Marshall Discusses Role of Regorafenib in Second-Line mCRC Care

John L. Marshall, MD, discusses second-line treatment options for patients with metastatic colorectal cancer, along with who is most appropriate to receive regorafenib (Stivarga) and how to manage doses and toxicities when using the multikinase inhibitor.

John L. Marshall, MD

Determining the next step of therapy when a patient with metastatic colorectal cancer (mCRC) progresses on first-line treatment centers on patient selection and preferences, explains John L. Marshall, MD.

“Of course, we have choices,” says Marshall. “We have regorafenib (Stivarga), we have TAS-102, we have recycling of chemotherapy, and we have clinical trials. Whereas, up until now, we were really pretty crisp about what we thought they should do next. [It was] ‘Here’s what we’re going to do first, here’s what we’re going to do second.’ Now it’s, ‘I’ve given you this buffet of choices.’”

Despite its commonly observed adverse event of hand-foot skin reaction, one agent in particular—regorafenib—has demonstrated a stable disease benefit since the FDA approved it in September 2012.

The approval was based on results of the randomized phase III CORRECT trial, which demonstrated a significant improvement in overall survival (OS) in patients who received treatment with regorafenib. The median OS was 6.4 months in the regorafenib arm and 5 months in the placebo arm (HR, 0.77; 95% CI, 0.64-0.94; P = .0102). Median PFS was 2 months for regorafenib and 1.7 months for placebo. (HR, 0.49; 95% CI, 0.42-0.58; P <.0001).

OncLive: How do you tell your patients they have progressed on second-line treatment? What are the implications for them?

The main benefit of regorafenib is stable disease, not response. How do you discuss those treatment objectives with patients?

In an interview with OncLive, Marshall, chief of the Division of Hematology/Oncology at Medstar Georgetown University Hospital, and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer, discusses second-line treatment options for patients with mCRC, along with who is most appropriate to receive regorafenib and how to manage doses and toxicities when using the multikinase inhibitor.Marshall: Most of the patients at this point are pretty savvy. They might even already know before I walk in the room that their scan is not good. With any patient, bad news is what oncologists do well. You each have your own way of telling a patient that things aren’t going in the right direction, so you tell them things are worse and you’re making a plan to move on to different therapy. The good news, of course, is that there are other therapies with proven OS benefit. You begin the discussion of “what next” and that’s when regorafenib comes up as the main next step.The reality is, most of the time, frontline is where we see our response. Particularly in the RAS-mutated patient, there aren’t very many responses with second-line traditional chemotherapy. That is really true in third-line because studies show that regorafenib wasn’t really associated with any significant responders. It was significant stable disease.

How do treatment objectives differ in third-line compared with those in first- and second-line?

Which patients are most eligible to receive regorafenib versus other therapies in this setting?

In some patients, that’s important to dwell on. In others, it’s benefit. We talk about benefit, so the things I emphasize when presenting regorafenib is not exactly response versus not response; I explain that this is a medicine that controls your cancer. Forty percent of patients will have control of their cancer at their first scan at 8 weeks, and 20% or more will, in fact, have control of their cancer at 6 months. It is not so much emphasis around response; it’s about stabilization of their cancer in prolonging survival.It’s different now. Their objectives are different now; they still want to be cured—don’t get me wrong—but they also value quality of life more. When presenting regorafenib as an option here, you also don’t have to come and get infusions. You don’t have to carry a pump at home. You can take oral therapy and control your cancer. While we tend to dwell on side effects as oncologists, we need to really emphasize, in this case, the fact that it does stabilize their cancer that was growing previously.The best candidates for regorafenib, in my opinion, are patients who have had their initial lines of therapy and still have a very good performance status of 0 or 1 and, arguably, relatively small-volume disease. We don’t tend to think of this medicine in that space. We’ve tended to think of regorafenib as for a more “beat-up, heavier, no-other-option” kind of patient. The less “beat-up” patient clearly would get better benefit.

What aspects of regorafenib’s mechanism of action do you find is most important to patients?

The second piece is we have to value the survival. Whether you’re tempted to recycle chemotherapy or try some other approach, those things don’t have survival benefit, so we don’t want to leave the survival benefit on the table—we want to play it. Therefore, play it early in the refractory setting, low-volume disease, and good performance status. Your results will be much better than that patient who’s on the decline and the drug really won’t work there.It’s not clear to me that patients ask or care much about mechanism of action. They do like this concept of biologic or targeted therapy, so we clearly put regorafenib in that category. However, it hits 19 different targets, so I don’t think any of us really understands which of those is the mechanism of action.

