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The Use of Regorafenib in Clinical Practice

Insights From: Tanios Bekaii-Saab, MD, Mayo Clinic; Fortunato Ciardiello, MD, PhD, Seconda Universita di Napoli; Axel Grothey, MD, West Cancer Center & Research Institute
Published: Friday, Aug 09, 2019



Transcript:

Fortunato Ciardiello, MD, PhD: One of the problems with regorafenib is that it can have some adverse effects, and it can limit the use or require stopping the use or stopping the dose. And so precluding the possibility that these drugs would be efficacy for the patient. The original starting dosage of 160 mg per day for 3 weeks with 1 week of rest per cycle was really having problems in about 50% of patients. Some problems have relatively high adverse effects, including asthenia, cutaneous toxicity, different types of skin toxicity, and in some cases transat the beginning some liver toxicity. That requires reduction of the dose, or even interruption of the dosage.

Therefore, the ReDOS study has been a very clever evaluation of starting the completely different strategic approach. That means starting with the lower dose, 80 mg, and increase this dose step-by-step during the first weeks of treatment in order to define the best personalized dose for any individual patient. In this case, most patients will be treated between 120 and 160 mg. Some patients will stay with 80 mg. By doing this, we are able to understand the early signs of adverse effects, to manage them, and to do dose increase according to the ReDOS escalation scheme, but only in those patients in which this can be of value and can be tolerable.

Axel Grothey, MD: One of the treatment options in a later-line setting is regorafenib. Regorafenib created initial excitement when it came out because it was a new treatment option that improved survival for patients. Then a lot of this enthusiasm was tempered by the fact that it was considered not an easy drug to administer because of adverse effects and toxicities, and these toxicities actually came early in the management of patients within the first 2 or 3 weeks of treatment.

Based on the ReDOS data, which looked at comparison between a de-escalation and escalation strategy for patients on regorafenib, I think it is very clear that the standard of care when you use regorafenib in these patients with metastatic colorectal cancer should be to start with a lower dosage, 80 mg per day for the first week, and go to a potentially higher dosage, 120 mg per day for the second week and then 160 mg if patients tolerate it for week 3. Then patients have a week break, and then patients can actually be treated with the treatment option, the treatment dose, if they actually tolerate it in the first-line setting.

This has fed a new standard of care because we know patients’ quality of life in this randomized ReDOS study was not affected when they were on regorafenib. The quality of life was not mitigated by the use of this agent, which has some toxicity issues. Overall survival trended longer. It was clearly not harmful to patients who started with a lower dose, and patients tolerated it better. I think it is the new standard of care.

The question now is, if we have a better-tolerable drug, should we use it even in earlier lines of therapy? Cause there’s the idea, and actually we have some data, that regorafenib benefits patients even better when they’re less heavily pretreated. So far I still would reserve it as a third-line treatment setting. I think anything earlier would be a matter of clinical trials, unless patients have been treated with FOLFOXIRI [5-flourouracil, calcium leucovorin, oxaliplatin, irinotecan], so the use of 3 chemotherapy agents and then regorafenib will be your second-line setting. But I would not use it in earlier lines of therapy yet. If at all, I do believe we need to enhance its activity even further, and there are some intriguing data, there are immuno-oncology agents, immunotherapy in combination with regorafenib, which eventually might allow regorafenib to move further into earlier lines of therapy.

Transcript Edited for Clarity
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Transcript:

Fortunato Ciardiello, MD, PhD: One of the problems with regorafenib is that it can have some adverse effects, and it can limit the use or require stopping the use or stopping the dose. And so precluding the possibility that these drugs would be efficacy for the patient. The original starting dosage of 160 mg per day for 3 weeks with 1 week of rest per cycle was really having problems in about 50% of patients. Some problems have relatively high adverse effects, including asthenia, cutaneous toxicity, different types of skin toxicity, and in some cases transat the beginning some liver toxicity. That requires reduction of the dose, or even interruption of the dosage.

Therefore, the ReDOS study has been a very clever evaluation of starting the completely different strategic approach. That means starting with the lower dose, 80 mg, and increase this dose step-by-step during the first weeks of treatment in order to define the best personalized dose for any individual patient. In this case, most patients will be treated between 120 and 160 mg. Some patients will stay with 80 mg. By doing this, we are able to understand the early signs of adverse effects, to manage them, and to do dose increase according to the ReDOS escalation scheme, but only in those patients in which this can be of value and can be tolerable.

Axel Grothey, MD: One of the treatment options in a later-line setting is regorafenib. Regorafenib created initial excitement when it came out because it was a new treatment option that improved survival for patients. Then a lot of this enthusiasm was tempered by the fact that it was considered not an easy drug to administer because of adverse effects and toxicities, and these toxicities actually came early in the management of patients within the first 2 or 3 weeks of treatment.

Based on the ReDOS data, which looked at comparison between a de-escalation and escalation strategy for patients on regorafenib, I think it is very clear that the standard of care when you use regorafenib in these patients with metastatic colorectal cancer should be to start with a lower dosage, 80 mg per day for the first week, and go to a potentially higher dosage, 120 mg per day for the second week and then 160 mg if patients tolerate it for week 3. Then patients have a week break, and then patients can actually be treated with the treatment option, the treatment dose, if they actually tolerate it in the first-line setting.

This has fed a new standard of care because we know patients’ quality of life in this randomized ReDOS study was not affected when they were on regorafenib. The quality of life was not mitigated by the use of this agent, which has some toxicity issues. Overall survival trended longer. It was clearly not harmful to patients who started with a lower dose, and patients tolerated it better. I think it is the new standard of care.

The question now is, if we have a better-tolerable drug, should we use it even in earlier lines of therapy? Cause there’s the idea, and actually we have some data, that regorafenib benefits patients even better when they’re less heavily pretreated. So far I still would reserve it as a third-line treatment setting. I think anything earlier would be a matter of clinical trials, unless patients have been treated with FOLFOXIRI [5-flourouracil, calcium leucovorin, oxaliplatin, irinotecan], so the use of 3 chemotherapy agents and then regorafenib will be your second-line setting. But I would not use it in earlier lines of therapy yet. If at all, I do believe we need to enhance its activity even further, and there are some intriguing data, there are immuno-oncology agents, immunotherapy in combination with regorafenib, which eventually might allow regorafenib to move further into earlier lines of therapy.

Transcript Edited for Clarity
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TitleExpiration DateCME Credits
Oncology Briefings™: Individualizing Treatment After Second-Line Therapy for Patients With mCRCAug 29, 20191.0
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