Midostaurin (PKC412) Demonstrates a High Rate of Durable Responses in Patients with Advanced Systemic Mastocytosis: Results from the Fully Accrued Global Phase 2 CPKC412D2201 Trial

Background : Patients (pts) with advanced systemic mastocytosis (SM), including aggressive SM (ASM) and mast cell leukemia (MCL) ± associated clonal hematologic non–mast cell lineage disease (AHNMD), have a poor prognosis with few effective treatment options. More than 80% of pts express the activating KIT D816V mutation. The oral multikinase inhibitor midostaurin inhibits wild-type and D816-mutated KIT. In this global phase 2 trial ([NCT00782067][1]), the largest prospective trial in advanced SM, a planned interim analysis of stage 1 pts demonstrated a high overall response rate (ORR) with reductions in marrow mast cell (MC) burden and a favorable safety profile (Gotlib et al, Blood 2012). Updated stage 1 results showed improvements in symptoms and quality of life (QOL) (Gotlib et al, Blood 2013). Here, we report primary results for the fully accrued trial. Methods : This single-arm trial consisted of an adapted Fleming 2-stage design. Midostaurin 100 mg twice daily was administered in continuous 28-day cycles until progression or unacceptable toxicity. Eligibility and responses (modified from Valent et al , Leuk Res 2003) were adjudicated by study steering committee (SSC). Histopathology was centrally assessed. Eligible pts had ≥ 1 measurable C-finding (CF) defined as SM-related organ damage. The primary endpoint was ORR (major response [MR] + partial response [PR]) occurring in the first 6 cycles and maintained for ≥ 8 weeks (wk). Results : Of 116 enrolled pts, 89 (77%) were eligible for efficacy evaluation; pts were considered ineligible by the SSC due to absence of measurable CF (n = 14) or organ damage considered unrelated to SM (n = 13). Median age was 64 years (range 25-82). Overall, 73 pts (82%) had ASM, including 57 (78%) with an AHNMD (ASM-AHNMD); 16 (18%) had MCL, including 6 (38%) with an AHNMD (MCL-AHNMD). AHNMDs included chronic myelomonocytic leukemia (n = 25), myelodysplastic/myeloproliferative neoplasm unclassifiable (n = 22), hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL; n = 5), and 11 other subtypes. A total of 37 pts (42%) had received ≥ 1 prior therapy (median 1; range 1-4). Seventy-seven pts (87%) were positive and 10 pts (11%) were negative for KIT D816V/Y/L mutation; 2 pts were not evaluable. The ORR was 60% (53/89); most responses were MRs (40/53, 75%), subtyped as incomplete remission (IR) in 36%, pure clinical response in 28%, and unspecified in 11%. PRs included good PR (GPR) in 21% and minor PR in 4% of pts. Overall, 12%, 11%, and 17% of pts had stable disease, progressive disease, or were not evaluable for response, respectively. After a median follow-up of 26 months (mo; range 12-54), the median duration of response (DOR) and median overall survival (OS) were 24.1 and 28.7 mo, respectively (Figure). Median OS in responders was 44.4 mo. Of 16 MCL pts, 8 responded, including 7 MRs (44%); median DOR was not reached (NR), with 3 IRs ongoing (49+, 33+, and 19+ mo). Median OS was 9.4 mo among all pts with MCL and NR among responders. Median change in MC burden in 72 evaluable pts was -59% (range -96% to 160%); 41 pts (57%) had ≥ 50% reduction. Median best change in serum tryptase level in 89 evaluable pts was -58% (range -99% to 185%); 32 pts (36%) had ≥ 50% reduction lasting ≥ 8 wk. Four of 5 responding ASM/MCL-HES/CEL pts (1 IR, 3 GPR) also had complete resolution of eosinophilia (mean % and absolute eosinophils at baseline: 57% and 12.4 × 109/L). Improvements in symptoms and QOL were consistent with those reported previously (Gotlib et al, Blood 2013). All 116 pts received ≥ 1 midostaurin dose and were evaluable for safety. Grade 3/4 drug-related hematologic adverse events (AEs) were neutropenia (5%), leukopenia (4%), febrile neutropenia (3%), anemia (3%), and thrombocytopenia (3%). Low-grade nausea was common but usually manageable with antiemetics. The most frequent grade 3/4 drug-related non-hematologic AEs included nausea (6%), vomiting (6%), fatigue (4%), and increased lipase/amylase (4%/3%). As of July 9, 2013, 65 pts had discontinued therapy, most commonly due to progression (n = 31) and AEs (n = 18; 11 were considered drug related [3 hematologic and 8 non-hematologic AEs]). Seven patients developed acute myeloid leukemia related to a prior AHNMD. Conclusions : Midostaurin exhibits a high rate of durable responses in pts with advanced SM, particularly in MCL, which has a dismal prognosis. The reductions in MC burden suggest that midostaurin may impact the natural history of the disease. ![Figure 1][2] Figure 1 ![Figure 2][2] Figure 2 Disclosures Gotlib: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Support Other. George: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Akin: Novartis: Consultancy. Sotlar: Novartis Pharma: Laboratory Services, Laboratory Services Other; Nanostring Technologies: Consultancy. Hermine: Novartis: Research Funding. Awan: Boehringer Ingelheim: Consultancy; Lymphoma Research Foundation: Research Funding. Mauro: Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Oncology: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Speakers Bureau. Sternberg: Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Villeneuve: Novartis Pharma AG: Employment. Emery-Salbert: Novartis: Employment. Stanek: Novartis Pharmaceuticals Corporation: Employment. Hartmann: Novartis: Consultancy. Horny: Novartis: Consultancy. Valent: Novartis: Consultancy, Honoraria, Research Funding. Reiter: Novartis: Consultancy, Honoraria. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00782067&atom=%2Fbloodjournal%2F124%2F21%2F636.atom [2]: pending:yes