Novartis drug Rydapt (midostaurin) receives EU approval for newly diagnosed FLT3-mutated acute myeloid leukemia (AML) and three types of advanced systemic mastocytosis (SM)

Significant overall survival benefit seen with midostaurin, the first targeted treatment for newly diagnosed FLT3-mutated AML approved in the EU[1] 

As the first and only therapy for advanced SM in the EU, midostaurin offers a new treatment option for patients with this group of rare and life-threatening diseases

Approval based on data from largest trials in AML and advanced SM to date; first major development in targeted AML treatment in more than 25 years[2],[3]

Basel, September 20, 2017 - Novartis today announced that the European Commission (EC) approved midostaurin for two indications in rare, hard-to-treat cancers – newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive and aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN) or mast cell leukemia[1].

Midostaurin represents the first and only targeted therapy for FMS-like tyrosine kinase 3 (FLT3)-mutated AML and the only treatment for three subtypes of SM, collectively known as advanced SM, in the EU, all of which have limited life expectancy and few treatment options. Midostaurin represents the first major advancement for the treatment of patients with newly diagnosed FLT3-mutated AML in more than 25 years[2],[3].

For newly diagnosed FLT3-mutated AML, the approval is based on data from the RATIFY (CALGB 10603 [Alliance]) trial, which was conducted in collaboration with the Alliance for Clinical Trials in Oncology and 13 international cooperative groups. RATIFY is the largest trial to date among people with this specific type of AML and results of the trial were recently published in the New England Journal of Medicine (NEJM)[4]. The study showed a 23% reduction in the risk of death with midostaurin plus standard chemotherapy compared with placebo plus standard chemotherapy. Median overall survival of 74.7 months and 25.6 months, respectively (hazard ratio [HR] = 0.77, 95% confidence interval [CI], 0.63, 0.95; one-sided p=0.0078)[1].

In the RATIFY trial, the most frequent adverse reactions (incidence greater than or equal to 30%) in the midostaurin plus standard chemotherapy arm were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae (small red skin spots) and pyrexia. The most frequent Grade 3/4 adverse reaction (greater than or equal to 5%) was febrile neutropenia, lymphopenia, device-related infection, exfoliative dermatitis, hyperglycemia and nausea[1].

For advanced SM, the approval is based on two single-arm open-label multicenter trials, including the Phase II study (CPKC412D2201), the largest prospective trial ever conducted in this rare disorder, the results of which were also published in NEJM[5]. The efficacy of midostaurin was established using modified Valent criteria, with patients demonstrating an overall response rate, defined as a major or partial response, of 59.6% (95% [CI], 48.6, 69.8%). Efficacy was also assessed in a post-hoc analysis using the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria (n=113). This assessment estimated an overall response rate of 28.3% (95% CI, 20.2, 37.6)[1].

In advanced SM, the most frequent adverse reactions were nausea, vomiting, diarrhea, peripheral edema and fatigue. The most frequent Grade 3/4 adverse reactions were fatigue, sepsis, pneumonia, febrile neutropenia and diarrhea[1].

About AML
AML is the most common acute leukemia, or blood cancer, in adults; it accounts for approximately 25% of all adult leukemias worldwide, with the highest incidence rates occurring in the US, Europe and Australia[6]. It also has the lowest survival rate of all adult leukemias[6].

In AML, white blood cells are not able to mature and instead build up an accumulation of "blasts," blocking room for normal blood cells[7]. Mutations in specific genes, such as FLT3, are found in many cases of the disease[8]. Genetic testing for mutations in newly diagnosed AML patients can help to determine prognosis and potential treatment strategies[9].

In the EU, there are more than 18,000 estimated new cases of AML diagnosed each year[10]. Approximately one-third of AML patients have a FLT3 gene mutation[8]. FLT3 is a type of cell-surface receptor, which plays a role in increasing the number of certain blood cells[11]. The FLT3 gene mutation can result in faster disease progression, higher relapse rates and lower rates of survival than other forms of AML[8],[11],[12].

About Advanced SM 
In advanced SM, the uncontrolled growth of neoplastic mast cells causes organ damage (e.g., liver dysfunction), low blood counts and weight loss[13]. People with the disease also suffer from debilitating systemic symptoms such as pruritus (severe itching of the skin) caused by mast cells releasing inflammatory mediators, such as histamine, into the blood[13].

The uncontrolled proliferation of mast cells is caused in many people by a KIT gene mutation - the most common mutation, encoding the D816V substitution, occurs in approximately 90% of patients[14]. The KIT gene mutation results in activation of the KIT enzyme, which triggers the abnormal proliferation and survival of mast cells[15].

About Rydapt
Rydapt (midostaurin) is an oral, targeted therapy, a type of treatment that interferes with certain pathways that are involved in the growth, progression and spread of cancer. Midostaurin inhibits multiple kinases, including FLT3, which help regulate many essential cell processes, interrupting cancer cells' ability to grow and multiply. Midostaurin induces cell death in leukemic cells expressing FLT3 ITD or TKD mutant receptors, or in cells overexpressing FLT3 wildtype receptors[1].

Midostaurin also inhibits the activity of the kinase KIT (wild type and D816V mutant), inhibiting mast cell proliferation, survival and histamine release. In addition, midostaurin inhibits several other receptor tyrosine kinases such as PDGFR alpha/ß, VEGFR2, and members of the serine/threonine kinase PKC family, inhibiting signaling of the respective growth factors in cells, resulting in growth arrest[1].

Novartis media relations
Wenche Haegh, Kommunikationschef Novartis Onkologi Norden
wenche.haegh@novartis.com
+47 95701193

References
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[13] Arock M, Akin C, Hermine O, et al. Current treatment options in patients with mastocytosis: status in 2015 and future perspectives. Eur J Haematology. 2015;94(6):474-494.[14] Garcia-Montero AC, Jara-Acevedo M, Teodosi C, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006;108(7):2366-2372.
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