Therapeutic Strategies in Metastatic Colorectal Cancer - Episode 11

Regorafenib in Advanced Colorectal Cancer: Dosing Strategies

Transcript:John L. Marshall, MD: Let’s close with where we close with most of our patients, and that’s in the refractory setting. I’d like to set the stage. This is a different patient. We were talking about kitchen-sink, aggressive frontline therapy. This is a patient that we now know pretty well. We’ve known them for two, three, sometimes longer, years. They have a favorite parking spot at the infusion unit. They know the people at the front desk, right? They know when GI ASCO is, so they reschedule their appointment with us. You know these people, right? And they’ve actually said the word “hospice” at the kitchen table, probably. And they want to stay alive, but they also have an increasing value around quality of life. We now have a new world of treatments for refractory disease. Tony, we’re going to let you start with the regorafenib story because we have a little bit more experience with this medicine. So, set us up there.

Tanios Bekaii-Saab, MD: This is, thankfully, becoming a little bit more crowded than it used to be. Regorafenib is a multi-targeted tyrosine kinase inhibitor, so it’s a dirty, promiscuous, oral agent that hits VEGF, but also hits others that are not just involved with the microenvironment, and directly hits some tumor targets. Regorafenib is an oral agent, and two large randomized trials consistently showed improvement in overall survival and progression-free survival in patients with metastatic colorectal cancer beyond a standard therapy. So patients progressed on FOLFIRI, FOLFOX, and EGFR inhibitors if they were KRAS wild-type.

John L. Marshall, MD: That’s really important. These are real-time patients. These received all of the US accessible drugs, right? So lots of places around the world can’t get all of these drugs.

Tanios Bekaii-Saab, MD: Absolutely.

John L. Marshall, MD: This was done in our backyard, and these are our kinds of patients. The results of this study, what do they do to your practice? How do you deal with it?

Tanios Bekaii-Saab, MD: The results, actually the hazard ratios, were very interesting, and this agent has made it where…Naturally it was studied after patients failed two or three lines of therapy. Patients eventually progressed to regorafenib, and that’s where it found its place in my practice.

John L. Marshall, MD: When this drug first came out, lots of us were holding patients off waiting for the drug, and their performance status was falling, and we tried it and it didn’t work very well and it was toxic to them. How’s your experience over the last year or so been in terms of changing your use and when you think about using this drug?

Johanna Bendell, MD: Getting a little savvier about doing. In my own practice, only maybe 10% of patients tolerate the full dose of regorafenib.

John L. Marshall, MD: So 160? Where do you start?

Richard Kim, MD: 120.

Charles S. Fuchs, MD: 80.

John L. Marshall, MD: 80!

Tanios Bekaii-Saab, MD: 160.

John L. Marshall, MD: You’re a full-doser. I’ve recently become a 120er. But anyway… I’ll let you flow it back over here.

Johanna Bendell, MD: A couple things. One is, I start at 120 now, but I do a lot of education with the patients. And our nurses also know a little bit more about these regorafenib patients. When we see the toxicity, at least in my experience, it’s been early and so you start to get a little bit more tired. You start to get a little hand-foot syndrome.

John L. Marshall, MD: Early, meaning?

Johanna Bendell, MD: First week, first week or two. And so I stress the importance of the patient’s need to call in if they’re having a problem, and I do see them. I see them weekly for that first cycle until I get their dose down, and sometimes I can bump it up, sometimes I have to take it down.

John L. Marshall, MD: And the original study said you see them every two weeks. When it first came out, it was, make sure you see them monthly. And we basically learned that you’ve got to see them sooner. What do you tell a patient? Use some of the language you use to describe this drug to a patient?

Richard Kim, MD: Toxicity-wise, probably the most common toxicity we see with this drug is fatigue, hand-foot skin rash, and diarrhea. And usually the hand-foot skin rash is dose-dependent. So I definitely have to be proactive. My nurses are proactive, telling some side effects they may expect. I do see them once a week. But, clinically, we’ve had experience doing this with other drugs such as capecitabine and sorafenib. This is nothing new in terms of dose modification. I don’t think anybody starts capecitabine at full dose or even sorafenib. We start at a half-dose and try to titrate up.

John L. Marshall, MD: And it took us a year or two to try to figure that out.

Richard Kim, MD: Exactly, right.

John L. Marshall, MD: We didn’t know it right out of the gate.

Richard Kim, MD: This is the same learning curve with regorafenib. Being proactive is very important, educating the patient what to expect. If you see them once a week and if the side effect occurs, you could dose-reduce right away so the patient could get through the second cycle. And they could get a CT scan to see if it’s effective or not.

John L. Marshall, MD: Tony, I know you fiddle with doses all the time. How are you holding firm on this one?

Tanios Bekaii-Saab, MD: My concern is that those patients have a median progression-free survival that’s equivalent to the first scan. So, toying around with a dose that may be defective; Johanna mentioned 10%. In the study, it’s about 20%. For the majority, patients do not tolerate the 160, but you have a baseline of patients who tolerate it and may benefit from it. And toying around with the dose when your life span is limited is a bit problematic.

We’re learning more about the drug. We know how to support our patients. In fact, the toxicities do happen, if you pay close attention to them, in the first two to three weeks, and they’re dose-dependent. You reduce the dose, most of these patients can continue through the drug. The good news is we do have a study now that’s underway that’s looking at the two approaches. Either you start patients at 160 or you start patients at 80 and then escalate within a month. And we have about 20% accrued on that trial. By the end of the year, we’ll have some kind of an idea whether dose-escalation versus starting on a higher dose matters. And we’re hoping that we can answer this question soon.

John L. Marshall, MD: Yeah. It’s important that they’re taking the responsibility, supporting investigator-initiated studies, to answer this question so we can make sure we’re not losing efficacy and we can reduce the dose.

Tanios Bekaii-Saab, MD: Absolutely.

Charles S. Fuchs, MD: Tony’s study is very important because the jury is out on how we do this drug. It’s an important drug, right? We want to use it. And I know I came in on the low end across the panel on starting the dose, but the problem is that these are patients who are reaching the end of the line, and if you give them something that’s toxic at the onset, they quit. And I want to make sure that they do benefit from the drug. So I escalate from 80, but I start at 80, and I look forward to seeing what Tony’s study shows.

John L. Marshall, MD: Between sort of recycling chemotherapy, we’ve got oxaliplatin still in our back pocket and changing volume of disease, performance status. My practice has been to not lose this chance, not leave it too long on the table, because if they’re going downhill, you won’t do what you need to do. Using it earlier maybe as a tee-up for clinical trials later, is that similar to what you guys are doing? Have you shifted to an earlier time point when you’re using it? Not earlier line of therapy necessarily but pre-phase I, pre-recycle of chemotherapy?

Tanios Bekaii-Saab, MD: Yeah, definitely. You lose activity for these drugs in the later lines if you wait until the patient has a performance status of 2+ or 3. They’re less likely to benefit from it, and they’re more likely also to see the toxicities we’re concerned about. So yes, it does make more sense to actually place it as part of our standard of care. Clinical trials are important, and there are certainly some fantastic phase I trials that would be fitting, but before getting to the end of the line phase I trial, the PK trial or the phase 0 trial.

Transcript Edited for Clarity