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BLU-285 induces rapid responses in advanced systemic mastocytosis
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ATLANTA — BLU-285 appeared active and safe among patients with advanced systemic mastocytosis, according to phase 1 data presented during the plenary session of the ASH Annual Meeting and Exposition.
“These patients experience life-limiting problems that warrant therapy and right now, there are limited options,” Daniel J. DeAngelo, MD, PhD, director of clinical and translational research for adult leukemia at Dana-Farber Cancer Institute, and associate professor of medicine at Harvard Medical School, told HemOnc Today. “The only option up until May was chemotherapy, when midostaurin [Rydapt, Novartis] was approved for treatment. BLU-285 [avapritinib, Blueprint Medicines] seems to be — given its a more potent inhibitor and seems to have higher response rates with limited side effects — a step in the right direction.”
Systemic mastocytosis is a mast cell neoplasm that causes debilitating allergy symptoms, dramatically impairs organ function and shortens life expectancy.
“It is fairly uncommon, and many hematologists and oncologists are unaware of the life-threatening implications,” DeAngelo said. “These patients are often transferred from allergy or dermatology departments and then the hematologist needs to determine if they have systemic mass cell involvement or proliferation of these mass cells because they can invade many organs.”
KIT D816V mutations are a key genomic driver among nearly 90% of patients with systemic mastocytosis. However, no approved therapies target this mutation.
“BLU-825 is designed to inhibit the mutated form of KIT relative to the wild form of KIT to minimize toxicity,” DeAngelo said.
In the study, researchers administered BLU-285 once daily on a 4-week cycle following a 3 + 3 escalation and dose-expansion design to adults with advanced systemic mastocytosis or refractory hematologic neoplasms.
Investigators assessed adverse events, pharmacokinetics and biomarkers, including D816V mutant allele fraction in blood and bone marrow, co-occurring mutations and serum tryptase. They also measured liver and spleen size via CT or MRI.
At data cutoff, 30 patients — 15 with aggressive systemic mastocytosis, nine with systemic mastocytosis with an associated hematologic neoplasm, three with mast cell leukemia, and three with other D816V-mutant hematologic neoplasms — received BLU-285 in seven cohorts at doses of 30 mg to 400 mg daily.
Among the patients, 24 had KIT D816V mutation, two had KIT D816Y mutation, one had KIT polymorphism M541L and three patients had no detectable KIT alteration.
The overall response rate was 72%. Ten of 12 patients showed reduced urticarial pigmentosa lesions and 30 patients showed improvements in malabsorption.
Reductions in mast cell burden and D816V mutant allele fraction appeared durable — with 28 of 30 patients still on therapy, seven of whom remained on therapy for longer than 1 year — and occurred regardless of advanced systemic mastocytosis subtype, prior therapy, concomitant mutations and performance status.
Notably, researchers observed reductions in mast cell burden among two patients with mast cell leukemia who had progressed on midostaurin and two patients with aggressive systemic mastocytosis intolerant to midostaurin. These patients remained on therapy at 5, 12, 7 and 14 months.
BLU-285 appeared well tolerated. Most adverse events were grade 1 or grade 2. More than two patients experienced grade 3 treatment-related neutropenia (13%), anemia (7%) and periorbital (7%). Two patients discontinued treatment with BLU-285 unrelated to adverse events from treatment.
Based on safety profile, pharmacokinetics and antitumor activity, researchers selected the 300-mg dose to recommended for upcoming clinical trials. A phase 2 study is planned to confirm safety and reassess efficacy, DeAngelo said.
“Additional development is ongoing. There are future phase 2 studies planned next year both in advanced systematic mastocytosis mirroring the protocol [in this study], as well as in indolent mastocytosis and systemic mastocytosis,” DeAngelo said. – by Melinda Stevens
Reference:
DeAngelo DJ, et al. Abstract 2. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: DeAngelo reports consultant roles with Amgen, Ariad, Bristol-Myers Squibb, Incyte, Novartis and Pfizer; honoraria from Blueprint Medicines, Incyte, Immunogen, Novartis Pharmaceuticals Corporation, Pfizer, Shire and Takeda Pharmaceuticals; and research funding from Amgen, Ariad, Blueprint Medicines, Celgene, Glycomimetics, Immunogen, Novartis and Pfizer. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Akil Merchant, MD
Systemic mastocytosis has been challenging to treat. Patients’ symptoms in this disease can range from mild issues that still allow them to live normally, to rapidly progressing, life-threatening illness. Although medications can help with the milder forms of the disease, there have been no specific treatments for this disease until very recently.
What’s unique is to recognize systemic mastocytosis is really driven by the KIT activation and more specifically, the D816V mutation. This mutation makes malignant mast cells resistant to many tyrosine kinase inhibitors, like imatinib. Midostaurin, the first FDA-approved agent for this disease, is a kinase inhibitor that can block signaling in D816V mutated KIT; however, midostaurin responses are quite modest, with response rates around about 20%. Although that number is low, midostaurin does provide significant clinical benefit, and in the absence of any other treatment this was an important step forward.
BLU-285 represents the next step in targeted therapy for this disease. Unlike midostaurin, which is a multikinase inhibitor with a broad inhibitory profile, BLU-285 has a much narrower inhibitory profile. There are fewer off-target effects, and the drug seems to be better tolerated than midostaurin. Importantly, most, if not all, patients demonstrated responses to this drug and these responses appear to be durable, as presented in the plenary session by Dr. DeAngelo.
The study is an important step forward. Ideally, we would prefer to have head-to-head comparisons between this agent and midostaurin; however, a few patients who previous had failed treatment with midostaurin did achieve responses with this drug. Based on these early clinical data, I believe BLU-285 could become the preferred agent for treatment of aggressive systemic mastocytosis. Important questions to be addressed in the future are the long-term durability of response, and how to optimally combine this treatment with other therapies for systemic mastocytosis, including bone marrow transplant.
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