Boston – An international team of clinical collaborators, led by physician scientists from Dana-Farber Cancer Institute, performed a first-ever clinical test of the targeted therapy avapritinib in pediatric and young patients with a form of high-grade glioma. They found that the drug, already FDA-approved for certain adult cancers, was generally safe and resulted in tumor reduction visible on brain scans, as well as clinical improvement, in 3 out of 7 patients.
The study was published in Cancer Cell .
Pediatric-type high-grade gliomas are currently incurable brain tumors with median survival times less than 18 months after initial diagnosis.
Avapritinib is a small molecule that crosses the blood-brain-barrier and targets platelet derived growth factor alpha (PDGFRA), which is overactive in some pediatric high-grade gliomas and leads to uncontrolled growth of cancer cells. The team is now designing a clinical trial of avapritinib treatment for newly diagnosed pediatric patients with PDGFRA-altered high-grade gliomas to evaluate it in a larger patient population.
"In a highly aggressive disease with no effective targeted treatment options currently available, we were excited to observe a radiographic and clinical response in a subset of mostly relapsed, highly treatment-refractory patients following monotherapy with an oral small-molecule inhibitor," says lead senior author Mariella Filbin, MD, PhD , Jan Paradise Chair in Brain Cancer Research, co-director of the Brain Tumor Center of Excellence at Dana-Farber/Boston Children's Cancer and Blood Disorders Center and research director of the Pediatric Neuro-oncology Program at Dana-Farber.
Filbin's research team first identified that gene alterations activate PDGFRA in about 15% of pediatric high-grade glioma patients and contribute to the aggressive behavior of this disease, which is typically treated with surgery and radiation.
Efforts to target PDGFRA in high-grade glioma in the past were unsuccessful, most likely due to suboptimal pharmaco-kinetics and -dynamics of the drugs used. Avapritinib is a next-generation, highly selective and brain penetrant PDGFRA inhibitor. In pre-clinical research, Filbin's team found that avapritinib reduced tumor growth in patient derived tumor models and animal models. Those results inspired them to collaborate with clinical partners at the University of Michigan and the Medical University of Vienna to treat patients a small group of patients with PDGFRA-altered high-grade glioma with avapritinib through a compassionate use program.
"It was truly inspiring to witness how our scientific research could be rapidly translated into clinical practice, directly benefiting patients," says co-first author Sina Neyazi, MD, a postdoctoral fellow in the Filbin lab. "This discovery was made possible by the dedication of our clinical collaborators and the immense trust from patients and their families."
Filbin's team will next investigate which genetic alterations in tumors can predict response to avapritinib treatment, aiming to develop personalized treatment. Additionally, the team is developing combination therapies that include avapritinib alongside other FDA-approved drugs to maximize therapeutic effects and prevent treatment resistance.
"As a physician it is heartbreaking to tell a family that their child's tumor has returned despite standard-of-care therapy," says Filbin. "Our latest findings with brain-penetrant PDGFRA inhibitor avapritinib are encouraging for a subset of our patients who have genetic alterations in PDGFRA, and I am hopeful it will pave the way for developing innovative combination treatments that include avapritinib."
Funding: Sajni Chakrabarti Fund for Pediatric Brain Cancer Research, Caroline Mortimer Fund, DMG Precision Medicine Collaborative, Claudia Adams Barr Program, Cuming Family Fund for Pediatric Brain Tumor Research, Anita, Sophia, and Athena Fund to Advance DIPG Research and Care, Liv Like A Unicorn, We love you Connie Fund, MaleiaStrong Foundation, The Morris Family, the DIPG All-In Initiative, the National Institutes of Health, the Burroughs Wellcome Fund, the Sontag Foundation, the Helen Gurley Brown Foundation, Alex's Lemonade Stand Foundation, the Department of Defense, University of Michigan Chad Carr Pediatric Brain Tumor Center, Evans Family, ChadTough Defeat DIPG Foundation, Catching Up with Jack, Pediatric Brain Tumor Foundation, Michael Miller Memorial Foundation, Morgan Behen Golf Classic, and Yuvaan Tiwari Foundation, Forschungsgesellschaft fuer cerebrale Tumore and Verein unser_kind, the Medical University of Vienna, the Medical-scientific fund of the Mayor of the federal capital Vienna, the Austrian Science Fund, Ministry of Health of the Czech Republic, the German Research Foundation, Cancer Research UK, CRIS Cancer Foundation and Brain Tumour Research.
About Dana-Farber Cancer Institute
Dana-Farber Cancer Institute is one of the world's leading centers of cancer research and treatment. Dana-Farber's mission is to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement, and advocacy. We provide the latest treatments in cancer for adults through Dana-Farber Brigham Cancer Center and for children through Dana-Farber/Boston Children's Cancer and Blood Disorders Center . Dana-Farber is the only hospital nationwide with a top 5 U.S. News & World Report Best Cancer Hospital ranking in both adult and pediatric care.
As a global leader in oncology, Dana-Farber is dedicated to a unique and equal balance between cancer research and care, translating the results of discovery into new treatments for patients locally and around the world, offering more than 1,100 clinical trials.
