Abstract
Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study (NCT02561988) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30–400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 109/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.
Highlights
Systemic mastocytosis (SM) is driven by the KIT p.Asp816Val (D816V) mutation in approximately 95% of cases[14,15,16], yet until recently, therapies designed to target KIT D816V were unavailable[6,12,17]
We describe the results of a phase 1 international, multicenter, open-label study (EXPLORER, NCT02561988) evaluating the safety, pharmacokinetics (PK), efficacy and patient-reported outcomes (PROs) of avapritinib in adult patients with Advanced systemic mastocytosis (AdvSM) and other myeloid malignancies
Previously undiagnosed associated hematologic neoplasm (AHN) was identified by central pathology in 41% of patients with a local diagnosis of aggressive SM (ASM), resulting in reclassification as SM with an associated hematologic neoplasm (SM-AHN) for analysis
Summary
SM is driven by the KIT p.Asp816Val (D816V) mutation in approximately 95% of cases[14,15,16], yet until recently, therapies designed to target KIT D816V were unavailable[6,12,17]. The multikinase inhibitor midostaurin is approved for AdvSM; few patients achieve complete remission, and gastrointestinal adverse events (AEs) are common[7,8,11,23,24]. Approved avapritinib in June 2021 for adult patients with AdvSM, including patients with ASM, SM-AHN and MCL. It was recently approved in the United States for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutations at a recommended starting dose of 300 mg once daily (QD), based on dose-escalation and dose-expansion trials that evaluated efficacy and safety in this setting[27,28]. We describe the results of a phase 1 international, multicenter, open-label study (EXPLORER, NCT02561988) evaluating the safety, pharmacokinetics (PK), efficacy and patient-reported outcomes (PROs) of avapritinib in adult patients with AdvSM and other myeloid malignancies
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