The way I describe it to patients when it does come up is that there are a lot of broken genes in cancers and this drug hits a lot of those pathways, a lot of the switches that are stuck to slow them down. Through one of those mechanisms, it slows the cancer.

What is significant to mention about regorafenib’s adverse event profile? How important is it to monitor doses?

Patients understand this concept now. It’s on their television; it’s in advertising. They get the idea of personalized medicine. Even though we can’t narrow it to a specific target, we know these are all cancer targets and this medicine hits those cancer targets. Mechanism of action can be a useful thing to discuss. They’ve been on VEGF and EGFR inhibitors, for example, as well as chemotherapy. This is different. This is biologic therapy continued through lines of therapy, but it’s different biologic therapy.The main thing to focus on is the early hand-foot syndrome. Unlike some of the medicines they may have been on before, where it took a while for it to build up, this comes in fairly quickly. There can be early fatigue associated with it, and there are some other minor side effects that kind of build up. Patients mostly are used to chemotherapy and biologic side effect. They’ve had rashes and fatigue; they’ve had a lot of these side effects.

The current standard dose of regorafenib is 160 mg, 4 pills at once, and daily for 3 weeks on, 1 week off. Many people continue to use that dose as a standard frontline therapy, but we know that a high proportion of those patients are going to need dose reductions, even in that first cycle.

Are there reasons for sequencing regorafenib before trifluridine and tipiracil (Lonsurf) and vice versa?

Others have chosen to start a little lower and escalate if they can tolerate it. Everyone needs a dosing strategy just like you do with any chemotherapy and start at full dose, watch closely, and reduce if you need to. Or, you can start a little lower and dose escalate if you can, but you must come in there with a strategy for dosing right from the beginning.We now have a choice in the refractory setting. We have TAS-102. We have regorafenib; they’re both basically indicated in the same space. The answer is no one truly knows if there is an appropriate sequence. I don’t know if there’s an appropriate sequence between irinotecan and oxaliplatin, so I don’t think we have one here.

What are some other key considerations for physician/patient discussions and treatment selection in second-line mCRC care?

It’s patient selection. That’s how I pick between oxaliplatin and irinotecan. I assess their values, what is important, their disease and performance status, their bone marrow, and their skin. I don’t do it the same way every time, just like I don’t do it the same way between oxaliplatin and irinotecan. However, I tend to present regorafenib as the next choice. Mostly, they’ve been on chemotherapy. I like the biologic beyond progression and then bring back the chemotherapy later.We need to understand that this is really a time of uncertainty for us all. The patient is going to bring values to the table and prioritize certain side effects, certain goals, and certain landmarks that they want to meet. We have information about the different medicines, their side effects, and what they can and cannot do. It is really our job to listen to that patient, not just throw out the menu and say, “What would you like to order today?” but to really listen to them first and [then give your recommendation]. This is how we’re going to go forward.

Often, what we will do is start them on regorafenib while they think about clinical trials— half of those patients are going to come off of regorafenib in 8 weeks. Another half or so are going to be stable, so it gives us time to discuss.

We now have multiple options, multiple lines of therapy, and we all believe that the more of these lines of therapy we can expose patients to, the better they will do. We have already talked about most of our responses come in first line. We get a few responses in second line but mostly stable disease; clearly, our third- and fourth-line therapies are stable disease. However, they all have an OS benefit, so we don’t want to leave them on the table.

Picking which one you’re going to use when—which chess piece are you going to move when—has a lot to do with what that patient is like at that moment. Is their bone marrow really tired? You can’t give them TAS-102. Is their skin pretty torn up between either an EGFR therapy or capecitabine? Well, they’re not going to want 8 more weeks of hand-foot syndrome.

They’re going to tell you what’s next, in some level, if you stop and sit and listen to them. However, the mistake we make is not giving the known survival advantage drugs in favor of recycling chemotherapy or other strategies that don’t have proven benefit. We would never do that with second-line. The benefit there is not much different than the benefit in third and fourth-line. We need to value those treatments and our sequence as much as we do that second-line.