An Updated Analysis on Safety and Efficacy of Avapritinib in Patients with Advanced Systemic Mastocytosis from the Explorer Clinical Study: Long-Term Efficacy and Safety

Introduction: Systemic mastocytosis (SM) is a rare myeloid neoplasm driven by KIT D816V mutations in ~95% of patients. Advanced SM (AdvSM) includes three subtypes: aggressive SM (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN; most common), all typically with poor prognoses. Avapritinib, an oral, highly selective inhibitor of KIT D816V, is approved in the USA for treatment of adult patients with AdvSM, and in Europe after ≥1 prior systemic therapy. Avapritinib is not recommended for the treatment of patients with AdvSM with platelet counts of <50×10⁹/L. The aim of the multi-center, international, phase 1 EXPLORER (NCT02561988) clinical study was to determine maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and tolerability. Earlier data from this and the phase 2 PATHFINDER (NCT03580655) studies showed rapid, deep, and durable responses to avapritinib treatment regardless of prior therapy, AdvSM subtype, or presence of high-risk mutations. Here we present long-term analyses from EXPLORER showing sustained efficacy, deepening responses, mature progression-free survival (PFS), updated overall survival (OS), and consistent safety profile.

Methods: Analyses included patients aged ≥18 years with centrally confirmed AdvSM who initiated 30-400 mg once daily avapritinib. Primary endpoints were MTD and RP2D, safety, and tolerability. Secondary endpoints included overall response rate (ORR) per modified International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (mIWG-MRT-ECNM) response criteria defined as complete remission with full (CR) or partial (CRh) recovery of peripheral blood counts, partial remission, or clinical improvement, as well as changes in objective disease burden measures (bone marrow mast cell [BM MC] burden, serum tryptase, KIT D816V variant allele fraction [VAF], and spleen volume), PFS, and OS.

Results: As of April 5, 2022, 69 patients with AdvSM were enrolled; 12% (n=8) had ASM, 19% (n=13) MCL, and 70% (n=48) SM-AHN. Median age (range) was 67 years (34-83), 59% were male, 30% had Eastern Cooperative Oncology Group performance status 2-3, and 59% had prior systemic therapy. Median duration of treatment (range) was 23 months (2-67); after 24 weeks most patients (69%) were receiving 100 mg or 200 mg daily. ORR (95% confidence interval [CI]) per mIWG-MRT-ECNM criteria for evaluable patients (N=57) was 77% (64-87) (Table) with ORR of 100% (40-100), 85% (55-98), and 72% (56-85), for ASM, MCL, and SM-AHN subtypes, respectively. There were 4 additional CRs (n=57) since the previous analysis of 53 evaluable patients at median follow-up of 23 months and ORR of 75%. Median duration of response (DOR) for all responders was not reached (NR). In patients with no prior therapy, median DOR (95% CI) was 38 months (22-not evaluable [NE]) and NR for patients with at least one prior therapy. Most patients had observed reductions in objective measures of disease burden including ≥50% reduction in BM MC burden (94%, n=61/69), serum tryptase (99%, n=68/69), KIT D816V VAF (75%, n=50/69), and ≥35% reduction in spleen volume (83%, n=55/69). 52 (80%) patients had total clearance of neoplastic BM MC aggregates. Median PFS (95% CI) in response-evaluable patients was 49 months (31-NE). With a median follow-up of 45 months, only 17 (25%) patients had disease progression, including 7 who progressed to acute myeloid leukemia. Median OS was NR in all AdvSM, ASM, and MCL, and was 46.9 months (95% CI 29.6-NE) in SM-AHN (Table, Figure). The most frequent treatment-related adverse events (TRAEs; any grade) were periorbital edema (64%), anemia (42%), thrombocytopenia (36%), nausea (33%), and peripheral edema (33%). Grade ≥3 TRAEs were observed in 74% of patients. There were no additional intracranial bleeding events since previous reports. Cognitive effects were experienced by 44% of patients, mostly grade 1 and 2. There was no negative impact on clinical efficacy despite 73% of patients having dose reductions or 83% having dose interruptions due to TRAEs. TRAEs led to discontinuations in 27% of patients.

Conclusions: At almost 4 years of follow-up, survival benefit was ongoing with median OS not reached. Among all patients treated with avapritinib, rapid, durable responses were observed. Avapritinib was generally well tolerated with a safety profile consistent with previous reports.

DeAngelo:AbbVie, Blueprint Medicines Corporation, GlycoMimetics, and Novartis: Research Funding; AbbVie, Amgen, Autolus, Blueprint Medicines Corporation, Forty-Seven, GlycoMimetics, Incyte, Jazz, Kite, Novartis, Pfizer, Servier, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Radia:Cogent Biosciences: Other: Steering committee member for APEX study; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Blueprint Medicines Corporation: Membership on an entity's Board of Directors or advisory committees, Other: Educational events, Research Funding. George:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARUP Laboratories: Other: Associated; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cogent Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees. Robinson:Blueprint Medicines Corporation: Research Funding. Drummond:Novartis: Other: Personal fees, Research Funding; Blueprint Medicines Corporation: Research Funding. Bose:Pfizer: Research Funding; Sierra Oncology (now GSK): Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Promedior: Research Funding; BMS: Consultancy, Research Funding; Novartis: Honoraria; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Disc Medicine: Research Funding; Cogent: Honoraria, Research Funding; Ionis: Research Funding; NS Pharma: Research Funding; Pharma Essentia: Honoraria; Blueprint Medicines Corporation: Honoraria, Research Funding; Telios: Research Funding; Astellas: Research Funding; Kartos: Research Funding; Incyte: Honoraria, Research Funding. Hexner:Samus Therapeutics, Novartis Oncology: Research Funding; Blueprint Medicines Corporation: Consultancy, Research Funding; Tmunity Therapeutics: Research Funding; PharmaEssentia: Consultancy; American Board of Internal Medicine: Other: Member of the hematology exam committee. Winton:Blueprint Medicines Corporation, Samus Therapeutics and Incyte Corporation: Research Funding. Horny:Novartis: Consultancy; Blueprint Medicines Corporation: Consultancy. Tugnait:Blueprint Medicines Corporation: Current equity holder in publicly-traded company, Other: Former employee. Lin:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Dimitrijević:Blueprint Medicines (Switzerland) GmbH: Current Employment, Current equity holder in publicly-traded company. Munoz-Gonzalez:Blueprint Medicines (Switzerland) GmbH: Current Employment, Current equity holder in publicly-traded company. Bidollari:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Deininger:Incyte: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Galena Biopharma: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Research Funding. Gotlib:Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Cogent Biosciences: Consultancy, Research Funding; Allakos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.