Effective targeting of PDGFRA-altered high-grade glioma with Avapritinib

(Lisa Mayr et al., 2025. Cancer Cell. DOI: 10.1016/j.ccell.2025.02.018. PMID: 40086436)

[Discussion]

Recent collective sequencing efforts have identified several key molecular drivers of pediatric and young adult patients diagnosed with HGG or DMG. Among them, PDGFRA has emerged as a promising therapeutic target due to its frequent genomic alterations and its essential role in driving oncogenic signaling in pHGG. To address the critical need for effective PDGFRA-targeted therapies, this paper evaluated next-generation TKIs and identified Avapritinib as a potent, selective, and CND-penetrable PDGFRA inhibitor in patient-derived HGG and DMG models with PDGFRA alterations. As a bench to bedside approach, the paper also evaluated the tolerability and preliminary outcomes of Avapritinib treatment.

Although avapritinib was developed to target the PDGFRA D842V mutation (PDGFRA WT patient showed no clear response to avapritinib), the in vitro data showed that HGG models with PDGFRA gain/amplification also responded similarly. However, since limitations such as 1) patient-derived models used in the study representing tumors of various molecular subgroups, age groups, and with variable oncogenic co-mutations, the conclusions regarding potential differences in the response to avapritinib across different PDGFRA-alterations were limited. Also, there were 2) prior reports of concerns for intracranial hemorrhage for at-risk patients with CDN tumors, but since the baseline rate of intracranial hemorrhage in DMG patient is high (~20%), only one cmase (clinically insignificant) was observed.

The successful radiographic response to avapritinib led to the ongoing Rover study – a phase ½ multi-centre single-arm study to evaluate safety, pharmacokinetics, and efficacy of avapritinib in pediatric tumours with PDGFRA/KIT activating mutations, amplifications, or H3K27M DMGs (NCT04773782). Additionally, since KIT is frequently co-amplified in patients with PDGFRA copy-number gains, avapritinib also potentially enhanced response to a dual KIT/PDGFRA inhibitor.

Interestingly, whilst 3/8 patients’ primary lesions continued to respond to avapritinib showing no signs of tumor progression, they eventually developed metastatic lesions resistant to avapritinib – which suggests a new resistance mechanism developing in the metastatic HGG lesions. In the avapritinib-resistant tumor, 1) Some in-vivo results revealed de novo EGFR gain with increased EGFR expression and phosphorylation, 2) some in-vitro models showed RTK-independent activation of downstream pathways such as sustained AKT phosphorylation and restoration of S6 phosphorylation. 3) Long-term avapritinib-treated mice showed persistent phosphorylated AKT and ERK, indicating downstream activity independent of PDGFRA signaling in end-stage tumors. Highlights need for combinatorial targeted therapies. (Preliminary data of avapritinib in combination with EGFR inhibitors or compounds targeting MAPK or PI3K pathways revealed potential synergistic or additive combination strategies).

[Limitations of the Study]

1. Small cohort of patients: conclusions regarding biomarkers or genomic signatures predicting response need further evaluation in future clinical studies.

2. Durability of the response: This report does not address the duration of avapritinib therapy required for durability of response.

3. Developmental perspective: Given the high expression of PDGFRA signaling in normal OPCs and the importance of PDGFRA signaling in normal OPC development and myelination, the potential neurocognitive effects of long-term therapy in the pediatric population will need to be carefully assessed.

(Although in in vivo models, observed no decrease in non-malignant oligodendroglial cells).