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Sequencing and Dosing for Refractory Colon Cancer

Panelists: John L. Marshall, MD, Georgetown University; Bert H. ONeil, MD, Indiana University School of Medicine; Marwan Fakih, MD, City of Hope Comprehensive Care Center; Gabriela Chiorean, MD, University of Washington School of Medicine; Wells A. Messersmith, MD, FACP, University of Colorado Cancer Center
Published: Friday, Sep 21, 2018

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Transcript:

John L. Marshall, MD: Bert, let’s go back to religion here and talk about refractory disease. We’ve had some new data over the past year or so on some of our newer agents. Could you review for us the REVERCE clinical trial? This is back to Wells’ point earlier about sequencing. Is there 1 right way to do it?

Bert H. O’Neil, MD: Yes, I would say REVERCE, for me, was one of the bigger surprises of the past year. This is a small randomized Japanese study looking at sequencing—cetuximab and regorafenib. And it asked the relatively simple question: Which one should you give first in a patient who has already had chemotherapy? They actually demonstrated a survival advantage for giving regorafenib first followed by cetuximab over the opposite sequence. Again, it’s small. I don’t know how much weight to put on that, but they had a particularly long progression-free survival on cetuximab in the patients who had been treated with regorafenib first. Is there some biology there? I don’t know. It’s very interesting, and I think maybe it will lead to larger studies that would be more definitive there.

John L. Marshall, MD: Yes, I’ve never seen regorafenib really catch somebody who’s falling, the way I put it. But in a patient who’s doing well or has a small volume disease, you know those are the patients who might have the more controlled experience with it. But the dose—we hate the dose. So, the ReDOS study, Gabby, looks at, is there a better dosing schedule for that? Do you want to review that clinical trial that Tony did for us?

Gabriela Chiorean, MD: Yes, I’d be very happy to. So, I think that way too often, especially for those of us who do a lot of phase I trials, we are used to the 3 + 3 approach, and sometimes the drug companies choose to move forward a dose of a drug that’s maximally tolerated, despite maybe pharmacokinetics indicating that the lower dose might be achieving the target, etc.

So, sometimes, again, we are pushing drugs too far. And I think what the ReDOS trial tries to see is: Can we start with a lower dose of regorafenib and gradually increase it week by week, as long as patients are able to tolerate it, and compare the low-dose start with a standard dose of 160 mg for 3 weeks on, 1 week off, and see really how many patients can tolerate it? How many can move on beyond 2 months and stay on treatment, as well as then look at progression-free and overall survival? So, the goals were really to start low, don’t lose our patients due to adverse events in the first 2 weeks because they just simply can’t tolerate the drug, and give them the benefit of being treated.

What we observed is that there was at least as good of a progression-free survival with starting low at 80 mg, advancing to 120 mg the second week, and then to 160 mg. Some patients who don’t tolerate more than 80 mg, they were allowed to stay at 80 mg. And the progression-free with low dose was 2.5 months versus 2 months with a standard dose. But the overall survival was about 9 months with starting low versus just 6 months with a standard dose, which reproduces the phase III regorafenib study. The toxicities were better with starting low—the hypertension, specifically, and the fatigue. So, I think that that study taught us that using a judicious care for dosing of our patients and not really pushing the maximum dose is very important to really allow them to tolerate and allow their quality of life.

John L. Marshall, MD: Did this change your practice at all, these 2 studies?

Bert H. O’Neil, MD: The first one, no. The REVERCE definitely does not. And the ReDOS does, because I think when you’re having a limited benefit, which is important for some patients, it’s important not to tax them with quality of life issues. So, I’m not sure, however, with the ReDOS that there is that much of a difference. The OS difference is a little bit out of line with the hazard ratio the PFS, but I’m happy enough that the PFS is the same. And even if there is no difference in outcome, I think this is important, because toxicity is an issue.

Transcript Edited for Clarity.
 

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Transcript:

John L. Marshall, MD: Bert, let’s go back to religion here and talk about refractory disease. We’ve had some new data over the past year or so on some of our newer agents. Could you review for us the REVERCE clinical trial? This is back to Wells’ point earlier about sequencing. Is there 1 right way to do it?

Bert H. O’Neil, MD: Yes, I would say REVERCE, for me, was one of the bigger surprises of the past year. This is a small randomized Japanese study looking at sequencing—cetuximab and regorafenib. And it asked the relatively simple question: Which one should you give first in a patient who has already had chemotherapy? They actually demonstrated a survival advantage for giving regorafenib first followed by cetuximab over the opposite sequence. Again, it’s small. I don’t know how much weight to put on that, but they had a particularly long progression-free survival on cetuximab in the patients who had been treated with regorafenib first. Is there some biology there? I don’t know. It’s very interesting, and I think maybe it will lead to larger studies that would be more definitive there.

John L. Marshall, MD: Yes, I’ve never seen regorafenib really catch somebody who’s falling, the way I put it. But in a patient who’s doing well or has a small volume disease, you know those are the patients who might have the more controlled experience with it. But the dose—we hate the dose. So, the ReDOS study, Gabby, looks at, is there a better dosing schedule for that? Do you want to review that clinical trial that Tony did for us?

Gabriela Chiorean, MD: Yes, I’d be very happy to. So, I think that way too often, especially for those of us who do a lot of phase I trials, we are used to the 3 + 3 approach, and sometimes the drug companies choose to move forward a dose of a drug that’s maximally tolerated, despite maybe pharmacokinetics indicating that the lower dose might be achieving the target, etc.

So, sometimes, again, we are pushing drugs too far. And I think what the ReDOS trial tries to see is: Can we start with a lower dose of regorafenib and gradually increase it week by week, as long as patients are able to tolerate it, and compare the low-dose start with a standard dose of 160 mg for 3 weeks on, 1 week off, and see really how many patients can tolerate it? How many can move on beyond 2 months and stay on treatment, as well as then look at progression-free and overall survival? So, the goals were really to start low, don’t lose our patients due to adverse events in the first 2 weeks because they just simply can’t tolerate the drug, and give them the benefit of being treated.

What we observed is that there was at least as good of a progression-free survival with starting low at 80 mg, advancing to 120 mg the second week, and then to 160 mg. Some patients who don’t tolerate more than 80 mg, they were allowed to stay at 80 mg. And the progression-free with low dose was 2.5 months versus 2 months with a standard dose. But the overall survival was about 9 months with starting low versus just 6 months with a standard dose, which reproduces the phase III regorafenib study. The toxicities were better with starting low—the hypertension, specifically, and the fatigue. So, I think that that study taught us that using a judicious care for dosing of our patients and not really pushing the maximum dose is very important to really allow them to tolerate and allow their quality of life.

John L. Marshall, MD: Did this change your practice at all, these 2 studies?

Bert H. O’Neil, MD: The first one, no. The REVERCE definitely does not. And the ReDOS does, because I think when you’re having a limited benefit, which is important for some patients, it’s important not to tax them with quality of life issues. So, I’m not sure, however, with the ReDOS that there is that much of a difference. The OS difference is a little bit out of line with the hazard ratio the PFS, but I’m happy enough that the PFS is the same. And even if there is no difference in outcome, I think this is important, because toxicity is an issue.

Transcript Edited for Clarity.
 
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