Repurposed avapritinib reduced tumor size in hard-to-treat gliomas
Treatment approved for certain gastrointestinal tumors, mastocytosis
Avapritinib, an approved orally available medication, reduced tumor size in a subset of children and young adults with treatment-resistant high-grade gliomas, a study shows.
“We treated the first eight patients with high-grade glioma with avapritinib,” Carl Koschmann, MD, a research professor in the department of pediatrics at the University of Michigan (UM), said in a university news story. “The patients tolerated the drug well and, in three of the eight patients, we were able to see their tumors shrink.” The study, “Effective targeting of PDGFRA-altered high-grade glioma with avapritinib,” was published in Cancer Cell.
Brain tumors are the leading cause of cancer-related death among children, particularly high-grade gliomas (HGGs), which form in the brain or spinal cord and spread rapidly.
Mutations in the PDGFRA gene have been implicated in developing HGGs. The gene encodes for platelet-derived growth factor receptor alpha (PDGFRA), part of a family of proteins called receptor tyrosine kinases involved in cell signaling, growth, and division. Targeting PDGFRA is a promising therapeutic strategy for treating such cancers.
Attempts to treat HGGs with tyrosine kinase inhibitors (TKIs), a class of drugs that block the action of receptor tyrosine kinases, have been unsuccessful in the clinic, however. This is mainly due to their poor tolerability and lack of penetration into the brain and spinal cord.
Avapritinib, a next-generation TKI, is a highly selective small molecule targeted against PDGFRA and a similar receptor tyrosine kinase called KIT. It’s approved in the U.S. for adults with certain gastrointestinal tumors harboring PDGFRA mutations and adults with indolent systemic mastocytosis or advanced systemic mastocytosis, two diseases that affect immune mast cells.
Testing avapritinib in PDGFRA-related gliomas
Researchers from the University of Michigan, the Dana Farber Cancer Institute in Massachusetts, and the Medical University of Vienna in Austria collaborated to evaluate the preclinical efficacy and early clinical impact of avapritinib in PDGFRA-related HGG.
First, using a dataset of 261 pediatric HGG samples, the team detected PDGFRA mutations and/or amplifications in 15% of cases.
When researchers tested compounds with known potency against PDGFRA, all approved or under clinical investigation, avapritinib exhibited the highest potency in pediatric patient-derived or mouse high-grade glioma cells with PDGFRA alterations. Further experiments confirmed these findings in additional cell models of pediatric PDGFRA-altered HGG and diffuse midline glioma, an aggressive type of glioma.
“We’d been doing screens with a lot of commercially available drugs that inhibit PDGFRA,” said Koschmann, who is also a research professor at the ChadTough Defeat DIPG Foundation. “We found avapritinib to be the strongest and most focused inhibitor that targets PDGFRA alterations.”
Using healthy mice, avapritinib efficiently penetrated the brain and spinal cord and reached concentrations in target brain tissue greater than those typically used in treatment.
“When we gave mice the drug and showed that it reached the brain, we knew we were on to something,” said Kallen Schwark, an MD/PhD candidate at UM and one of the study’s lead authors.
When avapritinib was given to mouse models of HGG with PDGFRA alterations, the treatment blocked PDGFRA signaling, reduced tumor growth, and extended survival.
“We were excited to see that avapritinib essentially shut off PDGFRA signaling in mouse brain tumors,” Koschmann said.
Testing avapritinib in children, young adults with HGG
Building on these preclinical results, the team initiated avapritinib therapy through a compassionate use program in eight children and young adults, ages 4-29, with treatment-resistant HGG. Seven patients’ tumors harbored PDGFRA alterations. All had had surgery and local radiotherapy following their diagnosis
Avapritinib was given orally once daily for a median of four months. Three of seven evaluable patients (42%) showed a response, or tumor shrinkage, as assessed by MRI.
Across all eight patients, the median progression-free survival (PFS) after starting avapritinib, that is, the time alive without disease progression, was 2.8 months and the median overall survival (OS) was 6.1 months. For the responders, the median PFS was 5.2 months, and the median OS was 12 months.
All three responding patients developed metastatic lesions, or secondary tumors that spread to other parts of the body, that didn’t respond to avapritinib and they ultimately died. At the same time, the initial responding lesions showed no signs of progression in the last available MRI.
“We have very few examples of drugs entering brain tumors like this and shutting down key oncogenic [cancer-related] pathways,” Koschmann said. “These results support a lot of ongoing efforts to build on the success of avapritinib and other brain penetrant small molecule inhibitors.”
The early data helped support the inclusion of pediatric HGG patients in a Phase 1/2 study (NCT04773782), sponsored by Blueprint Medicines, to evaluate avapritinib in people, ages 2-17, with advanced treatment-resistant solid tumors. The work is preliminary and it’s hoped that avapritinib could be an additional tool to help cancer patients, Koschmann said.
“We know a single drug is not going to be enough for this disease,” he said. “The way to make true progress will be combining many different types of modalities, like combining drugs that are target pathways activated by the first drug. We already have a follow-up story on targeting avapritinib with MAP kinase inhibitors that we are just as excited about.”
MAP kinase inhibitors are a different class of drugs used to treat cancer.
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