Blueprint Medicines Presents Updated EXPLORER Trial Data for Avapritinib in Patients with Systemic Mastocytosis at 24th EHA Congress
These updated data from the EXPLORER trial support
"I believe that potently and selectively targeting KIT D816V, the disease driver in nearly all systemic mastocytosis patients, represents a promising therapeutic approach," said Dr.
"These results highlight the promise of avapritinib, a potent and selective KIT D816V inhibitor, to be an important disease-modifying treatment in patients with systemic mastocytosis," said
Highlights from EHA Presentation of EXPLORER Trial Data
As of the data cutoff date of
Clinical Activity Data
Thirty-nine patients with advanced SM (three ASM, 28 SM-AHN, eight MCL) 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
In evaluable patients across all doses studied, the confirmed ORR was 77 percent. Nine patients had complete remission with a full or partial recovery of peripheral blood counts (CR/CRh; 23 percent), 18 patients had partial remission (46 percent) and three patients had clinical improvement (8 percent). No patients had progressive disease as the initial response. In addition, the 12-month duration of response (DOR) rate was 74 percent, and 49 patients (71 percent) remained on treatment with durations up to nearly three years (34 months).
Across all enrolled patients, the median overall survival (OS) was not reached. The estimated 24-month OS rate was 78 percent in all advanced SM patients: 100 percent in ASM patients, 70 percent in SM-AHN patients and 88 percent in MCL patients.
Avapritinib demonstrated strong clinical activity in patients with SRSF2, ASXL1 and/or RUNX1 (S/A/R) mutation positive genotypes, who historically have particularly poor prognoses. In 22 evaluable patients with S/A/R genotypes, the confirmed ORR was 73 percent and five patients had a CR/CRh (23 percent).
Nearly all patients had significant declines on objective measures of mast cell burden. Across all patients evaluable on these measures, 100 percent had a ≥50 percent decline in serum tryptase, 93 percent had a ≥50 percent reduction in bone marrow mast cells, 84 percent had palpable spleens become non-palpable, and 88 percent had a ≥50 percent reduction in KIT D816V mutation allele fraction.
Clinical Activity Data – Indolent or Smoldering SM
Avapritinib showed strong clinical activity in patients with indolent or smoldering SM. Nearly all patients had ≥50 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 ≥50 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 (regardless of relationship to avapritinib) reported by investigators (>15 percent) 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 (>10 percent) 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 (4 percent) discontinued treatment with avapritinib due to treatment-related AEs. Nine patients (13 percent) discontinued treatment with avapritinib due to disease progression, with the majority due to either acute myeloid leukemia (n=3) or associated hematologic neoplasm (n=3).
These updated data on avapritinib are being presented at the 24th
Conference Call Information
About the Clinical Development Program for Avapritinib in SM
Blueprint Medicines is pursuing a broad clinical development program for avapritinib across advanced, indolent and smoldering forms of SM. Avapritinib is currently being evaluated in three ongoing, registration-enabling clinical trials for SM: the Phase 1 EXPLORER trial, the Phase 2 PATHFINDER trial and the Phase 2 PIONEER trial.
The Phase 1 EXPLORER trial was designed to identify the recommended Phase 2 dose for further study and demonstrate proof-of-concept in advanced SM, including patients with ASM, SM-AHN and MCL. The dose escalation portion is complete, and the expansion portion of the trial is ongoing at multiple sites in the United States and United Kingdom. Trial objectives include assessing safety and tolerability, response per modified IWG-MRT-ECNM criteria and patient-reported outcomes.
The Phase 2 PATHFINDER trial is an open-label, single-arm, registration-enabling trial in patients with advanced SM. Patient dosing is ongoing in the trial, which is designed to enroll up to 60 advanced SM patients at sites in the United States, Canada and European Union. The primary efficacy endpoints are ORR and DOR based on modified IWG-MRT-ECNM criteria.
The Phase 2 PIONEER trial is a randomized, placebo-controlled, registration-enabling trial in patients with indolent and smoldering SM. Patient dosing is ongoing in the trial, which is designed to enroll up to 112 indolent and smoldering SM patients at sites in
SM patients and clinicians interested in ongoing clinical trials can contact the Blueprint Medicines study director at SM@blueprintmedicines.com or 1-617-714-6707. Additional details are available at www.blueprintclinicaltrials.com/SM/ or www.clinicaltrials.gov.
SM results from the abnormal proliferation and survival of mast cells, which mediate allergic responses. The clinical presentation of SM is heterogeneous, ranging from indolent or smoldering SM to three advanced subtypes – ASM, SM-AHN and MCL. The KIT D816V mutation drives approximately 95 percent of all SM cases, causing debilitating and difficult-to-manage symptoms such as pruritus, flushing, headaches, bone pain, nausea, vomiting, diarrhea, anaphylaxis, abdominal pain and fatigue. While these effects occur across SM patients, symptom burden and poor quality of life are the predominant disease manifestations of indolent and smoldering SM. Advanced SM patients experience organ damage and a median overall survival of about 3.5 years in ASM, two years in SM-AHN and less than six months in MCL.
Currently, there are no approved therapies that selectively inhibit KIT D816V in advanced SM, and no approved therapies for indolent and smoldering SM. New treatments are needed that are more effective and better tolerated than existing advanced SM therapy, as well as for indolent and smoldering SM patients whose symptoms are often not well controlled with symptom-directed therapies.
Avapritinib is an investigational, oral precision therapy that selectively and potently inhibits KIT and PDGFRA mutant kinases. It is a type 1 inhibitor designed to target the active kinase conformation; all oncogenic kinases signal via this conformation. Avapritinib has demonstrated broad inhibition of KIT and PDGFRA mutations associated with GIST, including potent activity against activation loop mutations that are associated with resistance to currently approved therapies. In contrast to approved multi-kinase inhibitors, avapritinib has shown marked selectivity for KIT and PDGFRA over other kinases. In addition, avapritinib is uniquely designed to selectively bind and inhibit D816V mutant KIT, the common driver of disease in approximately 95 percent of all SM patients. Preclinical studies have shown avapritinib potently inhibited KIT D816V at sub-nanomolar potencies with minimal off-target activity.
Blueprint Medicines is initially developing avapritinib for the treatment of advanced GIST, advanced SM, and indolent and smoldering SM. The FDA has granted Breakthrough Therapy Designation to avapritinib for two indications: one for the treatment of unresectable or metastatic GIST harboring the PDGFRα D842V mutation and one for the treatment of advanced SM, including the subtypes of ASM, SM-AHN and MCL.
Blueprint Medicines is a precision therapy company striving to improve human health. With a focus on genomically defined cancers, rare diseases and cancer immunotherapy, we are developing transformational medicines rooted in our leading expertise in protein kinases, which are proven drivers of disease. Our uniquely targeted, scalable approach empowers the rapid design and development of new treatments and increases the likelihood of clinical success. We are currently advancing four investigational medicines in clinical development, along with multiple research programs. For more information, visit www.BlueprintMedicines.com and follow us on Twitter (@BlueprintMeds) and LinkedIn.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding plans and timelines for the clinical development of avapritinib and
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