HGG-19. clinical response to the pdgfra/KIT inhibitor avapritinib in pediatric and young adult high-grade glioma patients with H3K27M or pdgfra genomic alterations
Abstract
Abstract PDGFRA is commonly altered in pediatric and young adult high-grade gliomas (pHGGs) including histone 3 lysine 27-mutated diffuse midline gliomas (H3K27M DMG), a fatal disease with no current options for cure. We performed comprehensive genomic and transcriptomic analyses of n=259 pediatric high-grade glioma cases which revealed PDGFRA genomic alterations in ~15% of patients. H3K27M DMGs had significantly higher PDGFRA expression compared to H3 wild-type tumors regardless of genomic alteration. Tumors with PDGFRA gene amplification demonstrated significantly elevated PDGFRA expression in both H3K27M DMGs and H3 wild-type pHGGs relative to tumors with wild-type or point mutated PDGFRA. We tested a range of PDGFRA inhibitors against a panel of patient derived pediatric H3K27M DMG, pHGG, and adult HGG. Amongst the inhibitors tested, avapritinib, a potent small molecule inhibitor with relatively selective activity against both wild-type and mutant PDGFRA showed potent toxicity against a wide array of pediatric and adult cell lines. This molecule also demonstrated supra-micromolar blood brain barrier penetration in pre-clinical in vivo models, and demonstrated significant decrease in tumor growth and improved survival in orthotopic mouse xenograft models. Finally, building on this preclinical activity, we report the first clinical experience using avapritinib in eight pediatric and young adult patients with high-grade glioma (H3K27M DMG and/or PDGFRA altered). Avapritinib…
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 259 participants or records.
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