John Marshall, MD: Cathy, shifting gears a little bit to later lines of therapy, one of the most common questions I get asked is, REGO [regorafenib] or TAS-102 [trifluridine/tipiracil]? Give me your perspective on how to play that out.

Cathy Eng, MD: In clinic, one of our issues is patients with liver metastasis. If we have a lot of different degrees of tumor burden for those patients, that may dissuade me from utilizing regorafenib, just because of the risk of increased LFTs [liver function tests] in that patient population. Then, a schedule for TAS-102 is a little bit challenging, but I try to remind patients to take it Monday through Friday. Whether or not one is better than the other in which specific line, at the end of the day, you still want to utilize each of the regimens. Originally, unfortunately, regorafenib got a bad name because of the toxicities, but it’s come a long way, thanks to Tony’s data from the ReDOS study.

John Marshall, MD: He’s already full of himself, so we don’t really want to give him that.

Cathy Eng, MD: It validates what we were already doing, which is basically starting off your regorafenib at a lower dose so the patients could tolerate it better. That way, that’s another line of therapy for that patient population.

John Marshall, MD: You’ve adopted that strategy in all your patients?

Cathy Eng, MD: We’ve been doing it quite a while, even beforehand.

John Marshall, MD: Even before the data?

Cathy Eng, MD: Yes, even before his data.

Tanios Bekaii-Saab, MD: They could have saved a lot of money.

John Marshall, MD: Others?

Michael Morse, MD: I’d like to make a comment that, in contrast, with TAS-102, it appears that staying on dose in the closest dose may matter.

Cathy Eng, MD: Yes, that’s a different setting.

Michael Morse, MD: Right, I agree. The ReDOS is very critical for validating what we do, and potentially offers a better outcome for patients. With TAS-102, a different drug has to be managed totally differently.

John Marshall, MD: Yes, I do crazy stuff, I know, but if I’m giving TAS-102, for example, and they’ve been on BEV [bevacizumab], I still keep the bevacizumab going because I see that the regorafenib is having some VEGF [vascular endothelial growth factor] already in it. With the TAS-102, based on these new frontline data randomizing CAPE/BEV [capecitabine/bevacizumab] versus TAS-102/bevacizumab, the TAS-102/bevacizumab actually looked pretty good. This is purely anecdotal, but we’ve now got some minor responses in that space. I do think TAS-102 will evolve as a novel chemotherapy, either in combination, may move earlier, this sort of thing. Regorafenib, thanks to Tony’s work and others, has got its expanding space, as well.

Cathy Eng, MD: There were interesting data with nivolumab reported, too.

John Marshall, MD: Yes.

Tanios Bekaii-Saab, MD: Overall though, if you look at the dose optimization strategy, it did shift the survival to close to 10 months, versus 6 months with 160 mg. We actually did the meta-analysis, which will be published in The Oncologist, that looked at ReDOS and all the prior randomized regorafenib/TAS-102 studies. What’s clear is that regorafenib 160 mg and TAS-102 maintain very similar outcomes in comparisons through meta-analysis. The regorafenib dose escalation strategy remains, at least in the survival front, and even a little bit in the PFS [progression-free survival], superior, historically. That’s the caveat—the regorafenib 160 mg or TAS-102.

John Marshall, MD: With both of these drugs, my experience is, it never really rescues a patient whose performance status is falling, so I don’t even try in it in that space. I don’t throw the Hail Mary pass, but what it has made me do is, I want to make sure and use it. I combine the work from ReDOS, and I’m more comfortable with the dosing, and the controversial data from REVERCE. Even in that patient who’s got low-volume, asymptomatic metastatic disease, I might try regorafenib before I’d try my EGFR inhibitor, figuring my EGFR is still going to be active in later lines. Is anybody doing crazy stuff like that? Are you going to play your EGFR before or always?

Cathy Eng, MD: I’ve not utilized that regimen.

John Marshall, MD: It’s back to the rash; it’s back to the magnesium. If I can wait another 6 months….

Cathy Eng, MD: There are data from REVERCE, which is basically what you’re mentioning, and it looked to have some promise, but once again, I think a lot of us want to see some of that data validated in the United States.

Tanios Bekaii-Saab, MD: There’s a study that’s looking at this REVERCE-2, creatively called REVERCE-2.

John Marshall, MD: I’m not going after some innate biology. I’m just trying to make sure I get all the drugs in.

Tanios Bekaii-Saab, MD: It’s clear, on the right side, that since you’re going to push your EGFR inhibitors to the end, that’s a very clear pathway. I don’t disagree that it may be worthwhile to consider this, because if we look at all this cumulative knowledge we know about regorafenib, if you move it a little bit up the line, it actually seems to have a better performance than the lower line.

John Marshall, MD: This is my experience.

Tanios Bekaii-Saab, MD: Not necessarily for TAS-102, though.

John Marshall, MD: OK, fair enough. Dustin, did you have a comment?

Dustin Deming, MD: I’m trying to use the EGFR rechallenge more.

John Marshall, MD: Use it, get out; use it, get out.

Dustin Deming, MD: Exactly. It may not be pushing regorafenib to earlier lines, but trying to reuse EGFR.

Tanios Bekaii-Saab, MD: How do you do the rechallenge, though, to make it clear, because we don’t want to have patients just go back on EGFR inhibitors without a biologic driver.

Dustin Deming, MD: In my clinic, what I say is that I need to have at least a 4-month PFS on the first or the most recent time they had the anti-EGFR therapy, and it’s at least been 5 or 6 months since they’ve had the anti-EGFR therapy. In that setting, there’s now a number of studies showing that you can get response rates in the 20% range for that rechallenge.

Tanios Bekaii-Saab, MD: You can, but that’s primarily looking at some of the appearing and disappearing clones, which is a study that’s being done now, the PULSE, which is with EGFR rechallenge. I think that will probably be a better way to select those patients who may be benefitting most from EGFR inhibitors, but that’s a poor man’s way to do it right now, perhaps.

Transcript Edited for Clarity