Transcript:John L. Marshall, MD: So, Tony, regorafenib has been around a little longer than TAS-102. Give me a picture of the ideal patient you would put on regorafenib, and tell me a little bit about your starting dose.

Tanios Bekaii-Saab, MD: Patients who would eventually get on regorafenib in their line of therapy are RAS wild-type patients who failed with EGFR and VEGF inhibitors, FOLFIRI and FOLFOX in the RAS-mutated setting, a couple chemotherapy regimens, and then bevacizumab. Those patients are performance statuses 0 and 1.

John L. Marshall, MD: So, not 1.75.

Tanios Bekaii-Saab, MD: 1.75 may be okay depending on several factors. Like Dan said, you have to individualize patients at the end of the day. That’s what we do clinically. There’s no biomarker that will help you do that; you look at the patient and you look at the numbers. For example, for someone who has significant hepatic dysfunction or a risk of significant hepatic dysfunction, I’d be a little reluctant to give regorafenib.

John L. Marshall, MD: Good performance status (PS) is important.

Tanios Bekaii-Saab, MD: Relatively good PS is important for the line of therapy. It’s rare to see a performance status of 0 at this point in time, but a performance status of 3 should, frankly, not be given any agent.

John L. Marshall, MD: Tell me about your dosing.

Tanios Bekaii-Saab, MD: My preference, outside of a clinical trial, is to start with 160 mg.

John L. Marshall, MD: You give a full dose?

Tanios Bekaii-Saab, MD: The reason for that is two-fold. When we look at the progression-free survival at the median for all of these regimens at this point, it’s 2 months. By the first scan, you know whether the patient responded or not—responding meaning you have a mostly stable disease. We have a very short window of opportunity. Toying around with the dosage without any data that supports it makes it very difficult for me to actually start with a lower dose. If we had 6 or 10 months to play with, I wouldn’t mind starting with the lower dose.

John L. Marshall, MD: Cathy, what’s your dosing?

Cathy Eng, MD: My dose is 120 mg.

John L. Marshall, MD: I have to say, I used to be in Tony’s camp, but it was hard to give.

Cathy Eng, MD: It sometimes dissuades patients from continuing treatment if they have a bad reaction.

John L. Marshall, MD: I completely agree with you, because I’m nervous every time I do that. I wonder if I’m losing the margin that I was going to get. How are we going to solve this debate?

Tanios Bekaii-Saab, MD: Hopefully, we have a solution coming through. We’re conducting the ReDOS study, which essentially looks at two arms. It’s a large phase II randomized study looking at both a dose escalation strategy and a standard dosing strategy. Half of the patients will be randomized to 160 mg and the other half will be randomized to start with an 80-mg dosage. After a week, if there’s no toxicity, they’ll go to 120 mg. After another week, again, if there’s no toxicity, they’ll move to 160 mg. They’ll settle on the dose that is tolerable for them. This will require, as you should do in a clinic, that patients come on a weekly basis to be seen. They should come at least over the first 4 weeks, preferably over 8 weeks. You monitor them very closely and adjust the dosages. We’re about midway accrued on the study, so I’m hoping that by the end of the year, we’ll have some results about if that dose escalation strategy would allow us to actually induce the same benefits as starting with 160 mg.

Cathy Eng, MD: What’s the primary endpoint?

Tanios Bekaii-Saab, MD: The primary endpoint is essentially those patients that are able to get their scan at the end of the 8 weeks, and are able to continue through.

John L. Marshall, MD: So, it’s basically toxicity crossed with maintenance.

Tanios Bekaii-Saab, MD: Yes. It’s a hybrid endpoint with some benefit and toxicity.

John L. Marshall, MD: I think it’s really important to note that if you look at the label for capecitabine, it’s still the same dose, even though no one gives it. These sorts of upfront clinical trials try to answer this really important question of dosage.

Tanios Bekaii-Saab, MD: We’ve never done this with sorafenib, or with sunitinib. All these questions come all the time. I think this is good that we’re doing it in this setting, because it’s not just regorafenib, it’s any TKI. If you go ask 20 physicians how they do it, everyone does it differently.

John L. Marshall, MD: You’re all world experts. This drug hits 19 different targets. How does it work?

Daniel G. Haller, MD: Nineteen different targets, 19 different toxicities. The other issue is biologics. You don’t know what the right dose is, because the dose is based on the maximum you can give, not the best dose for tumor shrinkage. So, for a cytotoxic like with TAS-102, the initial dose may be important because it’s not like first-line therapy where you can glide into it. Unfortunately, we learned from the combinations of FOLFOX/bevacizumab and FOLFOX/cetuximab, if we had not given all eight drugs on the first day where you had a car crash and then you had to stop all the drugs, it may have been better to introduce them. But, in last-line therapy, I cringe a little bit when I talk about TAS-102 and people say, “Oh, well, I’m going to start with a half dose.” But, 50% of people come off after two cycles; you can’t ease into last-line therapy.

Transcript Edited for Clarity