Midostaurin Works in Advanced Systemic Mastocytosis

Pam Harrison

June 30, 2016

A desperately needed treatment for advanced systemic mastocytosis (SM) appears to have been found in midostaurin (Novartis Pharmaceuticals Corp), an investigational multikinase inhibitor that induces good responses in a high proportion of patients, even in those with highly fatal mast-cell leukemia.

The results come from an international phase 2 study published online June 29 in the New England Journal of Medicine.

"This really has been a 13-year journey for me, and to go through a long journey like this and to find a drug that has activity and that can help thousands of patients is incredibly gratifying," lead author Jason Gotlib, MD, associate professor of medicine, Stanford University School of Medicine, in California, told Medscape Medical News.

"So while it's taken years to get to this point, it's incredibly satisfying to see patients in front of you who were really sick and now they are doing beautifully," he added.

SM is a rare myeloid neoplasm affecting 1 in 20,000 to 40,000 people worldwide. It is characterized by the accumulation of mast cells in different organs, including the liver, spleen, and skin, as well as bone marrow.

Approximately 90% of patients with SM have the KIT D816V mutation, which is the main driver of the disease. KIT, a tyrosine kinase, controls the growth of mast cells, and mutations in KIT are responsible for many types of cancers, including advanced SM.

Currently, imatinib (Gleevec, Novartis Pharmaceuticals Corp), a tyrosine kinase inhibitor (TKI), is approved for patients with aggressive SM, which is not the same as advanced SM, Dr Gotlib emphasized.

Advanced SM is an umbrella term for three subtypes of the disease ― aggressive SM, SM with an associated hematologic neoplasm (also called systemic mastocytosis with an associated hematologic non-mast-cell lineage disease), and mast-cell leukemia.

"Generally speaking, imatinib doesn't work for the majority of patients with advanced systemic mastocytosis because 90% of these patients have the KIT D816V mutation, which is resistant to imatinib," Dr Gotlib observed.

Other drugs, including cladribine (Leustatin, Janssen Pharmaceuticals, Inc) and interferon alfa, have been tried in patients with advanced SM, but responses have been "hit and miss," and they were not durable, he added.

Historically, the median survival of patients with aggressive SM was 3.5 years, but it was only 2 years for those with SM with an associated hematologic neoplasm.

For patients with mast-cell leukemia, median survival has been less than 6 months.

The new drug, midostaurin (previously known as PKC412) is multitargeted kinase inhibitor; it targets both wild-type KIT and the KIT D816V mutation, among others. It is currently under development for use in the treatment of patients with acute myeloid leukemia with an FLT3 mutation, as well as patients with advanced SM.

International Study

The just-published international, multicenter, open-label study involved 116 patients with advanced SM.

"Of these patients, 89 were eligible for inclusion in the primary efficacy population," Dr Gotlib notes. To be included in the primary efficacy population, patients had to have at least one measurable "C-finding." These are clinical symptoms caused by the infiltration of mast cells into different organs; they include cytopenias, liver function abnormalities, hypoalbuminemia, weight loss, ascites, and osteolytic bone lesions.

The primary efficacy population included 16 patients with aggressive SM, 57 with SM with an associated hematologic neoplasm, and 16 with mast-cell leukemia.

The treatment protocol consisted of open-label use of oral midostaurin, given at a dosage of 100 mg twice a day in 4-week continuous cycles.

The primary outcome was best overall response in the first six 4-week treatment cycles. The response had to be sustained for 8 weeks or longer.

A major response was defined as complete resolution of one or more C-findings; a good partial response was defined as a greater than 50% improvement in one or more C-findings; a minor partial response was defined as a greater than 20% to 50% or less improvement in one or more C-findings.

Primary Efficacy Population

Investigators designed the study so that they could test their hypothesis at the end of stage 1 of the study. This allowed them to confirm that the drug had elicited a certain threshold of response before continuing with an extended-phase of the trial.

At the end of what they called "stage 1" of the study, treatment with midostaurin elicited a 60% response rate in 40 patients.

This was exactly the same response rate that was documented in the primary efficacy population, which included 89 patients who were assessed at the end of the extension phase of the trial (P < .001).

Of the primary efficacy population, 45% also achieved a major response, and 15% achieved a partial response.

"Major responses occurred primarily in the first 3 months and were maintained during the first year," Dr Gotlib observes.

In the intention-to-treat population, which included 116 patients, the overall response rate was 46%.

"The median duration of treatment was 11.4 months in the intention-to-treat population. The median follow-up was 26 months," Dr Gotlib writes.

Among the 53 patients in the intention-to-treat analysis who responded to midostaurin, "the median duration of response was 24.1 months," he notes.

Responses differed depending on the subtype of disease treated.

For example, among patients with aggressive SM, the response rate to midostaurin was highest, at 75%.

This dropped to 58% among patients with SM with an associated hematologic neoplasm and to 50% for those with mast-cell leukemia.

The median duration of response had not been reached at the point of data cutoff in either the aggressive SM group or the mast-cell leukemia group, but it reached 12.7 months for those with SM with an associated hematologic neoplasm.

