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Three-quarters of patients with the rare blood disorder advanced systemic mastocytosis responded to treatment with avapritinib (Ayvakit), an interim analysis of a phase II trial found.

Among 32 patients treated with daily avapritinib in the PATHFINDER study, 19% had a complete remission (CR) with partial hematologic recovery, 31% had a partial response, and 25% saw clinical improvement, with responses observed in all disease subtypes, reported Daniel DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

"Avapritinib at a starting dose of 200 mg induced rapid, durable, and improving responses," DeAngelo said during his presentation at the American Association for Cancer Research virtual meeting. "Reductions were seen in disease burden based on bone marrow mast cells, reduction in serum tryptase, KIT D816V variant allele fraction [VAF], and spleen volume."

Median time to response -- per International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) criteria -- was 2 months and the median time to CR with partial hematologic recovery was 5.6 months. At 10.4 months median follow-up, all responses remained ongoing.

"Importantly, there was no difference between patients who had had prior therapy or patients who were enrolled with de novo disease," said DeAngelo.

The overall response rate (ORR) was 74% in pretreated patients and 78% in the previously untreated group, with CRs with partial hematologic recovery in 13% and 33%, respectively.

"Overall avapritinib was well tolerated, with few patients discontinuing due to adverse events," said DeAngelo. He added that improvements in quality of life (physical, role, cognitive, and social functioning) started to approach that of healthy controls.

The findings are in line with a prior phase I dose-escalation and expansion study of avapritinib, dubbed EXPLORER, that showed an identical ORR.

Advanced systemic mastocytosis is a rare hematologic neoplasm, which is driven by KIT D816V in roughly 95% of cases. Patients with the disease have elevated mast cell disease burden leading to organ damage, poor quality of life, and poor overall survival.

The only is midostaurin (Rydapt), a multikinase inhibitor that demonstrated an ORR of 28% (on IWG-MRT-ECNM criteria) and a median overall survival of 2.5 years.

Avapritinib is a selective inhibitor of KIT D816V and platelet-derived growth factor receptor alpha (PDGFRA). The drug received FDA approval in early 2020 for treating gastrointestinal stromal tumors with PDGFRA exon 18 mutations, and the drugmaker is currently in advanced systemic mastocytosis.

In the current study, bone marrow mast cell count was halved in 88% of patients, with complete elimination in 60%. Additionally, a 50% reduction in serum tryptase levels was achieved in 93% of patients, with reductions to below 20 ng/mL in 43%.

Two-thirds of patients saw a minimum 35% reduction in their spleen volume, and 60% saw reductions by half in the KIT D816V VAF, with 35% achieving a VAF of less than 1%.

The enrolled 62 adults with a central diagnosis of advanced systemic mastocytosis, with the pre-specified interim analysis triggered when 32 patients had sufficient follow-up. Patients were started at a daily oral dose of 200 mg, with 92% having dose reductions to 100 mg or less. A larger cohort within the study consists of patients with at least one evaluable C-finding (n=52), with the remaining having none. ORR is the primary endpoint, with secondary outcomes including change in disease burden, patient-reported symptoms, and safety.

Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 and those with a platelet count <50 × 10⁹/L were excluded to reduce the risk for intracranial bleeding.

In the interim analysis, patients had a median age of 68, 44% were women, and one-third had an ECOG status of 2-3. The most common disease subtype was systemic mastocytosis with an associated hematologic neoplasm (81%), followed by mast cell leukemia in 13% and aggressive systemic mastocytosis in 6%. Baseline bone marrow mast cell burden was 50%, and the median baseline serum tryptase levels was 293 ng/mL.

Nearly all patients (94%) had detectable levels of KIT D816V in the blood; 53% had high-risk mutations in SRSF2, ASXL1, or RUNX1; and most had received prior treatment for their disease (53% midostaurin, 13% cladribine).

Most adverse events (AEs) were low grade, and included peripheral edema in 50%, periorbital edema in 48%, thrombocytopenia in 45%, anemia in 32%, neutropenia in 24%, and diarrhea in 23%.

Six patients experienced grade 1 cognitive AEs, and one patient experienced a grade 2 cognitive AE. The most common grade 3/4 AEs were neutropenia (24%), thrombocytopenia (16%), and anemia (16%), and there were no treatment-related deaths.

At data cutoff, 84% remained on treatment, with 5% discontinuing due to a treatment-related AE and 68% requiring dose reductions for toxicity.

Per IWG-MRT-ECNM criteria, a CR requires full resolution of all C-findings, elimination of bone marrow mast cells, reduction of serum tryptase levels to below 20 ng/mL, and resolution of palpable hepatosplenomegaly; partial hematologic recovery involves absolute neutrophil count >0.5 × 10⁹/L, platelet counts >50 × 10⁹/L, and hemoglobin levels >8 g/dL; while a partial response requires resolution of at least one C-finding and a 50% reduction in bone marrow mast cells and serum tryptase levels.

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