Margaret von Mehren, MD

When you think about GIST [gastrointestinal stromal tumor] and the landscape of GIST, I’ve been very fortunate in my career to start out as a very young faculty member with the first trial of imatinib, to now, 20-plus years later, being here with the approval of ripretinib and avapritinib. We’ve gone from having 0 drugs to now having 5 drugs that are approved for use in GIST, which is really exciting for our patients.

There are still some forms of GIST, though, for which we have less to offer. Fortunately, they are much rarer subtypes of GIST, but we still need to sort out what’s the best way to take care of these patients. One of the subtypes consists of patients who, many years ago, we called wild-type, because they didn’t have mutations in 

. But these commonly are tumors of the stomach that have lost expression of the protein called SDHB. That can happen either through a mutation of a family of genes, the 

 family of genes, or sometimes it can happen because of loss of expression of the genes based on abnormal methylation of the promoter of one of the genes, SDHC. That group of tumors is seen more commonly in young patients, or even in what we used to call pediatric GIST. But in general, if you look at patients with that class of tumors, they tend to be much younger.

Treatment of that type of GIST remains a question. We’ve looked at imatinib, but that really doesn’t seem to provide much benefit. Sutent [sunitinib] and regorafenib have shown disease control in studies for which a few patients with this type of GIST have been identified, and we think that’s because it targets the VEGF receptor pathway. But these patients probably need additional forms of therapy, particularly those with tumors that can be quite aggressive. Fortunately, in many patients, these tumors are rather indolent and don’t change much over long periods of time. Many patients live normal lives with their disease and are not limited by it, even when off therapy.

Patients with tumors that are associated with neurofibromatosis changes are also a challenge. Some of these patients will have routine 

 mutations and will respond to the standard drugs, and that’s terrific. But many of them do not. To date, we have not found a great way of addressing these tumors. Biologically, there’s some thought that impacting the RAS pathway using MEK inhibitors, for example, might be of benefit. But to date, there is little clinical data to support that, in part just because these patients are rare. Those are the 2 big groups of patients for whom we don’t have much to offer, or we might think about alternative therapies for.

I think the other area that we still seek treatment for is patients who progress on standard therapies. For patients who are initially diagnosed and receive adjuvant therapy, we probably are curing some, but could we cure more patients if we had a different approach? Does that approach mean we should be combining therapies that target more than just the KIT pathway, but maybe alternative pathways? What’s the role for immunotherapy? Certainly, there’s been some interesting preclinical work that suggests that there are certain subtypes of GIST that have more immune infiltration, particularly the 

 mutant GISTs. There is some information in preclinical models that suggests imatinib may activate parts of the immune system. And so, maybe combining with immunotherapy might be of benefit. I think these are unanswered questions. Are there better ways to deliver effective therapies that we currently are limiting because of adverse effects? So there are still lots of unanswered questions, and this is 1 of the reasons why I still enjoy getting up every morning and thinking about this disease and how to try to manage it and find more effective therapies for patients.

Case: A 68-Year-Old Man With Gastrointestinal Stromal Tumor

A 68-year-old man complains of a 5-month history early satiety and vague abdominal pain

PMH: hypertension, medically controlled; colonoscopy at age 55 unremarkable; no family history of cancer

PE: diffuse abdominal pain on palpation; otherwise unremarkable



Labs: Hb 10.1 g/dL, plt 100 x 109/L; other lab values WNL

Endoscopy: showeda submucosal ~ 5 cm mass with ulceration

EUS-FNA biopsy: irregular borders on extraluminal surfaces of the stomach with evidence of heterogeneous echogenicity

Biopsy showed gastrointestinal tumor with mitotic activity showed >5 mitoses/50 HPFs

Abdominal/pelvic CT confirmed a 5.4 cm lesion in the body of the stomach

MRI showed evidence of peritoneal metastases

He was started on imatinib 400 mg PO qDay, continued for 26 months until he complained of increased abdominal pain and decreased appetite

ECOG 1; Imatinib was discontinued due to progressive disease

Treatment with sunitinib 50 mg PO qDay for 4 weeks, with a 2-week drug-free interval was started

Treatment was well tolerated for 9 cycles when he developed an altered sense of taste, occasional vomiting and diarrhea; sunitinib was discontinued

Regorafenib 160 mg (four 40 mg tablets) PO qDay for the first 21 days of each 28-day cycle was started and tolerated except for hand-foot syndrome

Regorafenib was discontinued on progression of disease

The patient was started on ripretinib 150 mg PO qDay

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GIST: Future Treatment Landscape

