Abstract CT023: PATHFINDER: Interim analysis of avapritinib (ava) in patients (pts) with advanced systemic mastocytosis (AdvSM)
Authors: DeAngelo Daniel J. , Reiter Andreas , Radia Deepti , Deininger Michael W. , George Tracy I. , Panse Jens , Vannucchi Alessandro M. , Jentzsch Madlen , Alvarez-Twose Iván , Mital Andrzej , Hermine Olivier , Dybedal Ingunn , Hexner Elizabeth O. , Hicks Lisa K. , Span Lambert , Mesa Ruben , Bose Prithviraj , Pettit Kristen M. , Heaney Mark L. , Oh Stephen , Sen Jayita , Lin Hui-Min , Mar Brenton G. , Gotlib Jason 
Published: July 2021

Introduction: Systemic mastocytosis is a clonal, hematologic neoplasm driven by KIT D816V mutation in &gt;90% of cases, with limited treatment options. In a phase I study, ava, a potent inhibitor of KIT D816V, induced durable responses which deepened over time in pts with AdvSM, regardless of prior therapy or AdvSM subtype. PATHFINDER (NCT03580655) is a pivotal open-label, single-arm phase II study of ava in pts with AdvSM. Methods: Pts were aged ≥18 years with centrally confirmed diagnosis of an AdvSM subtype. Primary endpoint was overall response rate (ORR) by modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis criteria. This pre-specified interim analysis included 32 response-evaluable pts. Secondary endpoints included mean baseline change in AdvSM-Symptom Assessment Form Total Symptom Score (TSS) (Gotlib J et al. ASH 2018) and safety. Results: At June 23, 2020, 62 pts with AdvSM received ava primarily at 200 mg orally once daily (QD). Median age was 69 years (range 31-88), 31% had ECOG PS 2-3, and 68% had prior systemic treatment (55% with midostaurin). At 10.4 months median follow-up, 52/62 (84%) pts remained on treatment. ORR was 75% (95% CI 57-89; P=1.6×10-9) in 32 response-evaluable pts. Complete remission with full or partial hematologic recovery occurred in 19% of pts. Median time to response was 2 months; responses deepened over time. Median overall survival (OS) was not reached; estimated 12-month OS was 87%. There were ≥50% reductions from baseline serum tryptase (87%; n=54), marrow mast cell aggregates (71%; n=44), and KIT D816V allele fraction (53%; n=33). Mean TSS at baseline (n=56) was 18.3; fatigue, spots, itching, flushing, and abdominal pain were the most severe symptoms. Mean change in TSS was -7.7 (1-sided P&lt;0.001) after 6 months of treatment (n=36). Common (≥25%) adverse events (AEs; all grade, Grade ≥3) were peripheral (50%, 3%) and periorbital (35%, 3%) edema, thrombocytopenia (32%, 8%), and anemia (29%,16%). Overall, 5% of pts discontinued due to a treatment-related AE and 5% due to disease progression. There were 3 (5%) deaths, all unrelated to treatment. Seven (11%) pts had cognitive effect AEs (all Grade 1-2). One pt with pre-treatment severe thrombocytopenia (platelets &lt;50×109/L) had Grade 4 subdural hematoma. Subsequent pts with pre-treatment severe thrombocytopenia were excluded, platelet monitoring was intensified, and dose interruption for severe thrombocytopenia was recommended; no intracranial bleeding events occurred in 57 pts without pre-treatment severe thrombocytopenia. Conclusions: The pivotal PATHFINDER study showed that ava 200 mg QD induced rapid responses, which deepened over the course of treatment, and improved symptoms in pts with AdvSM. Ava was generally well tolerated with a manageable safety profile, including effective thrombocytopenia risk mitigation.

Citation Format: Daniel J. DeAngelo, Andreas Reiter, Deepti Radia, Michael W. Deininger, Tracy I. George, Jens Panse, Alessandro M. Vannucchi, Madlen Jentzsch, Iván Alvarez-Twose, Andrzej Mital, Olivier Hermine, Ingunn Dybedal, Elizabeth O. Hexner, Lisa K. Hicks, Lambert Span, Ruben Mesa, Prithviraj Bose, Kristen M. Pettit, Mark L. Heaney, Stephen Oh, Jayita Sen, Hui-Min Lin, Brenton G. Mar, Jason Gotlib. PATHFINDER: Interim analysis of avapritinib (ava) in patients (pts) with advanced systemic mastocytosis (AdvSM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT023.