Severe cognitive effects of avapritinib: Towards a mechanistic understanding.

Abstract

e24164 Background: Approximately 5-10% of Gastrointestinal Stromal Tumors (GIST) harbor a PDGFRα D842V mutation. For patients with advanced disease, avapritinib is currently the only approved therapy. However, emerging real-world data raises concerns about severe neurocognitive adverse events during and after avapritinib treatment. We hypothesize that avapritinib crosses the blood-brain barrier (BBB) and induces microvascular injury by affecting pericytes through PDGFRβ inhibition. Here, we report real-world patient data alongside complementary in vivo mouse studies designed to investigate this mechanism. Methods: We retrospectively reviewed neurocognitive and neurovascular events among Dutch GIST patients treated with avapritinib between August 2017 and December 2025, graded according to CTCAE version 5.0. In parallel, we conducted mouse experiments to (1) quantify brain penetration of avapritinib using LC-MS, (2) assess long-term effects with monthly MRI and histopathology, and (3) evaluate acute pericyte detachment following avapritinib exposure using electrophysiology and functional ultrafast ultrasound imaging to assess cerebral blood flow. This latter model was additionally used to explore the potential neuroprotective effect of the investigational agent C381. Results: Sixteen patients received avapritinib for a median duration of 442 days (range 27-1354). Memory impairment (12 patients; 75%), dullness (9; 56%), and aphasia (6; 38%) were the most frequently observed neurocognitive events, occurring after a median of 246, 96, and 682 days from treatment initiation, respectively. Eight patients experienced grade ≥3 neurocognitive events: four without evidence of cerebrovascular accident (CVA), three with a CVA, and one who developed grade 3 neurocognitive impairment followed by a CVA. Brain MRI frequently showed signs of vascular disease; but the absence of baseline and follow-up imaging in most patients limited causal inference. In mice, the avapritinib brain-to-plasma ratio was 0.69, indicating a modest BBB penetration. Interim analyses from the long-term exposure model (week 20) revealed no major MRI differences between control and high-dose groups. Results of histopathological analyses after long-term exposure, as well as effects on cerebral blood flow, are expected shortly. Conclusions: Severe neurocognitive events are common in patients treated with avapritinib. Clinical and radiological data suggest micro- and macrovascular brain injury. In vivo pharmacokinetic data confirm that avapritinib crosses the BBB. Ongoing in vivo experiments aim to elucidate whether avapritinib induces pericyte-mediated microvascular injury as a mechanistic basis for these neurocognitive events and to explore potential neuroprotective strategies. Final results are expected in early 2026.