Avapritinib in patients with advanced systemic mastocytosis (AdvSM): efficacy and safety analyses from the phase 2 PATHFINDER study with 2-year follow-up

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