Midostaurin shows promise for rare blood cancers

The oral multikinase inhibitor midostaurin exhibited efficacy in patients with advanced systemic mastocytosis, according to the results of an open-label, multicenter phase 2 study.

Further, patients with mast-cell leukemia, which is highly fatal, also responded well to midostaurin (PKC412, Novartis).

Systemic mastocytosis is a myeloproliferative neoplasm caused by the accumulation of abnormal mast cells in the bone marrow, liver, spleen and skin. Patients with advanced disease have a poor prognosis.

“Few patients with advanced systemic mastocytosis respond to the currently available drugs,” Jason Gotlib, MD, associate professor of medicine at Stanford University School of Medicine, said in a press release. “They desperately need an alternative treatment.”

Midostaurin inhibits the KIT D816V mutation, a primary driver of advanced systemic mastocytosis pathogenesis.

Gotlib and colleagues evaluated data from 89 patients with advanced systemic mastocytosis (median age, 64 years; range, 25-82; 64% men). Patients received continuous 4-week cycles of twice-daily midostaurin at a dose of 100 mg.

Treatment continued until disease progression, death, unacceptable toxicity or patient withdrawal.

Fifty-seven patients had systemic mastocytosis with an associated hematologic neoplasm. The remaining 32 patients had aggressive systemic mastocytosis or mast-cell leukemia (n = 16 for each).

Best overall response served as the primary endpoint.

The cohort had an overall response rate of 60% (95% CI, 49-70), which was significantly above the prespecified 30% threshold for rejection (P < .001).

A major response — defined as the complete resolution of at least one type of mastocytosis-related organ damage — occurred in 45% of patients. Fifteen percent of patients achieved a partial response.

The ORR in the entire intent-to-treat population (n = 116) was 46% (n = 53), and the median duration of treatment was 11.4 months (range, 0.3-51.5).

Patients with aggressive systemic mastocytosis had an ORR of 75% (95% CI, 48-93). The response rate for patients with systemic mastocytosis with an associated hematologic neoplasm was 58% (95% CI, 44-71), and the ORR for patients with mast-cell leukemia was 50% (95% CI, 25-75).

The median duration of response had not been reached in patients with aggressive systemic mastocytosis (95% CI, 24.1-not estimated) or mast-cell leukemia (95% CI, 3.6-not estimated). Patients with systemic mastocytosis with an associated hematologic neoplasm had a median duration of response of 12.7 months (95% CI, 7.4-31.4).

Seven of the eight patients with mast-cell leukemia who responded to treatment had a major response, four of which were ongoing at the time of data cutoff.

The primary efficacy population had an OS of 28.7 months (95% CI, 18.1-not reached), and median OS was 33.9 months (95% CI, 20.3-45.5) in the intent-to-treat population.

Median OS had not been reached in patients with aggressive systemic mastocytosis (95% CI, 28.7-not estimated). The median OS was 20.7 months (95% CI, 16-44.4) among patients with systemic mastocytosis with an associated hematologic neoplasm, and 9.4 months (95% CI, 7.5-not estimated) among patients with mast-cell leukemia.

Patients who achieved a response had a significantly longer PFS than those who did not (44.4 months vs. 15.4 months; P = .005).

Fifty-six percent of patients (n = 65) required dose modifications, of whom 32% (n = 21) could feasibly re-escalate to the original study dose.

The most common nonhematologic adverse events included nausea (any grade, 79%; grade 3, 6%), vomiting (any grade, 66%; grade 3, 6%) and diarrhea (any grade, 54%; grade 3, 8%).

New or worsening hematologic adverse events included neutropenia (any grade, 48%; grade 3, 24%), anemia (any grade, 63%; grade 3, 41%) and thrombocytopenia (any grade, 52%; grade 3, 29%).

At data cutoff, 48 patients remained alive. Median PFS was 14.1 months.

The most frequent causes for treatment continuation included disease progression (33%) and adverse events (22%). Thirteen patients developed secondary acute myeloid leukemia.

“We are very hopeful that midostaurin will soon be approved by the FDA for this rare disease,” Gotlib said. – by Cameron Kelsall

Disclosure: Novartis funded this study. Gotlib reports nonfinancial support and other support from Novartis during the conduct of this study. Please see the full study for a list of all other researchers’ relevant financial disclosures.