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ReDOS Trial: Optimizing Regorafenib Dosing in metastatic Colorectal Cancer

Insights From: Tanios Bekaii-Saab, MD, Mayo Clinic; Johanna C. Bendell, MD, Sarah Cannon Research Institute
Published: Monday, Oct 08, 2018



Transcript:

Tanios Bekaii-Saab, MD: The problem with regorafenib is that its toxicities come quite early, and they can be quite severe. Day 15 is usually where you start seeing a lot of these toxicities accumulate: hand-and-foot syndrome reaction and fatigue. That has been a main limiting factor. The CORRECT trial—the one that led to the approval of this drug—started with 160 mg in patients who were maintained at 160 mg if they were able to tolerate it. Eighty percent of patients will have some level of dose reduction or change in the schedule of the drug. Physicians and clinicians have used a lot of different schedules and dosing regimens without any substantiated data. That made it a little bit difficult to pick up the right schedule or dose for the drug.

Then comes the ReDOS trial that we presented recently at the ESMO GI [European Society for Medical Oncology World Congress on Gastrointestinal Cancer], and that study essentially looked at 2 dosing regimens with regorafenib. One was what we call a dose-escalation strategy starting with 80 mg; after a week, switching to 120 mg; then, after a week, switching to 160 mg. The goal is to try to reach 160 mg, and then take a week break. The standard was 160 mg. When we [looked] at the primary endpoints that would make sense for us, we chose one that would bring both the efficacy and the toxicity into play and that would be what percentage of patients could cross 2 cycles and then move to the third cycle. We thought that we needed 15% in arm A, which is the dose-escalation strategy, to be the superior versus arm B. The study ended up being positive. Going from 80 mg to 120 mg to 160 mg was superior to the 160 mg from the get-go. Almost double the percentage of patients were able to achieve success after cycle 2, going to cycle 3.

The survival was surprisingly superior in that dose-escalation strategy. In fact, it was a little bit more than 3 months’ superior, and those data were actually quite separated all the way up to 12 months. That was not statistically significant, but it was nonetheless numerically meaningful. This was not a primary endpoint. This was the endpoint. PFS [progression-free survival] was a little better. Quality of life for patients who went under the dose-escalation strategy was essentially maintained whereas 160 mg dropped a little bit.

Overall, our conclusion was that a dose-escalation strategy from 80 mg to 120 mg to 160 mg is a superior strategy to 160 mg based on us reaching our primary endpoint, and in fact, that should be the adopted strategy when using this drug. That has become a standard, and my clinic actually reinforced the positioning of regorafenib in the third line prior to TAS-102. The data made it easier—that study made it easier—for us to use regorafenib in the clinic. That superior survival, although not statistically significant, was pretty meaningful for us to consider this our preferred option.

For the ReDOS trial, when looking at the dose-escalation arm at 120 mg to 160 mg versus 160 mg, the toxicities were slightly improved overall with the dose escalation arm versus the 160 mg arm. That’s not surprising. Ultimately, the doses after cycle 1 will meet around the midpoint anyway, and patients start behaving similarly. There were fewer toxicities.

I think what’s most telling is that the quality of life of the patients on the dose-escalation arm did not seem to be compromised, so the toxicities were relatively more acceptable to patients. We did see some hand-and-foot syndrome reactions, and PPS [postprogression survival], specific quality-of-life measures, seemed to be slightly improved under the dose-escalation arm. I think that overall, there has been an improvement in how patients are able to tolerate their treatment and how they are able to move through first cycle to second cycle to third cycle.

Johanna C. Bendell, MD: The ReDOS trial taught us a lot about how to dose regorafenib for patients. What we’ve learned is that the 160-mg starting dose may be a bit high for most patients, and we should go ahead and start at a lower dose and then ramp it up if tolerated, which protects patients from having immediate toxicities and having a long time off of the drug. Some patients have such severe toxicities that they don’t want to go back on drug. Our best chance at giving regorafenib is probably to dose very similar to the ReDOS study, starting at 80 mg and seeing how patients do. We try to bring patients into clinic maybe once a week, once every other week, or follow up with them by telephone and really teach them that if they start to have adverse effects, they should call in and let us know so we can adjust the dosage right away.

I think we’re seeing some further studies that are looking at patients who are receiving regorafenib in the community setting, both in the United States as well as Europe, that are really suggesting that we’re learning better how to treat patients with regorafenib and do quick dose modifications as needed. Patients are having better survival outcomes because of that.

