P1023: Avapritinib in Patients With Advanced Systemic Mastocytosis (advsm): Efficacy and Safety Analyses From the Phase 2 Pathfinder Study With 2-year Follow-up
Year: 2023
Type: article
Abstract: Topic: 16. Myeloproliferative neoplasms - Clinical Background: AdvSM, a clonal mast cell (MC) disease, is driven by the KIT D816V mutation in ~95% of cases. Avapritinib, a highly selective KIT D816V inhibitor, demonstrated rapid, deep, and durable responses in patients with AdvSM in the phase 1 EXPLORER (NCT02561988) study and in an interim analysis of the phase 2 PATHFINDER (NCT03580655) study. Responses were observed regardless of prior therapy or disease subtype (aggressive SM [ASM], SM with an associated hematological neoplasm [SM-AHN], or MC leukemia [MCL]). Data from these studies led to approval of avapritinib to treat adult patients with AdvSM in the USA and in Europe after ≥1 prior systemic therapy. Avapritinib is not recommended for patients with a platelet count <50×109/L. Aims: We present efficacy and safety analyses with a 2-year follow-up. Methods: Adult patients with centrally confirmed AdvSM treated with avapritinib were included in these analyses. Primary endpoint was centrally-adjudicated overall response rate (ORR), per modified International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (mIWG) response criteria. Secondary endpoints were time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), mean change from baseline objective disease burden measures (bone marrow [BM] MC burden, serum tryptase level, blood KIT D816V variant allele fraction [VAF], spleen volume), and safety. Results: As of September 9, 2022, 107 patients with AdvSM (20% ASM, 66% SM-AHN, and 14% MCL) had initiated avapritinib 200 mg (n=105) or 100 mg (n=2) once daily; 36% were treatment-naïve, and 64% had received ≥1 prior systemic therapy. Median age (range) was 68 years (31–88), 58% were male, and 26% had ECOG performance status 2–3. In 83 mIWG response-evaluable patients, ORR (95% CI) was 73% (63–83), with 27% achieving complete remission (CR) or CR with partial hematologic recovery. In the largest subtype group, SM-AHN, ORR was 75% (61–85) overall, 91% (71–99) in treatment-naïve patients, and 64% (45–80) in those previously treated. Two patients had disease progression as best response. Median TTR (range) was 2.3 months (0.3–15) across subtypes. Median DOR, PFS, and OS were not reached; 24-month DOR, PFS, and OS rates (95% CI) were 89% (81–97), 76% (66–85), and 79% (70–87). Benefit was observed regardless of prior therapy or subtype (Table). Reductions of ≥50% in BM MC burden (88%, n=92/105), serum tryptase (92%, n=98/107), KIT D816V VAF (81%, n=87/107), and ≥35% reduction in spleen volume (70%, n=73/105) were observed. 70% (n=72/107) of patients had total clearance of MC aggregates, 61% (n=65/107) had serum tryptase <20 ng/mL, 58% (n=62/107) had KIT D816V VAF <1%, and 74% (n=40/54) with palpable spleens became non-palpable. The most frequent (≥25% of n=107) treatment-related adverse events (TRAEs) were (any grade, grade ≥3) thrombocytopenia (39%, 18%), periorbital edema (39%, 6%), peripheral edema (38%, 2%), and anemia (29%, 13%). Treatment-related cognitive effects occurred in 24% of patients, mostly Grade 1–2 (n=22/26) and managed with dose modification. Intracranial bleeds (ICBs) occurred in 2.8%; all discontinued treatment and events resolved. Incidence of ICBs, as well as general safety, was consistent with previous reports. There were no treatment-related deaths. Dose reductions, interruptions, and discontinuations due to TRAEs occurred in 75%, 64%, and 10% of patients. Summary/Conclusion: In patients with AdvSM, avapritinib continues to provide robust efficacy with a favorable benefit-risk profile, regardless of prior therapy or disease subtype.Keywords: Tyrosine kinase inhibitor, c-kit, Systemic mastocytosis
Source: HemaSphere
Authors: Jason Gotlib, Andreas Reiter, Deepti Radia, Michael Deininger, Tracy George, Jens Panse, Alessandro Vannucchi, Uwe Platzbecker, Ivan Alvarez-Twose, Andrzej Mital, Olivier Hermine, Ingunn Dybedal, Elizabeth O. Hexner, Lambert Span, Ruben Mesa, Prithviraj Bose, Kirsten Pettit, Stephen Oh, Hui-Min Lin, Sasa Dimitrijevic, Javier Muñoz-González, Daniel J. Deangelo
Institutions: Stanford Medicine, Stanford Cancer Institute, Stanford University, Heidelberg University, University Medical Centre Mannheim, Guy's and St Thomas' NHS Foundation Trust, University of Utah, ARUP Laboratories (United States), Universitätsklinikum Aachen, RWTH Aachen University, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Leipzig University, Gdańsk Medical University, Hôpital Necker-Enfants Malades, Institut Necker Enfants Malades, Assistance Publique – Hôpitaux de Paris, Institut des Maladies Génétiques Imagine, Oslo University Hospital, Abramson Cancer Center, University of Pennsylvania, University Medical Center Groningen, Mays Cancer Center at UT Health San Antonio, The University of Texas MD Anderson Cancer Center, University of Michigan, Barnes-Jewish Hospital, Washington University in St. Louis, Blueprint Medicines (United States), Dana-Farber Cancer Institute
Language: English
Topic: Mast cells and histamine
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,480
OpenAlex ID: W4385698251