Imatinib Remains Standard of Care in GIST With ‘a Long Way to Go’

Breelyn Wilky, MD

The limited treatment paradigm for patients with gastrointestinal stromal tumor (GIST) with ongoing progression means there is still “a long way to go” towards optimal treatment outcomes, 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 PDGFRA exon 18 mutation, which included PDGFRA D842V mutations.1 Notably, this is the first treatment approved for patients with GIST who harbor a PDGFRA 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, Wilky noted that imatinib as the standard of care (SOC) has yet to be effectively challenged.

“We’re putting [these tumors] to sleep—sometimes effectively—but we don’t have a way yet 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 management 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 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 [other sarcoma] subtypes are much rarer, and the chance of having a patient with one of these other subtypes is unlikely; GIST is fairly common among the most common GI sarcomas we have. Now, the problem is that these tumors can often be mistaken for something else. What's important about GIST Awareness Day is to get that out there about the tumor presentation and that we have effective treatments for GIST.

What was evaluated in the phase 3 VOYAGER trial (NCT03465722), and what were some key efficacy findings?

The VOYAGER trial was attempting to displace [another phase 3 trial, GRID (NCT01271712), which supported the FDA approval of regorafenib [Stivarga] in the third-line GIST setting]. VOYAGER [assessed] regorafenib vs avapritinib for GIST in the third-line setting. 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 and not all GISTs are the same, one of the key aspects of GIST is that it’s driven primarily by activating mutations in KIT. As patients move along their treatment, we have to watch for 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 position avapritinib as the third-line SOC, it did show that it was an active drug. Some patients had a benefit, and there was this first clue toward being able to tailor our choice of therapy, particularly after the first-line setting, based on the resistance mutation the patient has.

What continued research is needed to address treatment resistance in GIST?

KIT is a tyrosine receptor [similar to] an antenna on the surface of the cells. The most common activating mutation in the code for KIT is the one in exon 11, which occurs at the exact point where imatinib can bind. We’ve recognized that over time, in addition to that main mutation, which is usually in exon 11 or exon 9 to start with, the disease evolves resistance further down the receptor—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 towards at least designing drugs that are active against multiple different resistance mutations—the whole spectrum—or combining drugs that have overlapping capabilities, so 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 you’re treating, where their mutations are, and potentially down the road, selecting drugs accordingly. Most of the research right now is 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 [the field] realized the existence of KIT mutations driving GIST, we would try to treat patients with standard chemotherapies we use for other sarcomas. The prognosis was horrible. Patients would die quickly and essentially had a 0% response rate or benefit with traditional chemotherapy. Once imatinib came onto the scene in 2000, everything changed, and GIST is 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 patients who started on imatinib early in their treatment journey. That’s mind-blowing when you think that [GIST] was a universally fatal disease before 2000. As we develop new drugs, and as patients are benefiting from subsequent drugs, we’re seeing patients live longer. We’re seeing patients achieve a response that then gets them to a surgery where we can take out some of the tumor and reset the clock.

Right now, several exciting clinical trials are [ongoing] with brand new drugs. In the early phase 1 setting, there’s a push from pharmaceutical companies to develop novel therapies that are changing the paradigm. The future is bright for patients [with GIST]. We still have a long way to go, because we can’t cure patients.

Patients with the highest risk receive imatinib therapy after they’ve undergone 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 they stop imatinib, no matter how long it's been, a subset of them will recur approximately 6 months after stopping therapy. That tells us 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

1. 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
2. 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