Transcript Edited for Clarity.
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Transcript:

Tanios Bekaii-Saab, MD: The problem with regorafenib is that its toxicities come quite early, and they can be quite severe. Day 15 is usually where you start seeing a lot of these toxicities accumulate: hand-and-foot syndrome reaction and fatigue. That has been a main limiting factor. The CORRECT trial—the one that led to the approval of this drug—started with 160 mg in patients who were maintained at 160 mg if they were able to tolerate it. Eighty percent of patients will have some level of dose reduction or change in the schedule of the drug. Physicians and clinicians have used a lot of different schedules and dosing regimens without any substantiated data. That made it a little bit difficult to pick up the right schedule or dose for the drug.

Then comes the ReDOS trial that we presented recently at the ESMO GI [European Society for Medical Oncology World Congress on Gastrointestinal Cancer], and that study essentially looked at 2 dosing regimens with regorafenib. One was what we call a dose-escalation strategy starting with 80 mg; after a week, switching to 120 mg; then, after a week, switching to 160 mg. The goal is to try to reach 160 mg, and then take a week break. The standard was 160 mg. When we [looked] at the primary endpoints that would make sense for us, we chose one that would bring both the efficacy and the toxicity into play and that would be what percentage of patients could cross 2 cycles and then move to the third cycle. We thought that we needed 15% in arm A, which is the dose-escalation strategy, to be the superior versus arm B. The study ended up being positive. Going from 80 mg to 120 mg to 160 mg was superior to the 160 mg from the get-go. Almost double the percentage of patients were able to achieve success after cycle 2, going to cycle 3.

The survival was surprisingly superior in that dose-escalation strategy. In fact, it was a little bit more than 3 months’ superior, and those data were actually quite separated all the way up to 12 months. That was not statistically significant, but it was nonetheless numerically meaningful. This was not a primary endpoint. This was the endpoint. PFS [progression-free survival] was a little better. Quality of life for patients who went under the dose-escalation strategy was essentially maintained whereas 160 mg dropped a little bit.

Overall, our conclusion was that a dose-escalation strategy from 80 mg to 120 mg to 160 mg is a superior strategy to 160 mg based on us reaching our primary endpoint, and in fact, that should be the adopted strategy when using this drug. That has become a standard, and my clinic actually reinforced the positioning of regorafenib in the third line prior to TAS-102. The data made it easier—that study made it easier—for us to use regorafenib in the clinic. That superior survival, although not statistically significant, was pretty meaningful for us to consider this our preferred option.

For the ReDOS trial, when looking at the dose-escalation arm at 120 mg to 160 mg versus 160 mg, the toxicities were slightly improved overall with the dose escalation arm versus the 160 mg arm. That’s not surprising. Ultimately, the doses after cycle 1 will meet around the midpoint anyway, and patients start behaving similarly. There were fewer toxicities.

I think what’s most telling is that the quality of life of the patients on the dose-escalation arm did not seem to be compromised, so the toxicities were relatively more acceptable to patients. We did see some hand-and-foot syndrome reactions, and PPS [postprogression survival], specific quality-of-life measures, seemed to be slightly improved under the dose-escalation arm. I think that overall, there has been an improvement in how patients are able to tolerate their treatment and how they are able to move through first cycle to second cycle to third cycle.

Johanna C. Bendell, MD: The ReDOS trial taught us a lot about how to dose regorafenib for patients. What we’ve learned is that the 160-mg starting dose may be a bit high for most patients, and we should go ahead and start at a lower dose and then ramp it up if tolerated, which protects patients from having immediate toxicities and having a long time off of the drug. Some patients have such severe toxicities that they don’t want to go back on drug. Our best chance at giving regorafenib is probably to dose very similar to the ReDOS study, starting at 80 mg and seeing how patients do. We try to bring patients into clinic maybe once a week, once every other week, or follow up with them by telephone and really teach them that if they start to have adverse effects, they should call in and let us know so we can adjust the dosage right away.

I think we’re seeing some further studies that are looking at patients who are receiving regorafenib in the community setting, both in the United States as well as Europe, that are really suggesting that we’re learning better how to treat patients with regorafenib and do quick dose modifications as needed. Patients are having better survival outcomes because of that.

Transcript Edited for Clarity.
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