Regarding my personal experience with ripretinib, I’ve been fortunate to be able to participate in the phase 1 study, in particular the dose expansion part, where the dose was known and we were trying to check and see what activity was seen. I participated in the phase 3 INVICTUS trial [NCT03353753], and currently I am also participating in the phase 3 trial that is evaluating ripretinib versus sunitinib. The results are not known because the study is not finished. However, in general, as I’ve said, while I’ve listed and talked about adverse effects that the drug can have, I think most patients tolerate the drug very well. I have some patients who are continuing on the drug for more than 2 years and have been able to tolerate it without major adverse effects that limit their ability to do what they want to do. It’s been gratifying to see patients in whom the disease has been controlled and even patients with tumors that have decreased in size. Certainly, from the INVICTUS data and the phase 1 data, the number of patients whose tumors shrank is less than 10%. That is on a par with what we see with Sutent [sunitinib] and regorafenib. I think it’s sort of in that same ballpark.

In terms of tolerability, in general, it is well tolerated, on par with or better than the things that we think about in second- and third-line therapy. The real art of medicine for patients with gastrointestinal stromal tumors [GIST] is working with them to make a dose of therapy, of a drug, work for them. Certainly, studies look at using “X” dose of a drug in a certain way, but with time and experience, I think learning how to start a drug, titrate it up to where patients can tolerate it, are important. In my experience with ripretinib, less of that needs to be done. Patients really can tolerate 150 mg, for the most part. And then, if the disease has progressed and they need to, they can tolerate 150 mg twice a day. So I think it’s been, from my perspective, a very easy drug to use, and I think patients have found it to be very tolerable. One caveat of this drug is hair thinning, which is quite different from many of the other drugs that they’re on.

The patient in the case was treated with ripretinib as fourth-line therapy. That is now available based on the FDA approval from May 2020. I think that’s a very appropriate use of this drug, and I would expect that this will likely be what many physicians will choose for their patients. Avapritinib, as we know, was also recently approved, although the indication for its approval was much more narrow—for patients with the D842V [

]-mutation. Interestingly enough, the drug, when it was developed in the phase 1 setting, was tested not only in patients with that specific mutation, but also in patients with 

 mutations, and there are some patients who benefit.

We know that this drug was tested and there was a recent release in the media of the study comparing it with regorafenib. The end point that was being evaluated was progression-free survival. Investigators looked to see whether avapritinib would be even better than regorafenib. Based on the news release, that was found not to be the case. We haven’t seen that data, so it’s a little bit hard to comment on what this study means and what the implications are. But in my mind, based on data from the phase 1 study, which I participated in, as well as in the phase 3 trial, I have seen some activity with that drug. So I would think that is a drug you may be able to utilize in this group of patients. The toxicities are similar to the kinases, with 1 exception: It does seem to have some toxicities of special interest. Of concern are issues with cognition, memory, which I think will have to be managed and handled carefully in patients. But I think avapritinib is a drug that may have a role for selected patients whose disease is progressing beyond the standard therapies that have been approved for 

Utilizing Newer TKIs to Treat GIST

Ripretinib works by a very different mechanism than the other tyrosine kinases that we are used to using. Those drugs essentially work to inhibit the phosphorylation of the kinase. If you remember from your molecular biology or biochemistry, kinases function by being activated by ATP. Imatinib, Sutent [sunitinib], and regorafenib are really working to inhibit that process so that the kinase can no longer do its work because it doesn’t have the energy to be activated.

In reality, when that activation process occurs, there’s actually a conformational change of the protein. There is an activation loop that moves from an inactive conformation to an active conformation. Ripretinib essentially prevents that process from occurring and holds the molecule in the state that is inactive and can’t change. So it works very differently. I think one of the things that’s exciting about that is that when Sutent and regorafenib were designed, and when imatinib was discovered, the way they worked was somewhat dependent on the type of mutation that the kinase had. Some mutations would not allow for the binding of the drug. Ripretinib seems not to have that issue, and may, therefore, be effective across more and different types of mutations. I think the activity that was seen in terms of controlling disease suggests that it can work across many different types of mutations, because patients who are in the fourth-line or beyond settings tend to have a disease that not only has the initial diagnosing mutation that they were found to have at the time of their initial presentation but also multiple secondary mutations that are associated with resistance to the other medications.

Ripretinib likely has mechanisms of resistance as well. I don’t think that we fully understand what they are yet, but that’s going to be something to understand so that we can think about how we continue to treat patients as we move forward.

