Sequencing Therapy in CRC: REVERCE Trial

Transcript: John L. Marshall, MD: So this is a second-line study that really was, I think, very controversial in design. It gave us an interesting signal that I’d love for you to share—this REVERCE clinical trial of bringing regorafenib in an earlier line of therapy. Describe that trial.

Tanios S. Bekaii-Saab, MD: This is a Japanese study, and we’re building a reverse to try to understand whether that applies to our patients here, and that study will be starting soon. But REVERCE actually is an interesting study, and there were a lot of signals relating to regorafenib perhaps having a better effect if you move it up the line rather than wait for patients to essentially be drained before they receive regorafenib. So the question was, essentially, can we do regorafenib in KRAS and RAS wild-type patients followed by cetuximab in the refractory setting, or just do the reverse—cetuximab followed by regorafenib?

Interestingly, and we’ll talk about the limitations regarding how to interpret these results and make them clinically applicable at this point, the study showed that if you actually initiate regorafenib before cetuximab you have a differential survival effect that was statistically significant. This was powered for survival. About 5 months’ difference. And then the reverse, then starting with cetuximab followed by regorafenib.

What was interesting was actually that when you start piecemealing and breaking the study into trying to understand what’s doing what, the benefit on survival from regorafenib being pulled earlier seems to actually increase quite significantly, then, when you give it after cetuximab. However, cetuximab kept its benefit the same, whether you used it before or after.

So the conclusion from the study was essentially that perhaps pulling—and there are, you know, a number of preclinical reasons for that—regorafenib before cetuximab in patients may actually add to survival. The problem with the study, while it was a good phase II randomized study and was a great effort, is that it was cut short in terms of its accrual goals because of loss of funding. So you lose value, and you lose statistical significance, essentially. I think that although the P value is very solid and the survival curves look very convincing, it does establish a signal. What you do in clinic, I don’t think that study is yet applicable for prime time in the clinic until it gets reproduced.

John L. Marshall, MD: See, I’m in. So, Chris, this messes me up, because…

Tanios S. Bekaii-Saab, MD: On the right side.

John L. Marshall, MD: Well, I mean, even so. Is this just another sort of maintenance, if you will? If you’ve got a relatively asymptomatic patient—and let’s make them left-side RAS wild-type, and they have relatively small tumor burden—I know if I wait too late for regorafenib, it won’t work as well. So this actually, for me, gives me a little permission to try it earlier. Chris, where are you with this?

Christopher Lieu, MD: So I would agree with Tony that I don’t necessarily think it’s completely practice changing.

John L. Marshall, MD: You know, I’m the moderator here.

Christopher Lieu, MD: But having said that, I will, in a way, agree with you. I don’t think you’re going to get into any problems with getting this approved, in terms of reimbursement. And that’s a very practical part of this.

John L. Marshall, MD: There is a form that nurses fill out. I’m so glad you brought that up because it basically says, if you’re RAS wild-type, have you had an EGFR? And this is the insurance form to approve for regorafenib. So it might, actually.

Christopher Lieu, MD: So it could. I don’t recall getting that form, but I’ll be on the lookout for it now. But if you’re in a refractory setting, and you have a patient who presumably has a good performance status, I think it gives you some leeway to say, “Well, this is something that you want to try.” And again, this is a conversation with the patient. These are the potential adverse effects. This is the treatment plan. We want to start regorafenib, and then we’ll have cetuximab in our back pocket should we need it. There may be some hint of activity. It’s not phase III randomized data. We still need some more information. But I think it gives you some permission, if this is a strategy that you want to pursue, to give it a try.

Transcript Edited for Clarity