Ripretinib (QinlockTM, Diciphera Pharmaceuticals, LLC) represents a new option for patients with advanced gastrointestinal stromal tumor (GIST) previously treated with at least three kinase inhibitors, including imatinib. In this interview with i3 Health, Margaret von Mehren, MD, lead investigator of the INVICTUS study, on which ripretinib's recent FDA approval was based, discusses how this treatment compares with other options for advanced GIST in terms of efficacy and adverse events.
What are the greatest challenges of treating patients with advanced GIST?
Margaret von Mehren, MD: I think the greatest challenge arises in that at the beginning, even when they're metastatic and untreated, we think of these tumors as relatively simple because most of them have one biologic driver, and in 85% of patients, that driver is a mutation in either the KIT gene or the platelet-derived growth factor alpha (PDGFA) gene. So treating them is usually pretty straightforward. We start with a series of drugs, typically imatinib for the first line, and many patients remain on that for many months and sometimes many years.
When they start progressing on imatinib, there are additional drugs that are available, but it's clear from looking at patients who've had tumors removed that the tumor is now getting more complicated genetically. They can have secondary or additional mutations in those initial driver genes, but they can also have alternative mutations or activations of other pathways in the cell. So the tumors really are becoming much more complicated, and prior to ripretinib, the drugs really focused on trying to inhibit the altered kinases, KIT or PDGFA, in a very similar way; there's a limitation as to the number of ways in which you can change the structure of the drugs to overcome these alterations.
Another way in which these tumors are more complicated is that in one area, there will be one set of changes, but if you look at a second area, either in the same metastatic mass or in another part of the belly, you can find differences: they have become heterogeneous.
Can you comment on the significance of the ripretinib approval?
Dr. von Mehren: Besides the simple fact that it presents another drug that is active, the significance of ripretinib is twofold. First, the way that it works is different. These kinases often have two different states, an active state and an inactive state, and the structure of the molecule changes depending on the state. Most of the drugs that we've used in the past attempt to stop the activation of the kinase by blocking the structural change in one spot: there's a pocket where this activation loop goes, and the drug tries to block that pocket.
Ripretinib works differently. It essentially binds the molecule in two spots and almost blocks it from being able to move so that it can't become activated. I think part of its success, even in people who have had three or more lines of therapy, is due to the fact that this different mode of action enables it to block multiple different kinds of resistant mutations.
The other way in which it's a helpful drug is that some of the other drugs that we use in the second and third lines, particularly sunitinib and regorafenib, have substantial side effects––not that ripretinib doesn't have side effects, but its side effects seem to be more easily tolerated. Sunitinib and regorafenib can have issues with hand-foot syndrome; while this condition is seen in some patients taking ripretinib, it tends to be much milder. Overall, patients tolerate ripretinib very well.
Avapritinib was approved earlier this year for patients with platelet-derived growth factor receptor alpha (PDGFRA) exon 18–mutated GIST. How does ripretinib compare with avapritinib in that population?
Dr. von Mehren: Avapritinib was approved for a very specific subtype of GIST, and I would say we have less clarity about how ripretinib does for that particular subtype simply because the D842V mutation, which is what avapritinib is particularly beneficial for, is a relatively rare subtype, so as the studies were ongoing, I think many of the patients with that subtype ended up being shuttled to the avapritinib studies. So we have less information concerning ripretinib in that population.
In terms of side effects, avapritinib tends to have more issues with fluid retention than ripretinib does. There is also a side effect with avapritinib in terms of memory, which we have not seen to date with ripretinib. Overall, the side effect profile is probably a little bit better with ripretinib.
That leads into my next question: are there any particular adverse events with ripretinib that physicians and nurses should be aware of?
Dr. von Mehren: I think the first thing to mention, just because it's different, is that some patients will experience hair loss. In my experience, it tends to thin; it's not completely gone, but when it regrows, it can come in thicker, coarser, and often curlier. Patients with GIST typically have been receiving kinase inhibitors, for which this is not a big issue; it's the first time they're experiencing hair loss, and it can be distressing for some. It's important to prepare patients for this possibility.
Otherwise, I think the side effects that are seen with ripretinib are very similar to what we see with other kinase inhibitors in general, and they either are on a par with them or are less intense. There certainly are patients who have some issues with indigestion, nausea, and, rarely, vomiting. Some patients will have diarrhea. All of these are a class effect. We do see some patients who have some issues with increased blood pressure, which can also be seen with sunitinib and regorafenib. In general, however, the side effects are not severe. We monitor blood counts, and we monitor liver function tests. In general, I have not seen significant concerns with kidney function tests.
The other thing that patients can experience are muscle cramps. That is something that is seen with the other drugs, but for some patients, it may be a little bit more with ripretinib. That's something that can be managed by ensuring good hydration and making sure that patients are getting enough electrolytes like calcium, phosphorus, and magnesium.
About Dr. von Mehren
Margaret von Mehren, MD, is Chief of Sarcoma Medical Oncology, Physician Director of the Clinical Trials Office, Associate Director of Clinical Research, and Professor of Hematology/Oncology at the Fox Chase Cancer Center in Philadelphia. She specializes in the treatment of sarcomas and melanoma, and she researches new therapies for GIST and other sarcomas. She is a Translational Research Disease Group (TRDG) Member for Melanoma and Skin Cancer and for Sarcoma and GIST Cancer. In addition, she is a Member of the National Comprehensive Cancer Network (NCCN) Adolescent and Young Adult Oncology Panel and the Soft Tissue Sarcoma Panel.
For More Information
von Mehren M, Serrano C, Bauer S, et al (2019). INVICTUS: a phase 3, interventional, double-blind, placebo-controlled study to assess the safety and efficacy of ripretinib as _4th-line therapy in patients with advanced gastrointestinal stromal tumors (GIST) who have received treatment with prior anticancer therapies (NCT03353753). Ann Oncol (ESMO Congress Abstracts), 30(suppl_5):v851-v934. Abstract 4794. DOI:10.1093/annonc/mdz394
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.