The KIT Tyrosine Kinase Inhibitor Midostaurine (PKC412) Exhibits a High Response Rate in Aggressive Systemic Mastocytosis (ASM): Interim Results of a Phase II Trial.
Authors: Gotlib Jason , George Tracy I. , Corless Chris , Linder Andrea , Ruddell Alisa , Akin Cem , DeAngelo Daniel J. , Kepten Ilana , Lanza Carlo , Heinemann Heidrun , Yin Ophelia , Gallagher Neil , Graubert Tim 
Published: October 2019

Abstract
Background: Constitutively activated receptor tyrosine kinase (TK) D816V KIT contributes to the pathogenesis of most ASM cases and exhibits resistance to imatinib. Midostaurine (MST, PKC412) is an inhibitor of the KIT TK and can block D816V KIT-transformed cell growth at an IC50 of 30–40nM. We report updated results of our ongoing phase II study of oral MST in ASM patients (pts).
Methods: MS 100 mg bid was administered as continuous 28-day cycles until progression/intolerable toxicity. Lack of a major response (MR) or partial response (PR) per Valent criteria after 2 cycles resulted in pt discontinuation. To date, 15 pts have been enrolled, 9 with an associated MDS/MPD. Median age was 62 yrs (range 24–76), median # prior therapies was 1 (0–3). All 15 pts are evaluable for efficacy and safety. Responses were observed in 11/15 pts (73%). Best responses included 5 pts with a MR (all incomplete remissions), and 6 pts with a PR (5 good, 1 minor). Four pts were stopped after 2 cycles (2 stable disease, 2 progressive disease (PD)). The 5 MRs included resolution of hypoalbuminemia (n=3), increase in hemoglobin to >10 g/dL (n=1), and normalization of mild splenomegaly by CT (n=1). Additional MR findings in these pts included improvement in platelets to >100,000/mm3, and normalization of LFTs. Good PRs included reduction of ascites (n=2), >50% reduction in palpable hepatosplenomegaly (n=1), and >50% reduction in direct hyperbilirubinemia (n=2). In MR/PR pts, other findings included marked reduction in pleural effusion (n=2), reversion of weight loss, and improvement in cutaneous mastocytosis (MC) lesions. Among responders, the median duration of treatment was 10 cycles (4–18+). In 4 pts, the marrow MC burden decreased from the 50–60% to 10–15% range (stable in other responders). There was inconsistent reduction in the serum tryptase level among MR/PR pts.
Safety: Nausea and/or vomiting (N/V) was the most frequent non-hematologic toxicity. Grade 1 tremor, grade 1–2 diarrhea, fatigue, and headache (HA) were less common. Possibly related hematologic toxicity consisted of worsening anemia in 2 pts (grade 3), and recurrent grade 3 thrombocytopenia despite dose reduction to 50 mg bid. Dose reduction occurred in 4 additional pts (N/V, n=2; HA, n=1; recurrent pleural effusion, n=1). Dose re-escalation to 100 mg bid was feasible in 3 of these 4 pts. Two pts had MST discontinued after 4 cycles (grade 3 fatigue, grade 2 N/V, n=1 each), and after cycles 8 and 15 for PD (n=2). Real-time allele-specific PCR has preliminarily detected D816V KIT in 9/15 (60%) pts. Further accrual is required to render any correlation between KIT mutation status and response. Preliminary pharmacokinetic analysis reveals that plasma concentrations of MST reached a maximal level of ∼3462 ng/mL on day 3, gradually decreased with time, and reached a stable level of ∼1368 ng/mL after cycle 1. This time dependent pattern is consistent with previous findings in AML pts. In conclusion, Midostaurine has sustained partial remitting activity in a high proportion of ASM pts.