Case 1: Treatment Considerations in GIST


Third-line treatment recommendations for patients with GIST and a discussion on side effect management.

Mark Agulnik, MD: If we follow FDA guidelines, this patient’s third-line therapy would be regorafenib, which we all agree comes with some challenges that we don’t see certainly with imatinib and sunitinib. Just describe for me the challenges you see in treating patients in these later lines of therapy. 

Margaret von Mehren, MD: To start off, many patients are quite fit and want and are able to tolerate therapy. Regorafenib is a challenging drug to give. The FDA-approved dosage is 160 mg daily for 3 weeks on, 1 week off. I do not start anybody at that. Having done it in clinical trials, 7 to 10 days later people have rip-roaring hand-foot syndrome, and you end up sabotaging their care and their willingness to take the medication. I tend to start low at 80 mg and then will escalate as they demonstrate they can tolerate it. 

Richard Riedel, MD: I follow a similar practice. I’ll start at 80 mg. I’ll titrate by 1 tablet or 40 mg every 4 days or so. Within about a week or a little more than a week, we’re able to dose escalate them up to hopefully the maximum-tolerated dosage, no more than 160 mg daily, as you mentioned.

Mark Agulnik, MD: Most of us have very similar practices, except on clinical trials, when we’re tied to the approved dosing. I have seen before patients come for opinions where they’re on 80 mg continuous without any break, instead of 3 weeks on, 1 week off, they get 80 mg. It’s hard to gauge based on so few patients whether that truly makes a difference. 

This patient was started on standard regorafenib 160 mg, which is 4 tablets once a day for the first 21 days of every-28-day cycles. The patient experienced moderate hand-foot syndrome, severe nausea, and diarrhea. There was a dose reduction of 1 pill removal, which brings it down to 120 mg and then to 80 mg, and moderate nausea and diarrhea persisted. Because of the adverse effects, regorafenib was discontinued. 

In my practice, we’ve taken early on with the use of regorafenib to get our nursing involved, and our nurses will call patients weekly to try to keep them on and pick up any adverse effects very quickly. We also bring back the patients after 2 weeks, sometimes after a week, depending on how they’re doing.

We figured out that bringing them in a lot sooner, we’d be able to mitigate some of these adverse effects and figure out the proper dosing. As you guys said, we always start low and escalate, which really has completely changed. We see in clinical trials that starting high is not the best strategy for our patients. How do you guys monitor differently for this drug vs others that we use? 

Richard Riedel, MD: As you articulated, it’s an issue of having open and often communication with patients. It’s setting expectations. We’ll have our clinical pharmacists meet with our patients prior to starting. As you mentioned, your nurses do this. In our clinic, we have an oncological pharmacist who will reach out as well just to gauge any potential issues. We will see all patients back 2 weeks after starting therapy, similar to what you mentioned.

Generally speaking, with aggressive supportive care for managing these symptoms, nausea for example—twice-daily lotioning with a good moisturizing lotion, for example—I find that we can get individuals to a reasonable if not full dose.

Margaret von Mehren, MD: The other thing that I often will recommend to patients is getting a blood pressure cuff at home, particularly for sunitinib and regorafenib, where hypertension can be an issue—especially if they already have hypertension—so they can monitor for changes in their blood pressure. But similar practice. Everybody comes back 2 weeks after starting, for evaluation. 

Mark Agulnik, MD: We are now 3 drugs in, and we’ve progressed on all 3 or become intolerant to the third one. What options do patients have at this point?

Margaret von Mehren, MD: In 2020, ripretinib was approved for fourth-line setting, which compared with placebo, patients had their disease controlled for a significant amount of time. The ripretinib study was really instructive in that it reconfirmed what we’d seen in the sunitinib and regorafenib trials, in that patients who aren’t on therapies have very rapid progression. When you get to the fourth line, that can be effective on not only your disease but also your life, in that there were some patients who were not able to cross over the ripretinib arm because their disease was so advanced that they were no longer candidates for therapy.

It’s 1 of the take-home points that is important for a patient who has disease that’s advancing. I always make sure that the next plan is in place before stopping the drug, even if it’s not achieving everything I want. Because stopping therapy, you can see quite rapid progression. In the ripretinib study, it was less than a month, 2 to 4 weeks. 