As always, when there are adverse effects with medications, it’s important to manage them. We now have 4, maybe 5 drugs for these patients. We want to have patients benefit from them for as long as possible. With anemia, I think it’s always important to double check or be sure that there is no loss of iron, B12, or folate. Helping patients understand how to manage fatigue is also important. Then, just monitoring blood counts to make sure that, at some point, patients don’t require blood transfusions. Typically, that’s not something that we see, but it’s certainly important to monitor. When monitoring blood counts, you certainly don’t want to put a patient at increased risk with a low white blood cell count. This is not something that we saw that was a significant issue. Regarding kidney function abnormalities, these are probably not a major problem with ripretinib. There is a study that is specifically evaluating how ripretinib is tolerated and what types of pharmacokinetics the drug has, even in the setting of renal insufficiency.

With hand-foot syndrome, management is very similar to what we’ve done with other drugs. It’s important to make sure patients use good emollient moisturizing lotions. We tend to recommend udder cream if somebody has particularly bad hand-foot syndrome. Udder cream with urea is helpful. Some people will find that a steroid cream can be helpful in terms of symptoms. I typically will tell patients before they start taking drugs for hand-foot syndrome that they want to make sure that if they have any calluses that they try and minimize those as much as possible. I also tell them it’s important to wear shoes and socks that limit friction when they’re walking. So they should avoid shoes that are very tight. Many of those things are very helpful.

One adverse effect of ripretinib that can be seen with other agents as well is muscle cramps. For some patients, that is something that is particularly annoying because those can impact what they want to do on a daily basis—discomfort or sometimes even just muscle spasms where they’re cramped up and they sort of have to open, you know, unbend their fingers, for example. Why people get that is not 100% clear, but some of the ways that I have suggested patients work with this is, number 1, to make sure that they are well hydrated. We think that some of this may be associated with low electrolytes and things such as magnesium, calcium, phosphorus, potassium. Certainly, those are things that I check when patients are on these drugs. I check these to make sure that they’re not running low; and, particularly if they’re having symptoms, to make sure they’re getting supplemented. That may be helpful. Some patients learn stretching exercises. Use of some topical creams can be helpful, as well.

For the hair loss, there’s not much you can do about it. It happens. This depends on your patient. I have not found too many patients who have required or asked for something like a cranial prosthesis, but it’s certainly something to be cognizant of and make your patients aware of. Certainly, if anybody is reporting any changes in the skin, it is important for them to make sure that they’re seen by their dermatologist to make sure there is not a lesion that should be addressed by removal.

GIST: Treating With Ripretinib

In terms of the safety of the tyrosine kinase inhibitor ripretinib, it’s pretty safe. The types of things that we saw are things that we see with many of the other drugs. Certainly, patients had fatigue. There was some anemia, issues with nausea, and occasionally some vomiting, diarrhea noted. All of these are pretty consistent. Some patients had hand-foot syndrome, but that tended to be of low grade. Very few of them had this as a dose-limiting toxicity or a toxicity that required a dose reduction.

One of the different, or novel, findings that we saw was some hair thinning or hair loss. While you see this occasionally with Sutent [sunitinib] and regorafenib, it is much more prominent with ripretinib. I think one of the interesting things is oftentimes there is an initial round of hair thinning, and then the hair tends to regrow and often comes back coarser and curlier. So it is something to discuss with your patients. It is different, and you should prepare them. Interestingly enough, I think men were more upset about this than women in my experience, but it’s always challenging. Having GIST [gastrointestinal stromal tumor] is a difficult walk through life, and then to have a reminder that you’re sick because your hair is falling out is another. So it is best to prepare patients.

There were some patients who did have some skin changes, so it is important for patients to be seen by a dermatologist. Many of these were things like actinic keratosis, which was not malignant, but a few malignances were identified. So I think it’s important for patients to know this is a possibility—certainly they probably should already be getting annual skin checkups at that age—and have them monitor themselves and bring to your attention any changes that they have in their skin.

Lastly, I think ripretinib does have some VEGF-targeting properties, so blood pressure elevation was seen in some patients. I think it’s just important to ensure normal cardiac function at baseline, and then do some sort of ongoing monitoring. If you have a patient who you’re concerned is having more liver issues, is this the drug, or could this possibly be a sign of some impact on cardiac function? And also, double checking an echocardiogram again or MUGA [multiple-gated acquisition] scan is important.

Margaret von Mehren, MD | Authors

Articles

GIST: Future Treatment Landscape

Utilizing Newer TKIs to Treat GIST

GIST: Treating With Ripretinib

Safety and Efficacy of a Newer TKI for Fourth-Line GIST