Precision Medicine Stakes Claim in the Gastrointestinal Stromal Tumors Landscape

Margaret von Mehren, MD

Gastrointestinal stromal tumors (GIST), although rare, have recently seen advances in treatment. Specific GIST subtypes, including patients with KIT and platelet-derived growth factor receptor alpha (PDGFRA) mutations, have recently benefited from FDA-approved targeted therapies.

In January of 2020, the FDA granted approval to avapritinib (Ayvakit) for the treatment of adults with unresectable or metastatic GIST who harbor PDGFRA exon 18 mutations, including PDGFRA D842V mutations. It was the first precision medicine therapy approved for a genomically defined population of patients with GIST. The approval was supported by positive findings from the phase 1 NAVIGATOR clinical trial (NCT03347279), in which avapritinib achieved an overall response rate (ORR) of 84%. Responses included complete responses (CRs) in 7% of patients and partial responses (PRs) in 77%.¹

Later in 2020, ripretinib (Qinlock) was granted FDA approval for the treatment of adult patients with advanced GIST who had received at least 3 prior lines of therapy with kinase inhibitors, including imatinib (Gleevec). Results from the phase 3 INVICTUS trial (NCT03353753) served as the basis for the approval after it showed a significant decrease in the risk of disease progression or death by 85% when compared with placebo (HR, 0.15; P < .0001).²

In both studies, the targeted therapies showed tolerable safety profiles.

In an interview with Targeted Oncology, Margaret von Mehren, MD, chief of the Division of Sarcoma Medical Oncology, physician director of the Clinical Trials Office, associate director of clinical research and professor in the Department of Hematology/Oncology at Fox Chase Cancer Center, reviews the recent advancements in the GIST treatment landscape. She also explains what’s needed to move the needle further in the future.

TARGETED ONOCOLOGY: In GIST, a few approvals came through last year. Can you begin with explaining how these new agents have changed practice since then?

von Mehren: The first drug that was approved was avapritinib. This is a drug that was specifically designed to try and inhibit mutations that are found in a specific portion of both KIT and PDGFRA, which are the 2 genes that are most commonly mutated in GIST and drive the growth of GIST.

All of the other drugs that we have available just don't hit that portion of the molecule well, and so they aren't effective. When it was studied, avapritinib was very effective, particularly for GIST with a PDGFRA mutation in D842V where nothing has really worked. This has really changed how we manage those subtypes of patients. In addition, the approval was specifically for tumors with the PDGFRA mutations in exon 18. So, this is a drug that really has transformed treatment for a specific group of patients with a specific molecular change, where before we had no effective therapy. It's very exciting for that group of patients.

The second drug that was approved was ripretinib, and ripretinib was studied initially in phase 1 to figure out what the best dose was. Interestingly, they never identified a maximum tolerated dose, and they moved forward with looking at a dose based on what they had predicted would be helpful at inhibiting the kinases, KIT and PDGFRA, based on blood work in preclinical studies. Most of the patients enrolled on their studies had KIT mutations, and that's largely because they are more common. It also may be because [ripretinib was] being co-developed at the same time as avapritinib, so some of the PDGFRA-positive patients were sent towards the avapritinib studies.

Ripretinib works differently from the other kinases that we've worked with. Many of the other kinases have worked by binding the molecule KIT or PDGFRA, and preventing adenosine triphosphate, which is sort of the energy of the cell from binding and thus activating the molecule. Part of how these molecules work is that they become active and inactive by changing their shape, or what we call their confirmation, and ripretinib binds the molecules in 2 spots and prevents that change. It doesn't allow it to become activated.

One of the potential benefits of the way ripretinib works is that we know when patients have been on kinase inhibitors like imatinib or sunitinib (Sutent), they tend to develop secondary mutations. Those secondary mutations cause those kinase inhibitor to no longer be effective because the molecules can't bind or when they do bind, they don't cause inhibition. Simplistically, in GIST, these kinases or proteins that are present are mutated and altered in driving the growth of the tumor. I like to think of them as light switches—they’re always turned on and telling the cell to grow and divide. And when a drug like imatinib is effective, it's able to turn off the light switch and stop the cell from growing and dividing. But with these secondary mutations, the drugs are no longer able to turn off the light switch, so ripretinib is 1 of the ways we can do that.

TARGETED ONCOLOGY: What are some key takeaways from the INVICTUS trial of ripretinib and the NAVIGATOR trial of avapritinib?

von Mehren: The INVICTUS trial looked at patients who had received 3 or more prior standard treatments—some patients even received others—and compared what happened if patients weren't on treatment. If there's not an effective therapy in many situations, we think that doing good pain control and things like that is better than getting a drug that is ineffective.

In the INVICTUS study, what we showed is that patients who started on the placebo, really had their disease grow quite rapidly, and that demonstrated that there is clearly a need for additional drugs. Thankfully, the patients who started on ripretinib or were able to cross over from placebo to ripretinib had significant disease control. Patients who started on placebo patients had their disease controlled for about a month, because their disease just grew. For the patients on ripretinib, it was significantly longer and more like 6 to 7 months. So, I think the results show the benefit of this therapy. Patients also had significant outcomes, including benefit in terms of their survival.

The study was designed with a statistical design, which didn't allow the study to conclude statistically overall survival and that's because they looked at response rate, and the response rate was about 10%, which was lower than they had suggested might be, so the design required a look at the progression-free survival first, which they clearly benefited, but they didn't seem to benefit in terms of response rate, because they didn't meet the statistical design. Then they weren't able to say, “yes we see an improvement, and that's statistically meaningful.”

