Regorafenib Dose Escalation Superior in Metastatic CRC

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."

OncLive: Please provide an overview of the ReDOS trial.

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.Bekaii-Saab: 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.

What were the overall findings?

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.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.

The PFS was a little better, and the toxicity profile was slightly improved with the dose-escalation strategy because, ultimately, everyone gets onto the same dosage. Another finding that was very intriguing was the quality of life. The quality of life of patients, when you use the dose-escalating strategy from 80 mg to 120 mg to 160 mg, was not compromised when you use the dose-escalating strategy; it was a straight line.

Whereby, with the higher standard dose of 160 mg, we see a drop in the quality of life that readjusts as you readjust the dose of the medication. That difference was consistent across every parameter that was included in the quality of life. Ultimately, when you put this all together, it seems that a dose-escalation strategy may confer a larger benefit than just starting with 160 mg, and could perhaps change the standard of how we do things.

How do you think that these findings are going to impact the treatment landscape of metastatic CRC?

Certainly, there are limitations with this study. It is a phase II randomized study, not a phase III randomized study. However, it was powered enough to understand the question and it creates a new strategy for our patients when physicians decide to start with a lower dose. In my own practice, this is the strategy I am going to adopt based on ReDOS, meaning every patient I am going to see in clinic is going to start at 80 mg, come back in a week and go to 120 mg, and come back in another week and, if it is still tolerable, they go to the 160-mg dose.To put the global picture in context, there was another study from our Japanese colleagues called Reverce. It was a very interesting study which was essentially a randomized phase II study that was looking at a question that started with the CONCUR study.

CONCUR was a study with regorafenib in an Asian population. Due to lack of resources, many patents did not go through every biologic before they got to regorafenib. It was technically a study that looked at regorafenib earlier on. The…study was more significant than we've seen on the CORRECT study—meaning that the survival and the PFS were much more impressive, historically, at least.

Therefore, the Reverce study asked whether regorafenib can be given to patients with RAS wild-type tumors before having to go to cetuximab (Erbitux) versus starting first with cetuximab and bringing in regorafenib. It was a practical question, and the primary endpoint was survival. Surprisingly, if you go with regorafenib first and then go to cetuximab, the difference in survival was 6 months, and statistically significant; it met the primary endpoint. When they looked at PFS, it again confirmed that the benefit of regorafenib is more when you use it before cetuximab rather than after. Interestingly, cetuximab does not lose effect across lines of therapy, while regorafenib loses effect across lines of therapy.

What do you hope that oncologists took away from the dose-escalation study?

Are there any further steps as of now?

As we get more confirmatory studies, [we might want] to consider regorafenib a little earlier on if we want to get the full benefit of the agent rather than wait until the end when the patient is literally about to go to hospice. A dose-escalation strategy would make more sense now than the standard 160 mg. We have to become more proactive about how we place our drugs and how to optimize the dose-escalation strategy for regorafenib.The most important aspect of this study is that now we have another option. It is a preferred option of how to administer regorafenib. This one thing that we wanted to achieve with this study was to at least create a strategy for those physicians who are reluctant to start at 160 mg. This is better than just doing guesswork. Now, we have a strategy that shows that we do not lose benefit by starting with a lower dose and escalating to 120 mg and 160 mg. We may even have a superior strategy—yet to be confirmed in larger trials—but at least a non-inferior, equivalent, and possibly superior strategy.We are working on confirming the results of Reverce in the United States. We are working through the ACCRU network working on a proposal to ask the same question that was asked in Reverce in US patients with metastatic CRC. This is to understand whether indeed, moving regorafenib up the line, even before EGFR inhibitors, may improve outcomes as we are seeing with the Japanese Reverce study.

Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study. J Clin Oncol. 2018;36(suppl 4S; abstr 611).

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