Mark Agulnik, MD: When you switch your patients to ripretinib, do you discuss with them the mechanism of action of the drug and how it may differ a little from other drugs we’re using for their disease?

Richard Riedel, MD: I’ll mention it in layman’s terms to say that it’s a new medication and works a little differently from some therapies they had been on, at least for second and third line, at least speak to some of the data according to use. Prior to its approval in 2020, in the GIST [gastrointestinal stromal tumor] community we were challenged in terms of where to go next. We could recycle agents that patients had had before. We could consider off-label use of other partially available TKI [tyrosine kinase inhibitor] therapies, but the ripretinib study has been really important, given that it was randomized and then clearly showed the benefit over no therapy.

We follow a similar practice to what Meg articulated with making sure that even in the setting of a progressive disease, individuals stay on that therapy until they have the next therapy. It’s expensive and we often have to leverage our patient-assistance programs, and that can take some time.

Mark Agulnik, MD: What I have often done in situations like this where they couldn’t tolerate the last dose that we were using, I’ve sometimes gone back to leftover imatinib that they have just to give them something to bridge until you get the other drugs approved. Certainly we’ve always discussed with patients that they need to be on something and there isn’t a role for a break.

When you’re switching over from regorafenib to ripretinib, do you find that there are challenges that you would anticipate? I find when patients come off regorafenib there is a sense of relief to some extent because it is a much harder drug. I see Meg smiling, so I gather that’s the same thing that she’s experiencing. This I find is the easiest one. With imatinib-sunitinib, I find there’s a lot of heartache involved because they’ve been on something so long. The sunitinib to regorafenib takes a little bit, but regorafenib to ripretinib, I feel like they can be doing cartwheels in the office. There certainly isn’t a barrier there for me.

Margaret von Mehren, MD: It’s not a barrier, but the biggest thing that’s different is that there can be hair loss with this agent. That is something that most of them have not had to experience before. That’s a piece that I do counsel patients about because they definitely have hair thinning. Sometimes after that event of hair thinning, there’s actually a change and many people will have very tight curls and a change in the quality of their hair, something they need to be educated about so they can anticipate that change, which is something they’ve not had to do.

Richard Riedel, MD: The concept of alopecia that’s seen in the use of ripretinib is something that has been talked about, and there were questions about whether patients would be really concerned about that. But to Mark’s point, as individuals are coming off regorafenib, which is more challenging in dealing with the hand-foot syndrome, for example, at least in my experience alopecia is not a particular concern in the global context of an improved quality of life.

Mark Agulnik, MD: For my patients, I always somehow put ripretinib in a box and think about three things that I have to counsel them about. I have this perceived notion that they will receive what I’m saying worse than most of them are fine with it. One is the hair loss in alopecia that they have or the thinning. The other is the need to see a dermatologist, and I set them up ahead of time just to have the skin exam with the risk of cutaneous malignances. 

Then it’s these cardiac toxicities that they could have that I don’t always—I’ve gotten ECGs [echocardiograms] with the other drugs but don’t focus as much on the cardiac aspect as I do with this 1 with respect to getting an echo beforehand, an ECG. These are the things that I differentiate in my mind, but I find that most patients actually walk into it and are OK with the transition. 

Margaret von Mehren, MD: It’s interesting, Mark, because I typically do get an echo, switching to sunitinib just because there can be hypertension. I certainly have had people who have developed congestive heart failure rarely, but because of the VEGF targeting, I often do, especially if there are comorbidities with cardiac history that I’m concerned about.

Richard Riedel, MD: I’ll get an echo in individuals who have significant coronary disease or some history of a cardiac event. In the absence of that, I don’t routinely do it.

Mark Agulnik, MD: What dosing are you guys starting your ripretinib as? The FDA-approved dosing is 150 mg once a day. Are we all sticking with that?

Margaret von Mehren, MD: I have found that most patients can tolerate that. The 1 thing we haven’t talked about is that some patients will have a little hand-foot syndrome, and it tends to be those people who may have had it before. I do counsel patients about that. It tends not to be as severe or as significant. Very occasionally do I see it. I have 1 patient right now who has bad hand-foot syndrome. 

Richard Riedel, MD: I’ll also start it at the FDA-approved dosing and haven’t seen significant issues yet that would warrant me to follow a similar practice to what I do for regorafenib.

Mark Agulnik, MD: I agree completely.

Transcript edited for clarity.

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