Moving on to the NAVIGATOR trial, it really demonstrated, particularly for patients that have tumors with PDGFRA, that there is very significant efficacy in that group. The dose that was chosen and was subsequently approved was 300 milligrams daily, and although that dose was very effective, lower doses of avapritinib were also effective.

There does seem to be a benefit to using a higher dose of avapritinib because the efficacy does appear to be longer, although the way the study was designed wasn't comparing doses. I think it's useful to remember that, particularly because avapritinib had adverse events (AEs) like all drugs do. One of the AEs, which is different from many of the tyrosine kinase inhibitors (TKIs) that we commonly use, is an impact on cognitive function. With some patients, we noticed they have issues with their memory. It can manifest as word-finding issues, and occasionally changes in their mood. That's something that is important to recognize early, because if it's recognized early, holding the medication or decreasing the dose of the medication really helps to prevent that from getting worse, or helps it go away. It is an identified toxicity that we just need to manage and be aware of. It's helpful to not only inform the patient of this, but also their families so that they can be on the lookout, and help identify when this change occurs and it can be managed effectively.

TARGETED ONCOLOGY: What have you observed with ripretinib in everyday practice in terms of safety and efficacy?

von Mehren: It's been similar to the clinical trials. Just to speak about toxicity because that's always from the patient's perspective and an important issue to be aware of. The ripretinib is quite tolerable for most patients. There are a couple of things that are slightly different or more pronounced than with other agents. In my experience, patients on ripretinib seem to have more issues with myalgias. There are also some hand-foot issues, which we see more often than other toxicities.

With sunitinib and regorafenib (Stivarga), for some patients, it's quite mild and for others it can be more concerning and more impacting on their activities of daily living. But the management is really similar to what we do with the other agents. The other thing with ripretinib that is different is that patients can have thinning of their hair. Alopecia is something we don't typically see with TKIs and many patients have not had that experience. So that's an important educational piece. Interestingly, it does seem to initially thin, and for many patients it then seems to come back a different texture. So that's something to educate patients about and have them be ready to manage that and meet their expectations.

Lastly, the other thing with ripretinib that patients need to be aware of is that the minority of patients who are treated with the drug have had some issues with developing skin cancers. For most of them, they are easily managed. Rarely, skin cancers can develop and be worrisome, or more aggressive cancers like melanoma. I think in the clinical trials, there's been only 1 reported case, but it's certainly something to be aware of having patients see a dermatologist and just making patients aware and asking them have they noticed any new lumps or bumps or changes in moles to monitor on their skin.

TARGETED ONCOLOGY: What have you observed with avapritinib in your clinic?

von Mehren: The experience with avapritinib has been very similar. I think of it in terms of AEs. It's a little bit more imatinib-like in the sense that patients can have fluid retention. They can also have anemia. The other issues that we see, while the drug has been approved for PDGFRA mutations, in the clinical trials, we did study KIT mutations, and there were certainly patients who did derive benefit from that. It has been studied further and compared to regorafenib and it did not appear superior to regorafenib. So, at this point, the use of avapritinib for patients with KIT mutation is investigational. It’s not FDA approved for that indication.

TARGETED ONCOLOGY: Sre there any unmet medical needs that still exist for this patient population? What novel agents are coming down the pipeline to address them?

von Mehren: Certainly. Patients who are treated with the kinase inhibitors that we have are still pretty healthy after progression and want more therapy. In terms of their kidney function, renal function, or liver function, they're perfectly able to do that. So, I think there is still the need for additional therapies. For patients who have the PDGFRA D842V mutations that I spoke about, avapritinib is the only drug that really works. So, what do you do when that drug stops working? It does seem to work for a long time for many patients, but even in the initial NAVIGATOR trial, some patients did develop resistance. There is significant attention and focus on how do we take care of those patients, because the other agents that are available have not really been of significant benefit.

TARGETED ONCOLOGY: Based on all this new research in the field, what advice would you provide to a community oncologist who encounters a patient with GIST in their practice?

von Mehren: I think first is the awareness that diagnosis is complex. Looking back 21 years ago, when we first were studying imatinib, we thought about this disease as sort of 1 disease. Now, we really recognize the different subtypes. Where they arise sometimes can give you hints as to what subtype it might be, and what it looks like under the microscope can give you some hints. So, for a community oncologist who has never seen a patient with GIST before or who has only seen 1 patient with GIST before, getting a good pathologic review, making sure there's molecular testing is key. If they're not clear about what to do, having the patient see a specialist to make sure that all of those things are being done and evaluated and interpreted appropriately is important.

_References:

_{1. Blueprint Medicines Announces FDA Approval of AYVAKIT (avapritinib) for the Treatment of Adults with Unresectable or Metastatic PDGFRA Exon 18 Mutant Gastrointestinal Stromal Tumor. News release. Blueprint Medicines Corporation. January 9, 2020. Accessed March 5, 2021. https://bit.ly/3vbuyCT}

_{2. FDA grants full approval of Deciphera Pharmaceuticals’ Qinlock™ (ripretinib) for the treatment of fourth-line gastrointestinal stromal tumor. News release. Deciphera Pharmaceuticals, Inc. May 15, 2020. Accessed March 5, 2021. https://bit.ly/2WZaMds.}