Colorectal Cancer: Dosing Strategies With Regorafenib

Transcript:John Marshall, MD: Alan, I’m going to let you take the lead on the regorafenib story of dosing and managing in clinic. I’ll just set you up by saying this has matured now. We’ve gotten more comfortable with the medicine and we’ve got some strategies that we all use. So, share yours.

Alan P. Venook, MD: Of course, the issue with regorafenib is, what dose do we use and how well tolerated is it? It’s similar to sorafenib, which is almost the exact same drug. I tend to err on the side of undertreating patients with regorafenib because I don’t find toxicity is acceptable in these patients. So, I tend to start lower and then build my way up.

John Marshall, MD: 80 mg or 120 mg?

Alan P. Venook, MD: Usually, it’s 80 mg at our group, but obviously, the dose per the package inset is 160 mg.

John Marshall, MD: Let me do a quick poll. I’m a 120er.

Johanna Bendell, MD: I do 120 mg.

Tanios Bekaii-Saab, MD: I’m a 160er.

Alan P. Venook, MD: I do think, we learned with imatinib years ago, for example, you can go up much easier than you can go down. And, of course, if you get a major toxicity early on, then it may be 3 weeks, 4 weeks before you can restart it. So, I tend to start at 80 mg and we’ll go up to 120 mg.

John Marshall, MD: So, if you start at 80 mg, you see them when?

Alan P. Venook, MD: We talk to them or see them weekly.

John Marshall, MD: Squeaky clean day 8. Are you escalating or holding?

Alan P. Venook, MD: If they’re squeaky clean at day 15, I’ll go up.

John Marshall, MD: Day 15 is when you’d go up. Squeaky clean at 120 mg, I’m holding.

Johanna Bendell, MD: Squeaky clean at day 8, holding.

John Marshall, MD: Some minor stuff at day 8, you going down or you’re going to keep with it?

Tanios Bekaii-Saab, MD: Starting with 160 mg? Probably stick with it.

John Marshall, MD: See them a week later and still squeaky clean?

Alan P. Venook, MD: I’ll start dose escalating. If it’s really squeaky clean, I might go to the full dose of 160 mg.

John Marshall, MD: For the last week of that 3-week cycle?

Alan P. Venook, MD: Correct, for that cycle.

John Marshall, MD: Alright. So, I probably am holding through the first 3 weeks at 120 mg. I’m still seeing them. But maybe if it’s really squeaky clean, when are you?

Johanna Bendell, MD: Next cycle.

John Marshall, MD: Have a little hand-foot, little tenderness, but got better by cycle 2, day 1 at 160 mg. Are you holding?

Tanios Bekaii-Saab, MD: Well, you have to have a discussion with the patient. It’s all about quality of life. If the patient says, “It’s reasonable, it’s not affecting my daily life,” I’d go with it. If it seems to be affecting their daily living, I definitely would go down. And just to be clear, I don’t disagree that the story with all these TKIs seems to be consistent with a dose-escalation, de-escalation issue. You brought imatinib. With imatinib and GIST, we’re talking about 2 to 3 years. In this setting, we’re talking about 2-month PFS. It’s very difficult when you know that there’s 20% of the patients who will tolerate 160 mg. They may not need it, but will tolerate 160 mg. It’s a little bit difficult for me to do this slow escalation when I know they may lose benefit very quickly. But I think the key is really to see them, as all of you do, on a weekly basis regardless of where you start.

John Marshall, MD: I think it helps with compliance. If the patient is engaged in what we’re looking for, it’s more time.

Tanios Bekaii-Saab, MD: The right dose. If you look across the studies, the average dose is close to 120 mg, so that seems to be the dose where most patients end up falling.

John Marshall, MD: Weekly CBC and LFTs?

Alan P. Venook, MD: Yes.

John Marshall, MD: And looking at those, everybody agree with that? I just want to throw this out: those patients that seem to fly through at 160 mg and no toxicities, I haven’t seen a responder yet. There are patients with some hand-foot syndrome. So, anybody else seeing toxicities and benefit?

Tanios Bekaii-Saab, MD: No, I can’t say that toxicities, at least in my practice, have been limited to benefit. But I have actually had a patient go a whole year on 160 mg.

John Marshall, MD: And so, benefitting on the dose without toxicities?

Tanios Bekaii-Saab, MD: Stable disease with drop in CEA (carcinoembryonic antigen). You don’t see the response.

Alan P. Venook, MD: I will be honest. In our group, we tend to move toward phase I or earlier phase studies in these patients. I will often reserve regorafenib or TAS-102 for after a research protocol if we think there’s one that’s really promising.

