<h3>Introduction</h3> Systemic mastocytosis (SM), a clonal neoplasm driven by <i>KIT</i> D816V mutation in ~95% of cases, has limited treatment options. We evaluated pooled efficacy and safety of avapritinib, a selective inhibitor of D816V-mutant <i>KIT,</i> in patients with advanced SM (AdvSM) from the phase I/II EXPLORER (NCT02561988) and from interim analysis of the phase II PATHFINDER (NCT03580655) studies. <h3>Methods</h3> Patients included in this <i>post hoc</i> pooled analysis were ≥18 years of age with centrally confirmed diagnosis of AdvSM and treated with once-daily avapritinib at starting doses up to 200 mg. Overall response rate (ORR), defined as complete remission with full (CR) or partial hematologic recovery (CRh), partial remission (PR), or clinical improvement, was evaluated per modified IWG-MRT-ECNM criteria. Other analyses included overall survival (OS), changes from baseline in mast cell disease burden, and safety. <h3>Results</h3> Efficacy of avapritinib was analyzed in 53 ORR-evaluable patients; median age was 67 years (range, 37–85), 32% had an ECOG PS of 2–3, 66% had prior anti-neoplastic therapy, 47% received prior midostaurin, and 94% had a D816V mutation. Responses occurred in 72% (95% CI, 58–83) of patients, with 57% achieving a PR or better (95% CI, 42–70) and 28% with a CR/CRh. Median duration of response was 38.3 months (95% CI, 21.7–NE), and median time to response was 1.9 months (range, 0.3–26.7), with responses deepening over time. Median estimated 12-month OS rate was 84%. Patients achieved ≥50% reductions from baseline in serum tryptase (49/53, 92.5%), marrow mast cell aggregates (46 of 52 evaluable, 88.5%), and blood KIT D816V allele fraction (37 of 52 evaluable, 71.2%). In all AdvSM patients (safety population) receiving the starting avapritinib dose of 200 mg (n=80), common AEs were edema (79%), diarrhea (28%), nausea (24%), and fatigue/asthenia (23%). Decreased platelets (64%), hemoglobin (55%), and neutrophils (54%) from baseline were the most common laboratory abnormalities. Overall, 4 (5%) patients discontinued treatment due to drug-related AEs and 6 (8%) from disease progression. Of 2 (3%) AE-related deaths, neither were treatment-related. <h3>Conclusions</h3> Pooled study results showed ≤200 mg avapritinib induced rapid and deepening clinical responses and had a manageable safety profile.