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Understanding the RESORCE Data in Second-Line HCC

Insights From: Richard S. Finn, MD, Geffen School of Medicine;Arndt Vogel, MD, Hannover Medical School
Published: Thursday, Dec 15, 2016


Transcript:

Richard Finn, MD:
We have been trying for a long time to find an active agent that improves survival after treatment with sorafenib. There have been many negative, phase III studies performed to date, really over the past 9 to 10 years since sorafenib’s approval. Only recently did we hear, at the World GI meeting in June of 2016, that regorafenib, a multi-kinase inhibitor, improved survival in the second-line setting. So, this study, the RESORCE study, evaluated patients who, like in the other studies, had prior sorafenib and had documented progression on sorafenib. These were not patients who were sorafenib-intolerant, but were on sorafenib and had progression of disease. They had a good performance status, and they were randomized in a blinded fashion to receive regorafenib, 160 mg daily for 3 weeks on and 1 week off, versus a matched placebo. The primary endpoint of the study was overall survival. The study went to completion, and, as the data were presented, we saw an improvement of roughly 3 months in median overall survival. I think it was 7.6 months to roughly about 10 and a half months, but really a hazard ratio of 0.62 for overall survival, which is a 38% decrease in the risk of death. Time to progression and progression-free survival were both doubled from approximately 1 and a half months to 3 months or so.

Unlike sorafenib, which does not have real responses on imaging—most patients get a benefit from sorafenib from slowing of progression and prolonged stable disease—regorafenib did have a response rate. The response rate was around 10%. That was by conventional RECIST. It was a little higher with the modified RECIST assessment. But, needless to say, the drug did improve overall survival, which is the most important endpoint. I think a lot of physicians have some reservations about regorafenib’s use because of its toxicity. It’s been used in advanced colon cancer, and the toxicity there makes it challenging to give to that population. But, interestingly, in the RESORCE study, while patients had the typical toxicities such as fatigue, diarrhea, some degree of hand-foot skin syndrome, the discontinuation rate was not out of the ordinary. It was well tolerated in that regard. Patients did need dose reductions, but the average daily dose was fairly close to the prescribed dose. And, I think, the feeling is that this was a selected population of patients. This is a group of patients who had been on sorafenib, tolerated sorafenib, and then progressed. And, therefore, they tolerated regorafenib better. In addition, they’re being managed by a group of doctors who are used to managing sorafenib. Given the similar side-effect profile between regorafenib and sorafenib, it made the patients able to stay on the drug for a longer period of time.

Arndt Vogel, MD: If we discuss the RESORCE data, I think there are 2 points we have to consider. First of all, the outcomes data are good because we have a significant improvement in overall survival. And, very interestingly, if you look at the overall survival data in the placebo and in the regorafenib group, they are very similar to the data we have seen in the STORM trial 10 years ago. Because, here, we also have an improvement from 7.8 to 10.6 months, which is very similar to what we have seen with sorafenib in first line, indicating that we have a patient population that has a very good survival because they already progressed on sorafenib.

And this brings me to the second important point here, the inclusion criteria of this trial. In contrast to most other trials that have been undertaken in HCC so far, the inclusion criteria were quite restrictive, which means only patients were included that were tolerant to sorafenib and who have progressed on sorafenib. So, intolerance to sorafenib was an exclusion criterion, basically, and the patients should have received sorafenib for at least 4 weeks in a dose of 400 mg. And the reason for that is because we have seen quite a considerable toxicity with regorafenib in colon cancer, for example. And, therefore, this trial was designed to really minimize the risk that we have toxicity problems with sorafenib in this population of patients.

Transcript Edited for Clarity
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Transcript:

Richard Finn, MD:
We have been trying for a long time to find an active agent that improves survival after treatment with sorafenib. There have been many negative, phase III studies performed to date, really over the past 9 to 10 years since sorafenib’s approval. Only recently did we hear, at the World GI meeting in June of 2016, that regorafenib, a multi-kinase inhibitor, improved survival in the second-line setting. So, this study, the RESORCE study, evaluated patients who, like in the other studies, had prior sorafenib and had documented progression on sorafenib. These were not patients who were sorafenib-intolerant, but were on sorafenib and had progression of disease. They had a good performance status, and they were randomized in a blinded fashion to receive regorafenib, 160 mg daily for 3 weeks on and 1 week off, versus a matched placebo. The primary endpoint of the study was overall survival. The study went to completion, and, as the data were presented, we saw an improvement of roughly 3 months in median overall survival. I think it was 7.6 months to roughly about 10 and a half months, but really a hazard ratio of 0.62 for overall survival, which is a 38% decrease in the risk of death. Time to progression and progression-free survival were both doubled from approximately 1 and a half months to 3 months or so.

Unlike sorafenib, which does not have real responses on imaging—most patients get a benefit from sorafenib from slowing of progression and prolonged stable disease—regorafenib did have a response rate. The response rate was around 10%. That was by conventional RECIST. It was a little higher with the modified RECIST assessment. But, needless to say, the drug did improve overall survival, which is the most important endpoint. I think a lot of physicians have some reservations about regorafenib’s use because of its toxicity. It’s been used in advanced colon cancer, and the toxicity there makes it challenging to give to that population. But, interestingly, in the RESORCE study, while patients had the typical toxicities such as fatigue, diarrhea, some degree of hand-foot skin syndrome, the discontinuation rate was not out of the ordinary. It was well tolerated in that regard. Patients did need dose reductions, but the average daily dose was fairly close to the prescribed dose. And, I think, the feeling is that this was a selected population of patients. This is a group of patients who had been on sorafenib, tolerated sorafenib, and then progressed. And, therefore, they tolerated regorafenib better. In addition, they’re being managed by a group of doctors who are used to managing sorafenib. Given the similar side-effect profile between regorafenib and sorafenib, it made the patients able to stay on the drug for a longer period of time.

Arndt Vogel, MD: If we discuss the RESORCE data, I think there are 2 points we have to consider. First of all, the outcomes data are good because we have a significant improvement in overall survival. And, very interestingly, if you look at the overall survival data in the placebo and in the regorafenib group, they are very similar to the data we have seen in the STORM trial 10 years ago. Because, here, we also have an improvement from 7.8 to 10.6 months, which is very similar to what we have seen with sorafenib in first line, indicating that we have a patient population that has a very good survival because they already progressed on sorafenib.

And this brings me to the second important point here, the inclusion criteria of this trial. In contrast to most other trials that have been undertaken in HCC so far, the inclusion criteria were quite restrictive, which means only patients were included that were tolerant to sorafenib and who have progressed on sorafenib. So, intolerance to sorafenib was an exclusion criterion, basically, and the patients should have received sorafenib for at least 4 weeks in a dose of 400 mg. And the reason for that is because we have seen quite a considerable toxicity with regorafenib in colon cancer, for example. And, therefore, this trial was designed to really minimize the risk that we have toxicity problems with sorafenib in this population of patients.

Transcript Edited for Clarity
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