Tanios Bekaii-Saab, MD
A weekly dose-escalation strategy of regorafenib (Stivarga) beginning at 80 mg and ending at 160 mg was found to be superior than the previously standard starting dose of 160 mg in patients with metastatic colorectal cancer (mCRC), according to a study reported by lead author Tanios Bekaii-Saab, MD, during the 2018 Gastrointestinal Cancers Symposium.
The phase II regorafenib dose optimization study (ReDOS) randomized patients with mCRC to either the dose-escalation arm, which began at 80 mg per day and increased weekly up to 160 mg per day if no significant drug-related toxicities occurred, or the standard dose of 160 mg of regorafenib daily.
Results showed that the median overall survival (OS) was improved in the dose-escalation arm versus the standard arm (9.0 months vs 5.9 months; P
= .094). Additionally, the median progression-free survival (PFS) was 2.5 months and 2.0 months for the dose-escalation and standard arms, respectively. Investigators noted that toxicity was more favorable in the dose-escalation arm, and quality of life parameters were improved as well.
"These findings are certainly practice changing for many,” said Bekaii-Saab in an interview with OncLive
. “The most important aspect of this study is that now we have another option, and I think it is a preferred option, of how to administer regorafenib."
In an interview during the meeting, Bekaii-Saab, professor of medicine, Mayo Clinic, discussed the results and significance of the ReDOS study, as well as shared some insight on the Reverce trial.
OncLive: Please provide an overview of the ReDOS trial.
: The whole premise of what we call “the regorafenib optimization study” started with the idea that regorafenib is an active drug and it has shown to be active in 2 studies—CORRECT and CONCUR. There were some limitations to understanding the dosing strategy, given some of the toxicities that have limited its use in actual practice. One-third of the patients would start at the standard dose of 160 mg, and for the other two thirds, physicians would start a random dose here or there without a strategy. Therefore, we thought that through the ACCRU network we would like to do a study that helps inform clinical practice asking [the question], what is the best strategy to treat our patients effectively?
The study design was essentially simple. [It had] two arms; one arm was the standard 160 mg dose; the other arm was what we call a dose escalation. The intent was to get to 160 mg, but the question is, “How do we do it?” We followed the strategy where you start at the lowest dose—80 mg—and then after 1 week, patients came to the clinic. We assessed them for toxicities and went to 120 mg, and the goal in the third week was to try to get them to 160 mg—the optimal dose. Then, whatever that dose was [in the third week], we proceeded to the second cycle. That was the premise.
The primary endpoint of the study was one that would capture both the potential efficacy as well as the toxicity. It was a patient who could actually go through 2 cycles, and then get to their scan with the intent to go to the third cycle. We were looking for a 15% difference, meaning that we were hoping that the dose-escalation strategy would be better than the standard strategy, and an acceptable gain of 15% would declare the study positive.
What were the overall findings?
The study accrued approximately 123 patients throughout the United States through our network, and the primary endpoint was met—so it was a positive study. The difference was pretty impressive between the 2 arms; it was a little bit less than double, and was statistically significant. Essentially, the study was positive, suggesting that the dose-escalation strategy from 80 mg to 120 mg to 160 mg was superior in that aspect to the 160 mg.
What was interesting and intriguing was also looking at the secondary endpoint of survival. With the dose-escalation strategy, the survival was 9 months versus the standard dose strategy which is 6 months. Now, 6 months is the number that we see in CRC with 160 mg, so that is what you would expect from regorafenib and from certain other drugs in the same space such as TAS-102 (Lonsurf) and other agents, which produce a survival close to 6 months.
We are very pleasantly surprised that the survival with the dose-escalation strategy was 9 months and 3 months superior. Even though it was not statistically significant, if you look at those curves, they separate very nicely from the beginning and stay all the way through beyond 1 year. That got us excited that there was a favorable secondary endpoint.