sort of reinforced what a lot of people are doing in practice, which is not jump immediately to the 160 [mg/day] of regorafenib but dose escalate in a slow way and do it carefully. And, if you don’t reach 160, well, maybe that’s not the biggest deal as long as patients are sustained on a tolerable dose. Personally, since that data has been presented and found its way into popular mainstream, I think that’s, in my opinion, a better way to go. I do it now almost uniformly in all my patients who get started on regorafenib.

Johanna C. Bendell, MD: So, Dirk, Zev’s alluding to the ReDOS data. What was the ReDOS study and what did we see?

Dirk Arnold, MD, PhD: Well, it goes to this series of studies which are, let’s say, playing around with the right dosing of drugs like regorafenib. And the question is, does it make sense to start with a lower level and then to escalate [the] dose or does it make sense to de-escalate [the] dose? Well, very likely these escalating dose strategies may be better.

Johanna C. Bendell, MD: Yeah. So it sounds like [they are] if you start at 80 [mg/day] and then escalate up.

Dirk Arnold, MD, PhD: Yeah, to 120 [mg] and then maybe 160 [mg]  but never reaching, nearly never reaching 160 [mg]. However, we really have to acknowledge with these flat-dosing drugs, we have to see the gestalt of the pace and see, since we have a very tiny, slim old lady, I think the optimal dosing lies already in this type, in the phenotype of the patient.

Johanna C. Bendell, MD: So are you a ReDOS person? Do you start at 80 and go up or do you start at 120?

Dirk Arnold, MD, PhD: Well, I personally would; I’m still a believer that we should have a go with 160 [mg] in an average size, an average weight patient and then go down as soon as we have to. So I would start with 120 [mg] if I would go up. I would not go down to 80 [mg].

Johanna C. Bendell, MD: Heinz?

Heinz-Josef Lenz, MD, FACP: I have adopted ReDOS like Zev because when I look at the ReDOS studies, one of the most convincing [things] is not only that more patients went into cycle 3, that the endpoint what I thought was very smart because to continue cycle 3, you had to be ongoing and have no toxicity to get off, and you had at least stable disease. So that didn’t jeopardize efficacy. Actually the survival curve at 6 versus 9 months, so you’re not jeopardizing starting. And I think regorafenib needed to do that because one of the biggest arguments within the clinical setting is you have TAS and you have regorafenib, same efficacy on the phase III level but difference in subjective toxicities, not the ones you see in the [laboratory], but subjective. There’s 7 more. However, with ReDOS, I think we have now a handle on it.

Now, when you look back on the clinical trial, there is documented survival benefit of REGO [regorafenib] over TAS-102 in PO1s, performance status 0 and 1, as well as under the age of 65. So, in this patient population, there is clearly demonstrated benefit of REGO over TAS. And you can use regorafenib and can use TAS-102 after REGO without losing efficacy. It’s the same efficacy after REGO. So I use them in this patient population and move it to third-line, doing the ReDOS and having them still eligible for other treatments. So that’s kind of my take.

Johanna C. Bendell, MD: I think what we’ve learned here is that we, as oncologists, have learned how to dose the drugs better. Because what we’ve seen is dose consistency plays such an important role in terms of dose efficacy, where you give very high doses of an agent and then they have to stop it for a long time to recover from the toxicity, rather than low and slow.


Transcript Edited for Clarity
 
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