With a limited treatment landscape for gastrointestinal stromal tumor (GIST) with ongoing progression, there is still “a long way to go,” according to Breelyn Wilky, MD.
In January 2020, the FDA approved avapritinib (Ayvakit) for the treatment of patients with unresectable or metastatic GIST harboring a PDGFRα exon 18 mutation, which included D842V mutations.1 Notably, this is the first treatment approved for patients with GIST who harbor a PDGFRα exon 18 mutation. Furthermore, in May 2020, the FDA approved ripretinib (Qinlock) for the treatment of patients with advanced GIST who were previously treated with 3 or more kinase inhibitors, which included imatinib (Gleevec).2 The regulatory decision was based on efficacy data from the phase 3 INVICTUS trial (NCT03353753). However, imatinib as the standard of care has yet to be effectively challenged.
“We’re putting [these tumors] to sleep—sometimes very effectively—but we don’t have a way yet to be able to detect those residual cells and figure out who needs lifelong imatinib therapy or long-term imatinib therapy,” Wilky explained during an interview with OncLive® ahead of GIST Awareness Day, recognized annually on July 13. “Certainly, we don’t have a way to cure them yet.”
In the interview, Wilky discussed the importance of highlighting GIST Awareness Day, research in GIST treatment paradigm, the management of resistance to therapies, and how GIST has evolved and will continue to evolve.
Wilky is the director of Sarcoma Medical Oncology, the Cheryl Bennett and McNeilly Family Endowed Chair in Sarcoma Research, deputy associate director for Clinical Research, and associate professor of Medicine-Medical Oncology at the University of Colorado Medicine in Aurora.
OncLive: What is the importance of highlighting GIST Awareness Day?
Wilky: GIST is one of those sarcomas that’s incredibly rare, overall. However, it’s the most common sarcoma that we see as sarcoma experts, and it’s one of the tumors that a general oncologist might come across during their career. Some of the subtypes are much rarer, and the chance of having a patient with one of these other subtypes is pretty unlikely, but GIST is fairly common among the most common gastrointestinal sarcomas that we have. Now, the problem is that these tumors can often be mistaken for something else. What’s really important about GIST Awareness Day is to get that out there about the tumor, about the presentation, and that we have very effective treatments for GIST.
What was evaluated in the phase 3 VOYAGER trial, and what were some key efficacy findings?
The VOYAGER trial actually was attempting to displace [another phase 3 trial that supported regorafenib [Stivarga] in the third-line setting]. VOYAGER [assessed] regorafenib vs avapritinib for GIST in the third line. It was a negative study, [and therefore,] regorafenib kept its spot as the third-line treatment. However, what we learned is that there was some importance about particular mutation types. Even though GISTs are rare, not all GISTs are the same, and one of the key things with GIST is that it’s driven primarily by activating mutations in a gene called KIT, and as patients move along their treatment, the thing that we have to watch for is the emergence of resistance mutations. Although most [patients] upfront are sensitive to imatinib [Gleevec], which is our first-line KIT inhibitor, over time, they can develop resistance mutations. Although the VOYAGER trial did not put avapritinib into the third-line for standard of care, it did show that it was an active drug. Some patients did get benefit, and there was this first clue of being able to tailor our choice of therapy, particularly after the first line, based on the particular resistance mutation the patient had.
Regarding resistance to treatment, are there therapies that are currently being evaluated to address this?
KIT is a tyrosine receptor [similar to] an antenna on the surface of the cells, and most of the time, when there’s an activating mutation in the code for KIT, the most common one is called exon 11, which occurs at the exact point where imatinib can bind. What we’ve recognized is that, over time, in addition to that main mutation, which is usually exon 11 or exon 9 to start with, you evolve resistance further down the receptor, so inside the cell, either at a point called the activation loop or the ATP binding site. Using genetic testing or looking at circulating tumor DNA, which is an emerging hot theme, we can find those resistance mutations in many patients. There’s this push toward at least designing drugs that are active against multiple different resistance mutations, sort of the whole spectrum, or combining drugs that have overlapping capabilities, so that we are covering for the emergence of resistance across the board. Even more so, there’s this push for precision medicine. This is [about] understanding the patient that you’re treating, where their mutations are, and potentially down the road, selecting drugs accordingly. Most of the research right now is really targeted at one of those two things: either drugs that cover the entire scope of potential mutations or combining drugs in a novel way to try to cover the entire spectrum.
How has the management of GIST evolved over the years, and what do you hope to see regarding future research?
Before imatinib came along, in 2000, when people realized the existence of KIT mutations driving GIST, we would try to treat patients with standard chemotherapies we use for other sarcomas, and the prognosis was horrible. Patients would die very quickly and essentially had a 0% response rate or benefit to traditional chemotherapy. So once imatinib came onto the scene in 2000, everything changed, and GIST is sort of the classic example of the success story for precision medicine. Once you identify that driver mutation, you have a drug to go with it, and you completely change outcomes for patients.
Now, even with metastatic disease, there are patients out there who’ve been living on imatinib and never went on to develop that resistance, and they’ve remained stable for 10 to 15 years. There are a couple of patients who started on imatinib very early in the journey. That’s absolutely mind-blowing when you think that this was a universally fatal disease before 2000. As we develop new drugs, and as patients are benefiting from subsequent drugs, we’re seeing people live for longer and longer. We’re seeing patients are getting a response that then gets them to a surgery where we can take out some of the tumor and sort of reset the clock, if you will.
Right now, several really exciting clinical trials are [ongoing] with brand new drugs. In early phase 1, there’s a push from pharmaceutical companies to develop novel therapies that are changing the paradigm. The future is really bright for patients [with GIST]. We certainly still have a long way to go, because we can’t cure patients. Even with imatinib, what we know is that patients with the highest risk receive imatinib therapy after they’ve had surgery. We’ve done clinical trials testing 3 years, 5 years, and 7 years of imatinib, and for that high-risk group of patients, when you stop imatinib, no matter how long it’s been, a subset of them will recur about 6 months after stopping therapy. It tells us that we’re not killing every GIST cell in these patients. Still, we don’t have a way to go after those resistant cells yet and kill everything to get patients free of the disease. [There has been] lots of lots of progress, but [there’s still] a long way to go.
References
- FDA approves avapritinib for gastrointestinal stromal tumor with a rare mutation. FDA. January 9, 2020. Accessed July 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-avapritinib-gastrointestinal-stromal-tumor-rare-mutation
- FDA approves ripretinib for advanced gastrointestinal stromal tumor. FDA. May 15, 2020. Accessed July 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ripretinib-advanced-gastrointestinal-stromal-tumor