KIT Inhibitor Midostaurin in Patients with Advanced Systemic Mastocytosis: Results of a Planned Interim Analysis of the Global CPKC412D2201 Trial

Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) with or without an associated clonal hematologic non-mast cell lineage disease (AHNMD) are myeloproliferative neoplasms (MPN) with inadequate treatment options. The activating KIT D816V mutation occurs in ≈80% of patients (pts) with these advanced forms of SM and is central to disease pathogenesis. Midostaurin is an oral inhibitor of multiple tyrosine kinases, including wild-type and D816-mutated KIT. Promising results of an investigator-initiated trial (Gotlib et al. Blood. 2010;116:316) led to initiation of this multicenter phase 2 study (NCT00782067) of midostaurin in pts with advanced SM. Here, we report the efficacy and preliminary safety results of stage 1 of this trial.

Midostaurin (100 mg BID) was administered continuously in 28-d cycles until progression or intolerable toxicity. Enrollment into an extension phase was permitted if the null hypothesis of an overall response rate (ORR) ≤ 30% was rejected per Fleming 2-stage design. Pts were required to have ≥ 1 measurable C-finding(s) (CF; eg, cytopenias, liver dysfunction) considered related to SM. The primary endpoint was ORR (major response [MR] + partial response [PR] according to Valent criteria) occurring in the first 6 cycles and maintained for ≥ 8 weeks (wk). International Working Group criteria for myelodysplastic syndrome (MDS; with slight modifications) were used to evaluate changes in transfusion dependence.

62 pts were enrolled in stage 1, of whom 40 (65%) were eligible for efficacy evaluation. Reasons for ineligibility included absence of measurable CF (n = 11) or CF considered unrelated to SM (n = 11). Median age of eligible pts (25 males, 63%) was 64.5 y (range: 48–80 y). 33 (83%) pts had ASM (27 with an AHNMD) and 7 (18%) had MCL (3 with an AHNMD). AHNMDs (n=30) included 10 chronic myelomonocytic leukemia (CMML), 10 MDS/MPN-unclassified (MDS/MPN-u), 4 hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL), and 6 other subtypes. 22 (55%) pts received at least 1 prior therapy (median: 1.5; range: 1–4). 28 (70%) pts were KIT D816V/Y–positive, 3 (8%) were KIT D816V/Y–negative, and 9 (23%) were not evaluable for mutation status. The ORR was 60% (24/40), and most responses were MRs (21/24; Table). With a median follow-up of 27 months (mo), the median duration of response and median overall survival (OS) have not been reached. Of the 7 pts with MCL, 4 (57%) achieved an MR, including 3 ongoing incomplete remissions (IR) (19⁺ mo in 2 pts and 32⁺ mo in 1 pt). The OS in MCL pts was 22.6 mo. Additionally, 3 of 4 responding ASM/MCL-HES/CEL pts exhibited resolution of blood eosinophilia (mean baseline % and absolute eosinophils: 64% and 15.6 × 10⁹/L). Median change in serum tryptase level among the 40 pts was −61% (range: −97% to 16%), with 16 (40%) pts exhibiting a ' 50% reduction lasting ≥ 8 wk. Median change in marrow mast cell (MC) burden in 32 evaluable pts was −41% (range: −92% to 83%), with 15/32 (47%) pts exhibiting a ≥ 50% reduction. All 62 pts received at least 1 dose of midostaurin and were included in the safety analysis. Grade 3/4 hematologic adverse events (AEs) considered drug-related were neutropenia (11%), anemia (3%), and thrombocytopenia (3%). The most common grade 3/4 drug-related non-hematologic AEs were fatigue (6%), nausea (6%), vomiting (5%), diarrhea (5%), and increased lipase (5%). As of March 15, 2012, therapy was discontinued in 26/40 pts: 7 for AEs (5 drug-related), 12 for disease progression, and 7 for other reasons. 3 of 30 pts with an AHNMD (2 CMML and 1 MDS/MPN-u) developed AML.

In advanced SM pts, midostaurin was well tolerated and demonstrated a high rate of durable responses, including in MCL, which historically has a dire prognosis. The drug can produce significant reductions in MC burden, indicating the potential for disease modification. The stage 1 ORR was sufficient to reject the null hypothesis and permitted enrollment in the extension phase, where full accrual of 116 pts has been completed.

Gotlib:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. George:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Akin:Novartis: Consultancy. Sotlar:Novartis: Consultancy. Awan:Allos Therapeutics: Speakers Bureau. Morariu:Novartis: Employment. Squier:Novartis: Employment. Villeneuve:Novartis: Employment. Emery-Salbert:Novartis: Employment. Horny:Novartis: Consultancy. Valent:Novartis: Consultancy, Honoraria. Reiter:Novartis: Consultancy, Honoraria.