Advances in Later-Lines of Therapy for GIST - Episode 5

Current Treatment Options in GIST

Brian Van Tine, MD, PhD, and Fadi Braiteh, MD, discuss the current treatment options that are available for the treatment of gastrointestinal stromal tumor (GIST).

Brian Van Tine, MD, PhD: It’s unfair, and it’s really disappointing that avapritinib, which was randomized in the VOYAGER trial against an active drug of regorafenib and was no better, wasn’t approved. In parallel, there was another drug that went against placebo in the fourth-line setting. The classic treatment for exon 11 patients is imatinib at 1 dose, imatinib at 2 doses, and sunitinib with various dosing, depending on who you talk to. Then we go to regorafenib. But now we have a new drug that is approved in the fourth-line setting, ripretinib. Have you been able to use this for your patients?

Fadi Braiteh, MD: Yes, I actually had the chance to use it in the fourth-line setting, for which it was developed, and even in later lines. In our practice, when a drug comes, especially for later-line therapy, sometimes we use it in much later lines because we have patients who have been on clinical trials in between and manage to get to 5, 6, 7-line clinical trials. Sometimes these patients do not meet the same inclusion criteria for a trial, and sometimes we’re worried about how they will perform. But the safety profile is very well acceptable, and patients perform well.

We set the expectation to the patient. It will be very interesting to see if ripretinib will move to earlier lines of therapy. I’m not going to share any opinion. In ongoing clinical trials, I’m not familiar with any outcome. The challenge is the guidelines list other drugs in the fourth line, and sometimes you get a pushback from payers. Like everything we’re doing in oncology, we have to make the case for why we’re using drug A vs drug B.

Brian Van Tine, MD, PhD: The guidelines are hopefully finally getting cleaned up. The guidelines had a lot of access to drugs where we saw activity of what to do. If there was limited activity with nilotinib or dasatinib, there was access after going through the drugs with high activity, because you had that occasional patient who did well. But now we have moved into a new world where ripretinib is a fourth-line therapy. INVICTUS, when it was first presented at ESMO [European Society for Medical Oncology Congress], was transformative. Margaret von Mehren got up at the lectern and showed there was a progression-free survival benefit and overall survival benefit in the fourth-line setting. This was a really active drug, and it mattered if you waited in the placebo arm to get to it. This is clearly an active drug with a new mechanism of action. One of the interesting things is that it’s a dual switch inhibitor. It binds to 2 parts of KIT. This makes it hard to mutate around. It is actually better if you have later-line mutations. It locks it in.

It’s going to be very interesting, because as an intrigued investigator, I can’t say much about second-line therapy. But we should stay tuned. We’ll hear soon. And so the question of when to use these is really important. Would I advise anybody to start using these drugs out of order? Not necessarily. We don’t have any data to do that. Do you really want to jump to second-line therapy with a new drug just because you can get it, and maybe not because the mutational landscape that led to your fourth-line activation is actually better and you want to use that drug then? We don’t know the escape pattern yet. It’s still very new, so you may affect overall survival. We just don’t know, but the data right now suggest that ripretinib is a fourth-line drug. When the Intrigue trial reports out, we’ll see if we should move it up to the second line. I liked this drug. It’s an interesting drug. It does have an interesting set of adverse effects that are slightly different from imatinib, mainly hair thinning. Otherwise, it’s well tolerated.

Fadi Braiteh, MD: I agree. I couldn’t disagree at all. I raise a concern the way we see it, as I mentioned, in general community oncology, with any physician who has treated a handful of GIST [gastrointestinal stromal tumor] patients in their career vs tertiary centers with high volumes. There is an expertise into not only comorbidity management and symptom management but also how we drive sequencing.

INVICTUS and other trials are heavily recruiting patients through tertiary centers rather than in the big community, and that makes sense. It’s important to go back if I’m sitting with a colleague at a tumor board talking about a GIST tumor. Anytime I get a patient referred to me for a later line of therapy or for a phase 1 trial, I can go back to see their history and the imaging. I can see anytime the drug has been switched from first- to second-line therapy, or second- to third-line therapy. The switch has been significantly delayed. In other words, the patient has been progressing for months before the drug switch. Maybe community radiologists would not comment in detail like a specialized radiologist about progression. The second thing is it’s a tolerance.… One may want to apply the classic RECIST criteria. In some other places, especially if the drug is poorly tolerated, you may decide it’s time to switch and not waste too much time. So I would raise those concerns. We’re not moving ripretinib to the second-line setting, but at the same time don’t delay it. Don’t delay the sequencing until the time when the patient is sick and doesn’t have the chance to use the drug.

Brian Van Tine, MD, PhD: I’m in absolute agreement. The other thing that’s really interesting about the treatment of GIST is that we developed Choi criteria because sometimes the tumors become bigger and hyperdense when they’re actually responding. And so this partnership got reestablished. For a very long time, academic centers treated GIST. A lot of the patients with GIST moved completely out with the community, and appropriately so. When we went to do these trials, there was a partnership between the private practices and the academic practices, which was healthy to reinvigorate and reestablish some of its radiology parameters. There are some interesting data that I cannot wait to see, which goes back to something we were talking about earlier.

Transcript edited for clarity.