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

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 usage showed no significant acute toxicities within this patient cohort. Most importantly, our preliminary data reveal radiographic response evaluated by RAPNO criteria in 50% of patients, a striking outcome rarely seen in this patient population. In summary, we report that avapritinib, a selective, CNS penetrant small molecule inhibitor of PDGFRA has potent activity in preclinical models and produced promising clinical responses with good tolerability in pediatric and young adult patients with high-grade glioma, suggesting a promising role for avapritinib therapy in pediatric high grade glioma.

Therapeutically targeting the unique disease landscape of pediatric high-grade gliomas

“…PDGFRA amplifications were predominantly observed within the DIPG subset (62%) while PDGFRA mutations were conversely found more often within hemispheric GBMs (54%) (204). A recent study revealed 15% of pHGGs to be harboring PDGFRA alterations, of which H3K27M DMGs exhibited significantly higher levels of PDGFRA, highlighting a targetable locus (205). Another study has shown that 50% of hemispheric H3.3G34R/V mutations harbor a PDGFRA mutation (201).…”

“…As a result, combinatorial therapy in conjunction with PDGFRA inhibition may offer a more viable solution for tumor regression. Avapritinib, a BBB penetrating PDGFR inhibitor, is currently being investigated as a potential therapeutic against PDGFRA mutant pHGG and has shown favorable toxicity profiles (205)(206)(207)(208). Adult GBM cell lines of the proneural subtype have shown sensitivity to PDGFRA inhibition (209).…”

“…PI3K-inhibitor paxalisib is currently under clinical investigation in a subset of DMG (NCT05009992). Combinations of MEK and PI3K inhibitors have also showcased synergistic efficacy (205,216,217). Interestingly, the synergistic activities of upstream activator RTKs and downstream signaling molecules of the PI3K pathway highlight a therapeutic opportunity for combinatorial therapy in suitable pHGG patients.…”