Durable Responses and Improved Quality Of Life With Midostaurin (PKC412) In Advanced Systemic Mastocytosis (SM): Updated Stage 1 Results Of The Global D2201 Trial
Authors: Gotlib Jason , Kluin-Nelemans Hanneke C. , George Tracy I. , Akin Cem , Sotlar Karl , Hermine Olivier , Awan Farrukh , Hexner Elizabeth , Mauro Michael , Morariu Rodica , Squier Margaret , Villeneuve Matthieu , Emery-Salbert Fabienne , Coombs John , Hartmann Karin , Horny Hans-Peter , Valent Peter , Reiter Andreas 
Published: October 2019

Abstract

Background
Patients (pts) with advanced SM, including aggressive SM (ASM) and mast cell leukemia (MCL), often exhibit debilitating mediator symptoms and impaired quality of life (QoL) due to mast cell degranulation and organ damage. Limited treatment options are available for these poor-prognosis conditions. Midostaurin is an oral inhibitor of multiple tyrosine kinases, including wild-type and D816-mutated KIT. In vitro studies have shown that midostaurin inhibits growth and mediator release in human mast cells and basophils. Previously reported results from stage 1 of the ongoing phase 2 study in pts with advanced SM (D2201/NCT00782067; n = 40) showed a high (60%) overall response rate and good safety profile (Gotlib, et al. ASH 2012). Here, we report QoL results and updated duration of response and overall survival (OS) data for these 40 pts.

Methods
Midostaurin (100 mg twice daily [BID]) was administered continuously in 28-d cycles until progression or unacceptable toxicity. Responses and eligibility were adjudicated by a study steering committee using modified Valent criteria. Symptoms and QoL were assessed at baseline and after each treatment cycle with the Memorial Symptom Assessment Scale (MSAS; ranging from 0 [no symptoms] to 4 [maximum symptom frequency, severity, and distress]) and the Short-Form Health Survey (SF-12; ranging from 0 [worst] to 100 [best]). The total MSAS score (TMSAS), the global distress index score (GDI), the physical score (PHYS), and the psychological score (PSYCH) were derived from the frequency, severity, and distress values of selected symptoms and summarized for the MSAS questionnaire. The composite physical (PCS) and mental health (MCS) scores were summarized for the SF-12 questionnaire. Scores > 50 in the PCS and MCS represent above-average health status. Median values were computed at baseline and for the best value on treatment. In addition, the prevalence of the most frequent symptoms at baseline and at the time of the best TMSAS value was calculated.

Results
With a median follow-up of 35 mo for all pts (range, 20-46 mo), the median duration of response was 37 mo in the 24 responders (Table). Median OS was 41 mo in the 40 stage 1 pts and not reached in MCL pts. The median best reductions in symptom burden on treatment were 65%, 80%, 68%, and 77% as measured by the TMSAS, GDI, PHYS, and PSYCH assessments, respectively. Compared with baseline, 32% of 37 assessable pts had a > 50% improvement in TMSAS lasting more than 6 cycles, 35% in GDI, 27% in PHYS, and 30% in PSYCH, reached at a median time of 142, 114, 59, and 91 days, respectively. The 6 most prevalent symptoms at baseline were lack of energy, drowsiness, diarrhea, bloating, difficulty concentrating, and difficulty sleeping. The prevalence of all 6 was reduced on treatment from −17% for difficulty sleeping to −35% for bloating. The median PCS and MCS scores at baseline were 36 and 45 compared with 45 and 59, respectively, on treatment. Similar trends were observed in responders, indicating substantial physical and mental improvement. QoL was improved and symptom burden reduced in both pts with ASM and MCL.

Conclusion
In pts with advanced SM, midostaurin demonstrates a high rate of durable responses that are associated with improvement of disease-related symptoms and QoL. These data are the first systematic analyses of symptom burden and QoL changes with any therapy for ASM and MCL.

Disclosures:
Gotlib: Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, travel support Other. Off Label Use: This abstract describes a clinical trial evaluating the investigational agent midostaurin for use in patients with advanced systemic mastocytosis. George:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Akin:Novartis: Consultancy. Sotlar:Nanostring: Honoraria; Novartis: laboratory services compensation, laboratory services compensation Other. Hermine:AB Science: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Celgene: Research Funding. Awan:Lymphoma Research Foundation: Research Funding; Spectrum Pharmaceuticals: Speakers Bureau. Mauro:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Morariu:Novartis: Employment. Squier:Novartis: Employment. Villeneuve:Novartis: Employment. Emery-Salbert:Novartis: Employment. Coombs:Novartis: Employment, Equity Ownership. Hartmann:Novartis: member of a Steering Committee Other. Horny:Novartis: Consultancy. Valent:Novartis: Consultancy, Honoraria, Research Funding. Reiter:Novartis: Consultancy, Honoraria.