John Marshall, MD: The one thing that’s steering me away from that—because we all have that kind of center—is that the more they’re looking at PS2 patients, they really don’t benefit from either of these oral therapies. I know we’re all clinical research doctors, but are we, on the other side, leaving known survival benefit on the table because we are going for the shiny thing over in the corner?

Alan P. Venook, MD: It may very well be. I’m the first to admit that I may be utilizing these drugs wrong because I tend to be shy about toxicity and don’t dose intensely. That may be wrong, and it’s perfectly true. I think, though, if you come upon a new drug that has activity, you are reminded of the value potentially of putting these patients on studies earlier, and perhaps I’m getting benefit from that.

John Marshall, MD: Tony, how are we going to figure out what the right dose is?

Tanios Bekaii-Saab, MD: We’re about to complete a study, the ReDOS study, through our accrual network, that essentially randomized patients to 2 different strategies. One is the dose-escalation cohort leading to 160 mg on a weekly basis as tolerated, and then the other is straight-up 160 mg. I’m hoping we’ll have the results of this study presented somewhere in the fall of this year. Again, it may give us guidance about what strategy works best; perhaps it’s the escalation strategy. And then, of course, that will change my practice and perhaps a lot of the other practices that start at 160 mg, or maybe not.

John Marshall, MD: Are you getting most of your patients through both of these drugs?

Alan P. Venook, MD: Rarely. I usually think we get one or the other into patients. It’s a rare patient who I can dose with a genuine course of each.

John Marshall, MD: Is that because of trials or they run out of body?

Alan P. Venook, MD: They actually may run out of enthusiasm rather than anything else.

John Marshall, MD: So, I agree with that. It’s unusual that I’m getting both in.

Johanna Bendell, MD: Yes, same thing; it’s usually one in. But mine’s a little bit more trial-related because they’re on something else.

John Marshall, MD: Sometimes picking right is important. Tony?

Tanios Bekaii-Saab, MD: I think it’s a 50% equation. Half are not getting through both. John Marshall, MD: We have approved drugs with survival benefit and yet we’re leaving them on the table. Why are we doing that?

Alan P. Venook, MD: Well, that’s a good question. I think part of the reason I might do that is I might go back to a drug that we used before. Remember, a lot of times we’ve moved beyond FOLFOX, not because of its lack of efficacy, but because of maybe early neuropathy. If you’re 1 year or 2 years down the road and the neuropathy is gone, I might go back and re-challenge with oxaliplatin. In fact, we know the disease morphs over time. The pressure of treatment will change the genetics of the cancer. So, we’re tending to go back and revisit other therapies again, perhaps rather than TAS-102 or regorafenib—if those are the ones we haven’t used—because we see that there may be an upside and patients believe there may be more of an upside. Especially with oxaliplatin, which if we abandon it because of toxicity, I will often go back to it later on because I think there may be still gas in the tank if we do that.

John Marshall, MD: So, for me, if I gave 6 cycles, no more than 8, it has been a couple of years. I’m also thinking I’m going to get a response, but I have to tell you I’ve lost enthusiasm for this. It’s rare that I see that re-response. I don’t know what you guys are seeing.

Tanios Bekaii-Saab, MD: I have not seen that.

Alan P. Venook, MD: I think we see stable disease.

John Marshall, MD: Yes, but I’m getting stable disease with this, too.

Johanna Bendell, MD: Sometimes it’s stable disease. I think what it is, is a desperation move. We just want something so bad to give our patients, we’ll try to find an excuse to re-challenge.

John Marshall, MD: So, is everybody’s enthusiasm down? I get where you are and that’s the card I’m playing, but my enthusiasm from 1 year ago has fallen.

Alan P. Venook, MD: That’s why we favor clinical trials. because we’re really looking for something else.

John Marshall, MD: If there are 3 VEGF antibodies, switch them out?

Tanios Bekaii-Saab, MD: No.

Johanna Bendell, MD: No.

Alan P. Venook, MD: No.

John Marshall, MD: If there are 2 EGFR antibodies, switch them out? Are they different? In our neck of the woods, we only have one. Switch them out?

Tanios Bekaii-Saab, MD: No.

Alan P. Venook, MD: No.

Tanios Bekaii-Saab, MD: You’ve had one, you’ve had one.

John Marshall, MD: Very good. I think this has been a great discussion around refractory disease and how to manage it and all the different drugs.

Transcript Edited for Clarity