Tovorafenib induces response in relapsed pediatric low-grade glioma
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Two-thirds of patients with relapsed pediatric low-grade glioma treated with tovorafenib responded to therapy, data released by the agent’s manufacturer showed.
Tovorafenib (DAY101; Day One Biopharmaceuticals) is an investigational, oral type II pan-RAF kinase inhibitor designed to target a key enzyme in the MAPK signaling pathway.
The agent is being investigated for treatment of primary brain tumors, as well as for treatment of brain metastases among patients with solid tumors.
The pivotal phase 2 FIREFLY-1 trial is evaluating once-weekly tovorafenib monotherapy for patients aged 6 months to 25 years with relapsed or progressive pediatric low-grade glioma, the most common brain tumor among children. There are no approved therapies and no standard treatment for this patient population.
Overall response rate by Response Assessment for Neuro-Oncology (RANO) criteria per independent central review served as the primary endpoint.
The 25 patients enrolled to date received a median three prior lines of therapy (range, 1-9).
Researchers reported a 64% overall response rate and a 91% clinical benefit rate among the first 22 evaluable patients enrolled in the open-label, single-arm trial. Fourteen patients achieved partial response — 13 confirmed responses and one unconfirmed response — and six patients exhibited stable disease. All patients with stable disease had tumor shrinkage that ranged from 19% to 43%.
Median time to response was 2.8 months.
Investigators observed responses among patients with BRAF fusions and BRAF V600E mutations who received prior MAPK-targeted therapy.
All patients who responded to therapy remained on treatment at data cutoff. No patients had discontinued tovorafenib due to treatment-related adverse events.
Safety data from the first 25 patients showed tovorafenib appeared generally well-tolerated, according to investigators.
Most adverse events were grade 1 or grade 2. The most common any-grade treatment-related adverse events included increased blood creatine phosphokinase, rash and hair color changes. Nine patients (36%) experienced grade 3 or higher treatment-related adverse events.
“These initial data demonstrate significant anti-tumor activity in children with relapsed/progressive pediatric low-grade glioma, including children who are refractory to available therapies,” Roger J. Packer, MD, senior vice president at Center for Neuroscience and Behavioral Medicine, as well as director of the Brain Tumor Institute at Children’s National Hospital, said in a Day One Biopharmaceuticals-issued press release. “Pediatric low-grade glioma is a truly challenging disease in which children face years of aggressive regimens that can carry a long-term impact on learning, cognition, and quality of life.”
Day One Biopharmaceuticals intends to present additional interim trial results at a medical conference in the second half of this year.
Topline results for the full study population are expected to be released in the first quarter of 2023 and, if they are favorable, a new drug application could be submitted to FDA in the first half of next year.
The company also plans to conduct the phase 3 FIREFLY-2 trial to evaluate tovorafenib as front-line therapy for pediatric low-grade glioma.
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