Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial

Abstract

Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.

Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management

“…The dose of midostaurin was reduced in 65 patients (56%), mostly due to AEs (in 48 patients). Re‐escalation to the initial dose level was accomplished in 21 of the 65 patients (32%).In an earlier Phase 2 study of midostaurin in 26 patients with advanced SM, similar responses were seen: overall 69% (major/partial response 50%/19%) during the first 12 cycles . Recently, data after a 10‐year median follow up were reported; 2 patients achieved a complete remission of SM and ≥50% reduction in BM MC burden and serum tryptase level was seen in 68% and 46% of patients, respectively.…”

“…The treatment of adult SM is highly individualized (Figure ); recent data reveal encouraging clinical and histologic responses following treatment with small molecule kinase inhibitors that potently target activation loop mutants of KIT receptor, cementing the view that KIT D816V represents the driver mutation for SM . For the rare SM patient with a transmembrane KIT mutation (eg, F522C or K509I), dramatic clinical responses to imatinib therapy can be observed .…”

“…For the rare SM patient with a transmembrane KIT mutation (eg, F522C or K509I), dramatic clinical responses to imatinib therapy can be observed . Data from 2 clinical studies with midostaurin (PKC412), a kinase inhibitor that targets both wild‐type and mutant KIT receptor, has shown 60% overall response rates (ORRs) in patients with advanced SM; the responses were durable and associated with symptom improvement and significant decreases in BM MC burden and serum tryptase levels (discussed below) . In comparison to historical controls, there is a suggestion that midostaurin prolongs overall and progression‐free survival, however there are no head‐to‐head comparisons with other cytoreductive agents.…”

FDA Approval Summary: Midostaurin for the Treatment of Advanced Systemic Mastocytosis

“…Durable responses to midostaurin were also achieved in the supportive study, PKC412A2213 [22,23]. Of the 26 patients treated, 23 had a confirmed subtype of SM.…”

Systemic Mastocytosis: Following the Tyrosine Kinase Inhibition Roadmap

“…Masitinib -Modest in ISM with related handicap -Under investigation in phase 3 trials in severe ISM and SSM with related handicap Midostaurin 142 (Gotlib et al, 2016;DeAngelo et al, 2018) High ( focused on exploring its potential utility for MC-mediator associated symptoms. Thus, a phase 2 trial in 25 patients with CM and SM with related handicap (i.e.…”