| 2019-06-16 12:59:58|
BPMC 12:59 06/16 06/16/19
Blueprint Medicines presents updated EXPLORER trial data for Avapritinib
Blueprint Medicines announced updated data from the ongoing, registration-enabling EXPLORER trial of avapritinib in patients with systemic mastocytosis. The updated data showed a confirmed overall response rate of 77% in advanced SM patients, as assessed by a central review committee of SM clinical experts. In addition, the data showed durable clinical activity across advanced, smoldering and indolent forms of SM, with patients on therapy up to 34 months and responses continuing to deepen over time. Avapritinib was generally well-tolerated, with most adverse events reported by investigators as Grade 1 or 2. These updated data from the EXPLORER trial support Blueprint Medicines' plans to submit a New Drug Application to the U.S. Food and Drug Administration for avapritinib for the treatment of advanced SM in the first quarter of 2020, subject to continued discussions with the FDA regarding the data required to support an NDA submission. Avapritinib has received FDA Breakthrough Therapy Designation for the treatment of patients with advanced SM, including the subtypes of aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia. As of the data cutoff date of January 2, 2019, 69 patients were treated with avapritinib in the Phase 1 EXPLORER clinical trial, including seven patients with ASM, 37 patients with SM-AHN, nine patients with MCL, 15 patients with indolent or smoldering SM, and one patient without SM who had chronic myelomonocytic leukemia. Diagnoses were centrally reviewed by a committee of SM experts following an initial assessment by local investigators. Forty-two patients had a prior treatment, including 15 patients who had previously received the multi-kinase inhibitor midostaurin. Thirty-nine patients with advanced SM were evaluable for response by the modified IWG-MRT-ECNM criteria, a rigorous method for assessing clinical response in advanced SM patients with regulatory precedent in the U.S. and Europe. Confirmation of response was defined as a response duration of at least 12 weeks. Evaluable patients generally had more advanced disease at baseline than the overall trial population. In evaluable patients across all doses studied, the confirmed ORR was 77%. Nine patients had complete remission with a full or partial recovery of peripheral blood counts, 18 patients had partial remission and three patients had clinical improvement. No patients had progressive disease as the initial response. In addition, the 12-month duration of response rate was 74%, and 49 patients remained on treatment with durations up to nearly three years. Across all enrolled patients, the median overall survival was not reached. The estimated 24-month OS rate was 78% in all advanced SM patients: 100% in ASM patients, 70% in SM-AHN patients and 88% in MCL patients. Avapritinib demonstrated strong clinical activity in patients with SRSF2, ASXL1 and/or RUNX1 mutation positive genotypes, who historically have particularly poor prognoses. In 22 evaluable patients with S/A/R genotypes, the confirmed ORR was 73% and five patients had a CR/CRh. Nearly all patients had significant declines on objective measures of mast cell burden. Across all patients evaluable on these measures, 100% had a greater than or equal to 50% decline in serum tryptase, 93% had a greater than or equal to 50% reduction in bone marrow mast cells, 84% had palpable spleens become non-palpable, and 88% had a greater than or equal to 50% reduction in KIT D816V mutation allele fraction. Avapritinib showed strong clinical activity in patients with indolent or smoldering SM. Nearly all patients had greater than or equal to50 percent reductions in serum tryptase, bone marrow mast cells and KIT D816V mutation allele fraction. In addition, improvements on these measures were deep and rapid. Thirteen of 15 evaluable patients had normalized serum tryptase levels, and 12 of 13 evaluable patients had complete clearance of mast cell aggregates from the bone marrow. All indolent and smoldering SM patients achieved a greater than or equal to50 percent reduction in serum tryptase by the first post-baseline assessment. Avapritinib was generally well-tolerated with most AEs reported by investigators as Grade 1 or 2. Across all grades, the most common non-hematologic treatment-emergent AEs reported by investigators were periorbital edema, diarrhea, nausea, fatigue, peripheral edema, vomiting, cognitive effects, hair color changes, arthralgia, abdominal pain, dizziness, decreased appetite, pruritis, constipation and dysgeusia. The most common hematologic treatment-emergent AEs reported by investigators were anemia, thrombocytopenia and neutropenia. In addition, intracranial bleeding occurred in six patients with pre-existing thrombocytopenia, a known risk factor for intracranial bleeding, and one patient who had a life-threatening fall prior to intracranial bleeding. Five of these patients resumed and remain on treatment with avapritinib following dose modifications. Updated dose modification procedures have been implemented for patients with thrombocytopenia, and to date, no new intracranial bleeding events have been observed. Cytopenias were the most common Grade 3 and 4 treatment-related AEs. No Grade 5 treatment-related AEs were reported by investigators. Only three patients discontinued treatment with avapritinib due to treatment-related AEs. Nine patients discontinued treatment with avapritinib due to disease progression, with the majority due to either acute myeloid leukemia or associated hematologic neoplasm.