ReDOS Study: Regorafenib Dose Optimization

Transcript:

Tanios Bekaii-Saab, MD: As I mentioned, regorafenib’s dose that was approved by the FDA was 160 mg based on the CORRECT trial, which led to a survival benefit of regorafenib versus placebo. When we actually look at that study, which was extremely well conducted, and then we take this agent to the clinic, what we see very quickly is that those patients end up with significant toxicities in the first 2 to 3 weeks. Their worst toxicity, their first and worst toxicity, will happen in the first cycle. That essentially is where we used it first. Those patients who run out of all other options became very sick, and then we started hitting them hard with an agent whose toxicities appear very quickly, and so the patients were essentially, of course, wanting to get off the drug. The physicians didn’t want to deal with it, understandably. Mostly these were not the patients who should have gone on regorafenib when we started using it, but that’s the reality of the market.

Secondly, I think the dose, as per CORRECT, was very tough for most patients with a refractory metastatic colorectal cancer. And that was true across the world, not just in the United States. Most physicians in the US, when they wanted to use regorafenib and actually throughout the world started playing around with the dose, some would start with 80 and go to 120 mg, some would go with 120 mg and would stick with 120, others would skip a week here and there. There were a lot of different ways to give this agent, but there were 0 data to support it.

So we designed ReDOS, which is regorafenib dose optimization that went through our ACCRU [Academic and Community Cancer Research United] network as a phase II randomized study. About 123 patients ended up on this study, randomized to 2 main arms. And the 2 main arms were essentially a dosage escalation strategy. You go from 80 to 120 to 160 mg. The 80 mg on week 1, 120 mg on week 2, and 160 mg on week 3 versus the standard 160 mg on B. Though this was not a 1:1 randomization, this was what we call a 1:1:1:1 randomization because there was a secondary question that we were asking. And that’s a preemptive strategy with a steroid cream, clobetasol versus a reactive strategy—meaning when you get the hand-and-foot syndrome, you just do it to see if there is a way for us to cut down on the risk of hand-and-foot syndrome reaction. So we had 2 questions here.

Let’s go back to the dose escalation question. In the dose escalation question, our primary endpoint essentially was creative, it was trying to capture both the toxicity and efficacy of the drug. In a phase II randomized setting, we’re comparing the same drug essentially, just a different dose escalation. It’s very challenging to be able to get a primary endpoint that would be more traditional, that would capture the essence of why we’re doing this. We thought about a primary endpoint where patients would be able to go through 2 cycles of treatment and then start cycle 3. The way you think about it is if patients tolerate the drug enough to get to cycle 3, that means it’s easier on them. Then if you get to cycle 3 and start cycle 3, that means the drug is working better, and you can initiate cycle 3. We captured the essence of both.

And the thought was that a lot of patients end up dropping off regorafenib too early when we know that drug has a short-acting life and half-life. And it also seems, in this group of patients who are very refractory, we will need maximal exposure earlier on and continuous exposure to be able to have its effect. Perhaps dose escalation strategy, easing the patient into the drug, will make it not just easier but more effective. And the primary endpoint of the study was met. It almost had half the patients on arm A, which is the dose escalation strategy, going and starting and cycle 3 versus about a quarter of the patients on the arm B that actually were able to get to cycle 3. That was a positive study. We looked at quality of life, and quality of life of the patients who went on the dose escalation strategy was preserved. But for those patients who went on the 160 mg seemed to dip around 2 weeks, as we expected, and really never recovered fully. So the quality of life was better.

We also just presented data at ASCO [American Society of Clinical Oncology] Annual Meeting 2019. This came from the USC [University of Southern California] group with Afsaneh Barzi and Heinz-Josef Lenz that essentially showed that the dose escalation strategy is cost-effective and, in fact, does not reach the threshold that was essentially, or actually reaches the threshold that would actually consider it as a cost-effective strategy. That not only is easier, probably working better, but seems to be a cheaper, at least a cost-effective alternative to regorafenib 160 mg. So that’s good. I like that.

And then we presented the other sub-study, which essentially is looking at the preemptive versus reactive strategy, and it was interesting. We saw that there were significant trends toward improvement of specifically hand-and-foot syndrome reaction, including quality-of-life measures in the preemptive-versus-reactive strategy. Now the data still need to be looked at a little bit more extensively, and we’re working on this. But at this point, I’d say for the patient for whom you’re concerned that they may not have the adequate support or those patients live far and they may not be able to come every week in the first cycle. But for those patients, I would actually consider a preemptive strategy. You don’t have to use clobetasol. I think clobetasol is quite expensive. You could use prednisone or hydrocortisone cream, which is cheap and over the counter. And that could certainly help, we hope, prevent some of these effects.

Transcript Edited for Clarity