Eleven (10%) patients experienced TEAEs leading to death, of which 1 was deemed related to avapritinib by the principal investigator. With 4-year follow-up, avapritinib-treated patients with AdvSM experienced deep and durable responses and a favorable benefit-risk profile.

Targeted therapy with avapritinib and ruxolitinib was initiated but yielded limited response. Given the consistent co-occurrence of KIT mutations in previously reported similar cases, we propose the recognition of a distinct disease entity: ovarian germ cell tumor/mastocytosis with KIT mutations. This report emphasizes the importance of early genetic profiling and multidisciplinary collaboration in diagnosing and managing rare, genetically unified malignancies in pediatric oncology.

P1/2, N=29, Completed, Blueprint Medicines Corporation | Active, not recruiting --> Completed

P=N/A, N=80, Recruiting, Blueprint Medicines Corporation | Not yet recruiting --> Recruiting

It suggests that avapritinib may bridge therapeutic gaps for atypical KIT-mutant systemic mastocytosis with associated hematologic neoplasm (SM-AHN) that is ineligible for Allo-HSCT or relapsed. Prospective trials are warranted to validate its efficacy, optimize dosing, and explore synergies with Allo-HSCT, offering new strategies for these high-risk patients.

Notably, 47% of patients received previous midostaurin. AdvSM subtype, the presence and number of additional comutated genes beyond KIT D816V, BM mast cell burden, and KIT D816V variant allele fraction were associated with the presence and/or number of WHO/mIWG organ damage findings. Our study provides a snapshot of the correlates of organ damage in patients enrolled in clinical trials of avapritinib and identifies a key association between molecular profile and burden of organ damage.

P=N/A, N=80, Not yet recruiting, Blueprint Medicines Corporation

P1/2, N=37, Active, not recruiting, Blueprint Medicines Corporation | Trial primary completion date: Feb 2025 --> Nov 2025

Both patients underwent allogeneic hematopoietic stem cell transplantation, but subsequently developed refractory disease progression unresponsive to multiple salvage regiments. Strikingly, avapritinib intervention achieved unprecedented clinical responses in these complex cases.

Molecular analyses confirmed the KIT mutation in multiple non-infiltrated tissues, demonstrating the germline nature of the mutation. Despite targeted treatment with pharmacokinetically monitored midostaurin and adjunct therapies, the disease progressed rapidly, resulting in fatal multiorgan failure.

P2, N=251, Active, not recruiting, Blueprint Medicines Corporation | Trial completion date: Jan 2028 --> Jun 2027

APB and encorafenib (ECB as the internal standard) were separated using an isocratic mobile phase approach on an Agilent SB-C18 (reversed-phase) column. The metabolic stability characteristics including the intrinsic clearance and the in vitro half-life of APB were determined to be 22.11 mL min-1 kg-1 and 36.67 min, respectively. In silico analysis suggests that minor structural changes to the methyl pyrazole moiety in drug design may improve the metabolic stability and safety relative to APB.