On June 29, 2016 Novartis reported that The New England Journal of Medicine (NEJM) published data for PKC412 (midostaurin) demonstrating an overall response rate, defined as a major or partial response, of 60% (95% confidence interval [CI], 49-70%; P<0.001) in patients with advanced systemic mastocytosis (SM) (Press release, Novartis, JUN 29, 2016, View Source [SID:1234513631]). The median duration of response for all responders in the primary efficacy population was 24.1 months (95% CI, 10.8-not estimated [NE])[1].
Advanced SM is a rare disease characterized by the accumulation of abnormal mast cells, a type of white blood cell, in the bone marrow, liver, spleen and other organs, leading to organ damage. It is also characterized by frequent activating mutations of the KIT gene[5]. Patients with advanced SM have a poor prognosis, with overall survival varying between less than 6 months to 3.5 years, depending on subtype[2],[3], and currently there is no approved treatment for the majority of patients[4],[5].
The pivotal Phase II study, CPKC412D2201, was the largest and longest-running prospective trial ever conducted in this rare disorder. Jason Gotlib, MD, of Stanford University School of Medicine and Stanford Cancer Institute, served as lead author of the study, which enrolled 116 people with advanced SM. Eligibility and responses were reviewed by a Study Steering Committee and 89 patients were eligible for inclusion in the primary efficacy population. Patients received single-agent, oral PKC412 (midostaurin) until disease progression or unacceptable toxicity. Results demonstrated a median overall survival (OS) of 28.7 months (95% CI, 18.1-NE). Improvements in both bone marrow mast cell burden and serum tryptase levels - a marker for mast cell burden - were seen in 78% of patients, and were associated with disease regression[1].
"These data show clear disease and symptom improvement with oral midostaurin treatment across a range of study participants who were reflective of the heterogeneity of this disease," said Professor Andreas Reiter, Department of Hematology and Oncology, University Hospital Mannheim of the University of Heidelberg, Germany and senior author of the study. "If approved, midostaurin will offer patients a much needed treatment option."
The most frequent side effects were gastrointestinal. With the exception of nausea and vomiting, all 32 symptoms self-reported with the Memorial Symptom Assessment Scale significantly decreased with treatment (P<0.001). Quality of life, assessed by the 12-item Short Form Health Survey (SF-12), was also significantly increased with PKC412 (midostaurin) treatment, compared to baseline values: improvement was shown by a 26% (P<0.001) increase in mental health scores and a 29% (P<0.001) increase in physical health scores[1].
"Patients with advanced SM are part of a very small, highly underserved community that has suffered from a lack of medical innovation for many years," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "Novartis is proud to have developed a treatment that shows benefit for these patients, and is now working with regulatory authorities to make midostaurin available as quickly as possible."
The Phase II study results are also reinforced in a letter published in the same issue of NEJM by the French Reference Centre of Mastocytosis (CEREMAST) regarding a compassionate use program for PKC412 (midostaurin) in advanced SM[6]. After a median follow-up time of 18.5 (3-36) months, the overall response rate to treatment was 71%. After a similar follow-up time, the overall survival (OS) rate was 42.7%, compared with 14.9% in a matched historic control group (P=0.03). A more than twofold higher risk of death was also observed in the control group (HR 2.2; P=0.02)[6]. The most frequent side effects were nausea/vomiting in 89% of patients (leading to failure/discontinuation in 18%), lymphocytopenia in 61% without opportunistic infection and photosensitivity in 25%. The authors concluded that PKC412 (midostaurin) is effective in advanced SM[6].
PKC412 (midostaurin) is an investigational, oral, multi-targeted kinase inhibitor that was recently granted Breakthrough Therapy Designation for adults with newly-diagnosed FLT3-mutated acute myeloid leukemia (AML) by the US Food and Drug Administration (FDA). PKC412 (midostaurin) additionally has orphan drug status in the EU and US for both AML and mastocytosis.
Since PKC412 (midostaurin) is investigational at this time, Novartis opened a Global Individual Patient Program (compassionate use program) to enable PKC412 (midostaurin) access to pediatric and adult patients presenting with aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL) or mast cell sarcoma (MCS). Physicians who wish to request PKC412 (midostaurin) for eligible patients should contact a Novartis medical representative in their respective countries. In the US, patients can call 1-888-NOW-NOVA (1-888-669-6682) for more information.
Additional information about the Phase II study
The Phase II, single arm, open-label study of adults (18 years and older) included the following subtypes of advanced SM in the primary efficacy population: aggressive systemic mastocytosis (ASM, N=16), mast cell leukemia (MCL, N=16) and SM with an associated hematologic neoplasm (SM-AHN, N=57)[1].
A key secondary endpoint of the study was OS, which varied between subtypes: 20.7 months (95% CI, 16.0-44.4) in patients with SM-AHN and 9.4 months (95% CI, 7.5-NE) in patients with MCL. Median overall survival in patients with ASM was not reached at the time of analysis (95% CI, 28.7 months-NE). Median progression-free survival (PFS) was longer in those with ASM (28.7 months, 95% CI, 24.8-NE) than in those with SM-AHN (11.0 months, 95% CI, 7.4-17.0) and MCL (11.3 months, 95% CI, 2.8-NE)[1].
The most frequent non-hematologic adverse events (>=50%) were nausea (79%), vomiting (66%) and diarrhea (54%). The most frequent Grade 3/4 non-hematologic adverse events (>=8%) were fatigue (9%) and diarrhea (8%). Dose reduction for toxicity occurred in 56% of patients[1].
For more information on the trial, visit clinicaltrials.gov (NCT00782067).
About systemic mastocytosis
Systemic mastocytosis (SM) comprises a group of rare diseases, affecting between 1 in 20,000 to 40,000 people worldwide[7], whereby uncontrolled growth and accumulation of mast cells occurs in one or more organs[5]. 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[8]. The KIT gene mutation results in activation of the KIT enzyme, which triggers the abnormal proliferation and survival of mast cells[7],[9].
In advanced SM, the uncontrolled growth of neoplastic mast cells causes organ damage (e.g. liver dysfunction), low blood counts and weight loss. Patients 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[5].
Advanced SM includes the subtypes aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL) and SM with an associated hematologic neoplasm (SM-AHN)[4]. Median overall survival is 3.5 years, less than 6 months and 2 years, for ASM, MCL and SM-AHN, respectively[2],[3].
About PKC412 (midostaurin)
PKC412 (midostaurin) is an investigational, oral, multi-targeted kinase inhibitor (targeting both wild type KIT and the KIT D816V mutation, among others), in development for the treatment of patients with AML with a FLT3 mutation, as well as patients with advanced SM. The safety and efficacy profile has not been fully established. There is no guarantee that PKC412 (midostaurin) will become commercially available.