Overall Survival

"Median overall survival was 28.7 months in the primary efficacy population and 33.9 months in the intention-to-treat population," Dr Gotlib continues.

Again, median overall survival differed among those with the different disease subtypes. Among those with aggressive SM, the median overall survival cutoff was not reached. The median overall survival was 20.7 months among patients with SM with an associated hematologic neoplasm and 9.4 months for those with mast-cell leukemia.

Median progression-free survival was 14.1 months in the primary efficacy population and was superior among those with aggressive SM, at 28.7 months, than among those with the other two subtypes of the disease, at approximately 11 months for each of the other two groups.

"Reversal of organ damage was observed across all types of C-findings," the investigators note.

For example, serum tryptase levels — a surrogate marker for mast-cell disease burden ― and bone marrow mast-cell burden dropped by at least 50% in most patients, which was of prognostic significance.

Of patients who were evaluable for spleen size at baseline and study endpoint, more than 75% had a decrease in the size of their spleen, which was noteworthy, Dr Gotlib said. Patients reported clinically relevant improvements in both symptoms and quality of life.

Gastrointestinal Adverse Events

Common adverse events were nausea, vomiting, and diarrhea. No more than 6% of patients experienced grade 3 and 4 toxicities. As Dr Gotlib noted, nausea from midostaurin needs to be addressed, "but if you're proactive about it, nausea can actually be well managed."

Grade 3 and 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of patients, respectively. Most of these patients had preexisting cytopenias, Dr Gotlib observed.

"Midostaurin produced marked and durable normalization of hematologic and nonhematologic organ function in 60% of patients, regardless of the subtype of advanced systemic mastocytosis, KIT D816V mutation status, or exposure to previous therapy," investigators state.

"Response to midostaurin was associated with a decrease in the risk of death that was particularly striking among patients with mast-cell leukemia," they note.

Long Haul From Idea to Clinical Results

In an interview with Medscape Medical News, Dr Gotlib explained that the idea of using midostaurin to treat mast-cell disease came to him back in 2002, when he and his colleagues were treating a patient with another type of cancer that eventually proved resistant to imatinib.

Animal studies had shown that midostaurin could overcome resistance to this TKI. This was the first demonstration that one TKI could overcome resistance to another.

"I thought to myself, is there another disease which we know is resistant to imatinib? It quickly came to me that mast-cell disease is resistant to it, so we decided to try midostaurin in advanced SM," he recalled.

Preclinical work proved that midostaurin worked beautifully against cell lines of advanced SM.

Proof of concept came when the drug's manufacturers made midostaurin available on a compassionate basis for one patient with SM with an accompanying hematologic neoplasm. The patient rallied from certain death and lived for several more months. She succumbed to her neoplasm but not to her mast-cell disease, which was well under control, Dr Gotlib recalled.

"Our study represents more than a decade of work and collaboration between academia, the pharmaceutical industry, and the SM patient community, and we are very hopeful that [results] will lead to its approval for this rare but devastating disease," Dr Gotlib said in a statement.

French Experience

Further results with midostaurin in SM are detailed in a letter that appears in the same issue of the New England Journal of Medicine.

In it, Marie-Olivia Chandesris, MD, of the French National Reference Center for Mastocytosis (CEREMAST), and colleagues reviewed their experience using midostaurin in 28 patients with mastocytosis.

Four patients had aggressive disease, 18 had disease associated with hematologic non-mast-cell disease, and three had mast-cell leukemia.

Patients were treated with the same dose of midostaurin, 100 mg, twice a day.

Responses were compared with those in a group of 44 control patients matched for subtype of mastocytosis.

"After a median treatment duration of 10.5 months...and a median follow-up of 18.5 months...the overall response rate in the midostaurin group was 71%, which included a major response in 57% of the patients, a partial response in 14%, stable disease in 11%, and progressive disease in 18%," Dr Chandesris and colleagues report.

The overall survival rate in the group was 42.7%, at a follow-up period similar to that of the study by Dr Gotlib and colleagues, they add.

This compared to an overall survival rate of 14.9% in control patients — "so the risk of death in the control group was more than twice that in the midostaurin group (P = .02)," Dr Chandesris and colleagues add.

The most frequent side effects seen in the French cohort were nausea and vomiting, which occurred in almost all patients. It lead to discontinuation of treatment in 18% of the group overall.

"On the basis of these findings, it appears that single-agent midostaurin has activity against aggressive systemic mastocytosis and mast-cell leukemia," Dr Chandesris and colleagues conclude.

The phase 2 study by Dr Gotlib and colleagues was funded by Novartis Pharmaceuticals, which also supported the French clinical study. Dr Gotlib has received reimbursement for travel expenses from Novartis and consultancy fees from Deciphera, Blueprint Medicines and Patara Pharma. Several coauthors have received fees from Novartis, as well as other pharmaceutical companies, as detailed on the N Engl J Med website. Dr Chandesris received personal fees from Novartis during the conduct of the study, as did several coauthors.

N Engl J Med. Published online June 29, 2016. Abstract, Letter

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