John L. Marshall, MD: Tony, I’m going to pick on you. May you remind our audience about the regorafenib study and its role in this setting? May you just provide a quick summary?

Tanios Bekaii-Saab, MD: Yes. Regorafenib, as you know, is a multi-kinase inhibitor. It’s a dirty drug in terms of that it hits on so many targets, a multitude of targets. A lot of them are relevant, or most of them are relevant, to cancer microenvironment, etc. The study that essentially led to regorafenib coming to our practice was the CORRECT trial, which randomized regorafenib versus placebo in patients with refractory metastatic colorectal cancer. This showed a survival benefit and a PFS benefit. There was a follow-up study, an Asian study, the CONCUR trial, that had the same design, but patients were less pretreated because of the nature of, essentially, treatment patterns.

John L. Marshall, MD: Less access.

Tanios Bekaii-Saab, MD: Less access to biologics and, again, very similar trends. What was interesting was that the deltas were more significant, which suggests that this agent works even better when patients are less preexposed in those patient populations. So, the efficacy has been established in those 2 studies. The safety of this drug is very similar to a lot of the tyrosine kinase inhibitors—although I must say, when we see those patients, they’ve been through a lot of therapies, and their performance status is typically compromised. What stands out from this agent is that you see hand-foot syndrome, and you see it quick—within 2 to 3 weeks. It’s pretty severe in about 10%, 15% of the patients. Then you see some of the VEGF toxicities, but less so.

John L. Marshall, MD: Hand-foot, fatigue—watch the liver.

Tanios Bekaii-Saab, MD: Fatigue and the liver—you have to watch the liver. You see elevations in liver function tests and a little bit of bilirubin. Fatigue is interesting. Fatigue is very confusing in this patient population. There’s probably some added fatigue from the agent, but you see it across the board with other agents. Even with capecitabine and TAS-102, when they’re used in this patient population, you see more fatigue.

John L. Marshall, MD: May I drill down on the dosing a little bit? You’re running the study looking at different dosing schedules—160 mg is tough. Some can give it, and some can’t. Yet, with the 80 mg dose, we’re worried it’s too low. What’s the study drilling down on?

Tanios Bekaii-Saab, MD: The study is about to complete. Actually, we’re on the last few patients. It’s a 120-patient study that randomizes patients to 160 mg, the standard dose at start-up, and then 80 mg escalating to 160 mg on an every-week basis—120 mg, and then 160 mg. There are multiple components to this study. In addition to comparing just the 2 doses, we’re doing what I think we should be doing in clinic. During the first month of therapy, you have to follow these patients on a weekly basis and adjust the doses and take care of the toxicities.

John L. Marshall, MD: What is the starting dose in a patient, off study—Paul?

Paul R. Helft, MD: It is 120 mg, usually.

Dirk Arnold, MD, PhD: Depending on the patient, it is between 120 mg and 160 mg. For my frail patients, 120 mg. For my fit patients, I would start at 160 mg.

Fortunato Ciardiello, MD, PhD: I would select, carefully, the patient. The patient should be, really, past PS 0 for being treated with regorafenib, and it is important to discuss with the patient that he has to come back to our hospital at least once a week for the first 4 weeks. And usually, toxicity to 160 mg is very quick in the first 2 or 3 weeks of treatment. So, these 2 or 3 weeks are very crucial.

We also have a trial that is running in Europe, a little different from yours, that compares the standard dose with a different approach—in the first month, the trial is doing treatment for 1 week on and 1 week off. This way, you can manage the toxicity and the recovery better. And then, according to what happens in the first month, the patient comes in every month. I don’t know if this will work or not, but clearly, if you do 1 week on, 1 week off, why were these things not done before?

John L. Marshall, MD: Very quickly, from phase I to the big phase III…

Fortunato Ciardiello, MD, PhD: About 60% of our patients go down to 120 mg, if they start at 160 mg, in 1 to 2 months.

John L. Marshall, MD: Yes, it’s quick.

Fortunato Ciardiello, MD, PhD: Very few patients can stay on a 160-mg dose.

John L. Marshall, MD: It took, really, me switching this to PS 0/1 patients to find this, but I now have patients on the so-called “tail of the curve,” where they’re stable beyond 6 months. My initial reaction to this was, this wasn’t a drug that was going to catch people—and it probably isn’t. If you’re falling quickly, it probably isn’t going to catch you. But, have you all got “tail of the curve” patients?

Fortunato Ciardiello, MD, PhD: We just recently released a publication discussing a series of 123 patients. We had 28 of these patients carefully selected because they were PS 0 or PS 1, good patients that you could invest on with this kind of treatment. The patients did at least 7 cycles of treatment. It is a small tail, up to 1 year, and for some, even to 2 years. Obviously, you go with most of these patients down to 80 mg, but you changed the history of the disease in these patients.

John L. Marshall, MD: I just had a patient, at just minor progression after a year on treatment, who sometimes was on 120 mg and sometimes on 80 mg, depending on the month.

Paul R. Helft, MD: I have a patient who went almost 2.5 years on regorafenib at 80 mg.

John L. Marshall, MD: So, it’s clearly changing the biology?

Tanios Bekaii-Saab, MD: It is. It is a very interesting agent. I think it’s a learning curve like all TKIs. The challenge for that patient population at that level is, it’s a drug that’s active but has its toxicities. It’s a learning curve. And once you learn how to use it, it’s actually, for selected patients, a very effective drug at this level.

Transcript Edited for Clarity