Abstract 73P
Background
Avapritinib is a KIT and PDGFRA inhibitor with high potency against KIT D816V and PDGFRA D842V mutations, and is used primarily in advanced GIST with PDGFRA D842V mutation. In the landmark phase III VOYAGER trial, cognitive events of any grade were reported in 26% of patients treated with avapritinib (grade 3: 1.3%). It is hypothesised that inhibition of PDGFRβ may lead to disruption of the blood-brain barrier and accumulation of neurotoxic proteins.
Methods
We established a cohort of patients exposed to avapritinib at our institution to build a case series. We reviewed all available medical records from the start of avapritinib treatment to the most recent record for all patients and recorded cognitive symptoms definitely or potentially attributable to avapritinib that occurred during treatment or after discontinuation. We used the CTCAE criteria to grade cognitive events and recorded the highest graded cognitive event for each patient in each category (definitely and potentially attributable to avapritinib).
Results
We identified 31 patients for inclusion in our case series who received avapritinib from 2016 to 2024. Sixteen patients (52%) had a cognitive event definitely attributable to avapritinib (grade 1: 9, grade 2: 5, grade 3: 2). Nineteen patients (61%) had a cognitive event potentially attributable to avapritinib (grade 1: 8, grade 2: 5, grade 3: 6). Of the patients with cognitive events, 8 out of 14 with available follow-up > 90 days after discontinuation showed persistence of cognitive symptoms. 6 of these 8 patients had a worsening of their symptoms after discontinuation. A higher proportion of patients with PDGFRA D842V mutations had cognitive symptoms than patients without PDGFRA D842V mutations (80% vs 52%; OR 3.49, p=0.29). Three patients developed intracranial haemorrhage (10%).
Conclusions
Cognitive impairment was more common and more severe than previously reported. Symptoms are persistent and may worsen after discontinuation. We assume that cognitive impairment might be linked to PDGFRβ innhibition, thereby compromising pericyte function and vascular integrity causing brain accumulation of blood-derived neurotoxic molecules. Further research into the mechanisms of avapritinib-induced cognitive toxicity is needed.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Axel de Bernardi.
Funding
Has not received any funding.
Disclosure
A. De Bernardin: Financial Interests, Institutional, Funding: Servier. All other authors have declared no conflicts of interest.