What You Need to Know About the FDA's Approval of Avyakit for GIST Subgroup


Patients with gastrointestinal stromal tumors have a new targeted therapy that looks to tackle secondary mutations after it showed a strong response rate in the clinic.

The Food and Drug Administration (FDA) recently approved Avyakit (avapritinib) for patients with an unresectable or metastatic gastrointestinal stromal tumor (GIST) who developed the secondary mutation platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations after diagnosis.

Avyakit, a drug specifically designed to treat GIST and its secondary mutations, marks a major step in the treatment of the disease, entering the landscape of targeted therapies. Other treatments have seen success for patients with various cancer types, especially for patients with lung cancer, changing the way most oncologists look to personalize treatment for their patients. This has impacted how biopharmaceutical companies and clinics have gone about making new cancer treatments. GIST, however, did not have many options for personalized treatment until this approval.

“The drugs that we were using, were never designed specifically to inhibit PDGFRA, they weren't designed specifically to treat just (GIST). They were developed to treat leukemia, kidney cancer or liver cancer, and so, none of the drugs were optimized for the resistance mutations that we knew (would) arise,” said Dr. Michael Heinrich, an investigator on the NAVIGATOR trial that led to the FDA approval, in an interview with CURE.

Targeting PDGFRA Exon 18

“The program was designed with forward engineering rather than reverse engineering. (Avyakit) was designed with these mutations (in mind), that our (current) drugs don't work against,” Heinrich, professor of medicine at Oregon Health & Science University, added. “Let's see if we can come up with a better drug and go forward with that.”In the case of GIST, the two secondary mutations that oncologists are concerned about are PDGFRA and KIT. Avyakit was submitted for approval for the treatment of patients with either of these secondary mutations in their disease; however, the FDA only approved the drug for patients with the PDGFRA exon 18 mutation. The agency is waiting on the results of the KIT arm of the study, according to Blueprint Medicine.

“We learned a lot about GIST and that, in addition to the original mutations, secondary mutations can arise. And those mutations make the drugs not work. The drug has to fit in very precisely, like a key into a lock,” Heinrich explained. “And in the beginning, the key fits perfectly and everything works. Except with those secondary mutations, then the lock changes and the key no longer works.”

While there is awareness in other cancer types for testing and targeting secondary mutations, GIST does not have that same awareness and prioritizing, yet. According to Heinrich, patients need to be asking their oncologists right away about testing for these mutations. Approximately, 20% to 25% of patients with GIST actually get tested for mutations, which can lead to the patient taking treatments that won’t ultimately work for them without either them or the care team knowing.


“We've been trying to say this to the GIST patients and GIST landscape, both doctors and patients for a long time: mutation, mutation, mutation. You need to know what your mutation is,” Heinrich said.To determine the efficacy of Ayvakit, researchers looked at 43 patients with GIST harboring PDGFRA exon 18 mutations starting at doses of either 300 mg or 400 mg of Ayvakit once daily. They came away with an 84% overall response rate in multiple lines of treatment, exciting researchers with such a strong, and immediate, response in patients.

“The second patient on the study, which was from the first dose cohort, had a really dramatic response to the drug even within two months of therapy,” Heinrich added, explaining the effectiveness of the drug they saw in clinic. “Her scan was done around Christmas or Christmas Eve. So, we call her the Christmas miracle because that was the first responding patient.”

Kate Haviland, chief operating officer of Blueprint Medicines, applauded Heinrich’s initiatives in an interview with CURE. “Dr. Heinrich has really done groundbreaking research to characterize what the molecular drivers are. And with our kind of scientific strategic approach about designing these potent and specific drugs against molecular drivers, it was a really nice meeting of the minds between a targeted compound and an advocate with an understanding of those targets,” she said, also stressing that patients with GIST should talk to their oncologist and care team about what this long-term treatment will mean for them and how they should approach their time on treatment.

Through the course of the study, Haviland met patients that were able to restructure their goals and think more long term as the medicine began to work for them, and that had a profound effect on her seeing these patients improve. “They thought about family and were able to plan a life again. And I think that that has been there from the beginning,” she explained. “When we started hearing some of these stories and we heard of patients who came out of the hospital and were able to go on vacation. These are the things, when we're working late and hard and taking on challenges, that really keep us going.”

Ayvakit will soon be available for oncologists to begin prescribing to their patients. Common side effects include edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash and dizziness.

Heinrich also cautioned patients to be aware of cognitive side effects unique to this treatment and to talk with their care team whenever they felt confused or felt like they were suffering from short term memory loss and word confusion.

Read CURE’s original coverage of Avyakit’s approval.

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