Efficacy and safety of avapritinib in previously treated patients with advanced systemic mastocytosis

Abstract

Advanced systemic mastocytosis (AdvSM) is a rare myeloid neoplasm, driven by the KIT D816V mutation in >90% of patients. Avapritinib, a potent, highly selective D816V-mutant KIT inhibitor, is approved for treatment of adults with AdvSM by the US Food and Drug Administration, regardless of prior therapy, and the European Medicines Agency for patients with prior systemic therapy, based on EXPLORER (#NCT02561988; clinicaltrials.gov) and PATHFINDER (#NCT03580655; clinicaltrials.gov) clinical studies. We present latest pooled efficacy and safety analyses from patients who received ≥1 systemic therapy prior to avapritinib in EXPLORER/PATHFINDER. Overall response rate in response-evaluable patients (n = 31) was 71% (95% confidence interval: 52% to 86%; 22/31), including 19% (6/31) with complete remission (CR)/CR with partial recovery of peripheral blood counts (CRh). Median time to response was 2.3 months, median time to CR/CRh was 7.4 months, and median duration of response (DOR) was not reached. Reductions ≥50% in bone marrow mast cell infiltration (89%), KIT D816V variant allele fraction (66%), serum tryptase (89%), and reductions ≥35% in spleen size (70%) occurred in most patients. Median OS was not reached (median follow-up 17.7 months). Avapritinib was effective in all AdvSM subtypes, regardless of number/type of prior therapies or poor prognostic somatic mutations. Treatment-related adverse events (TRAEs) were observed in 94% of patients, most commonly grade 1/2; 57% had TRAEs of at least grade 3; 81% remained on treatment at 6 months. Avapritinib in adults with AdvSM who received prior systemic therapy was generally well tolerated, with high response rates regardless of prior systemic therapy.

Conflict of interest statement

Conflict-of-interest disclosure: A.R. has received advisory board fees, speaking fees, and travel support from AbbVie, AOP Orphan Pharmaceuticals, Blueprint Medicines Corporation, BMS-Celgene, Deciphera, GSK, Incyte Corporation, and Novartis and received research support from Blueprint Medicines Corporation and Novartis. J.S. has received advisory board fees from Blueprint and Novartis. D.J.D. has served as a consultant for Amgen, Agios, Autolus, Blueprint Medicines Corporation, Forty-Seven, Incyte Corporation, Jazz, Novartis, Pfizer, Shire, and Takeda and has received research funding from AbbVie, GlycoMimetics, and Novartis. J.G. is Chair of the Response Adjudication Committee for the EXPLORER study and cochair of the Study Steering Committee for the PATHFINDER study and has received research funding and honoraria for these roles; has received research funding, served on advisory boards, and received honoraria and funding to cover travel expenses from Blueprint Medicines Corporation; has received research funding and serves on advisory boards for Deciphera; serves as the Chair for the Eligibility and Central Response Review Committee for Cogent Biosciences; and receives funding and honoraria for a study of bezuclastinib in patients with advanced SM. M.W.D. has received honoraria fees from Blueprint Medicines Corporation, Incyte Corporation, Medscape, Sangamo, and Takeda; has received consultancy fees from Blueprint Medicines Corporation, DisperSol, Fusion Pharma, Novartis, and Sangamo; has received research funding from Blueprint Medicines Corporation, Incyte Corporation, Leukemia & Lymphoma Society, Novartis, Pfizer, SPARC, and Takeda; is part of a study management committee for Blueprint Medicines Corporation and Takeda; and is a case author for Medscape. K.M.P. has participated in advisory boards for AbbVie, CTI Biopharma, PharmaEssentia, and Kura Oncology. I.A.-T. has served on advisory boards for and received honoraria from Blueprint Medicines Corporation and has participated in educational events for Novartis. A.M.V. has participated in speakers’ bureau for AOP Orphan Pharmaceuticals, BMS-Celgene, Novartis, and Shire and in advisory boards for Abbvie, BMS-Celgene, CTI, Incyte, and Novartis. J.P. has received honorarium fees from Alexion, Apellis, Blueprint Medicines Corporation, BMS, MSD, Novartis, and F. Hoffmann-La Roche and served on the speaker’s bureau of Alexion, Boehringer Ingelheim, Neopharm Israel, and Sobi. U.P. has received research funding from BMS, Amgen, Novartis, Curis, and BerGenBio. O.H. has received research funding from AB Science, BMS-Celgene, Alexion, Novartis, and Inatherys; consulted for AB Science; and is a shareholder for AB Science. I.D. has received advisory board fees from Novartis. H.-M.L., S.N.R., K.E., and S.D. are employees of and equity holders in Blueprint Medicines Corporation. D.H.R. has been a clinical advisory board/study steering committee member (EXPLORER and PATHFINDER studies) for Blueprint Medicines Corporation, was a Cogent Biosciences steering committee member for the APEX trial, and was involved with educational events and advisory boards for Novartis.

A full list of EXPLORER and PATHFINDER study investigators appears in “Appendix.”

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

Patient disposition from EXPLORER and PATHFINDER studies.aEighty-six patients in EXPLORER include 16 non-AdvSM and 1 with CMML by central diagnosis. bSmPC population included in supplemental Appendix. cOne patient enrolled who initiated 200 mg QD in EXPLORER with a local diagnosis of AdvSM was centrally adjudicated to have indolent SM. SmPC, summary of medicinal product characteristics.

Figure 2.

Percentage reduction from baseline in clinicopathological measures of response (prior systemic therapy pooled safety population, patients with baseline assessment data available). (A) Bone marrow mast cell infiltrates (median percent). (B) Serum tryptase (ng/mL). (C) KIT D816V VAF (median percent). (D) Spleen volume (mL).

Figure 3.

OS in different populations and according to baseline mutations and risk scores. OS shown in (A) all patients in the prior systemic therapy pooled efficacy population and prior systemic therapy pooled safety population; (B) S/A/R− (0 mutations at baseline) and S/A/R+ (≥1 mutation at baseline) patients in the prior systemic therapy pooled safety population; and (C) low, intermediate, and high MARS categories in prior systemic therapy pooled safety population.