Novartis PKC412 (midostaurin) data show 60 per cent response rate in advanced systemic mastocytosis

There is further evidence of potential benefit in rare blood cancers; regulatory submissions for advanced SM and acute myeloid leukemia are underway

Novartis has announced 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 per cent (95 per cent confidence interval [CI], 49-70 per cent; P<0.001) in patients with advanced systemic mastocytosis (SM). The median duration of response for all responders in the primary efficacy population was 24.1 months (95 per cent CI, 10.8-not estimated [NE]).

Advanced SM is a rare disease characterised 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. Patients with advanced SM have a poor prognosis, with overall survival varying between less than 6 months to 3.5 years, depending on subtype, and currently there is no approved treatment for the majority of patients.

The pivotal Phase II study, CPKC412D2201, was the largest and longest-running prospective trial ever conducted in this rare disorder. Jason Gotlib 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 per cent 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 per cent of patients, and were associated with disease regression.

“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,” he added.

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 per cent (P<0.001) increase in mental health scores and a 29 per cent (P<0.001) increase in physical health scores.

“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. After a median follow-up time of 18.5 (3-36) months, the overall response rate to treatment was 71 per cent. After a similar follow-up time, the overall survival (OS) rate was 42.7 per cent, compared with 14.9 per cent 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 per cent of patients (leading to failure/discontinuation in 18 per cent), lymphocytopenia in 61 per cent without opportunistic infection and photosensitivity in 25 per cent. The authors concluded that PKC412 (midostaurin) is effective in advanced SM.

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 leukaemia (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 programme) 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).