FDA Receives Rolling NDA of Tovorafenib for Pediatric Low-Grade Glioma


Data from the phase 2 FIREFLY-1 trial support the new drug application for tovorafenib in relapsed or progressive pediatric low-grade glioma. The regulatory agency anticipates filing the application by mid-November 2023

The FDA has received a rolling new drug application (NDA) seeking the approval of tovorafenib (DAY101) monotherapy for patients with relapsed or progressive pediatric low-grade glioma.1

Findings from the phase 2 FIREFLY-1 trial (NCT04775485) support the NDA as the 69 evaluable patients treated with tovorafenib achieved an overall response rate (ORR) of 67% per Response Assessment for Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, and the clinical benefit rate was 93%, including a complete response (CR) rate of 17%, a partial response (PR) rate of 49%, and a stable disease (SD) rate of 26%. The median duration of response (DOR) was 16.6 months (95% CI, 11.6-not estimable [NE]) per RANO-HGG criteria.

The regulatory agency is expected to file the application by mid-November 2023. Additionally, detailed findings plan to be presented at an upcoming medical meeting.

“We believe that tovorafenib, if approved, could change the treatment landscape for children living with this chronic and relentless disease,” said Jeremy Bender, PhD, chief executive officer of Day One Biopharmaceuticals, in a press release. “The NDA submission of tovorafenib is a significant milestone for Day One and an important step towards bringing a potential new targeted therapy to children with brain cancer.”

Human brain © Sergey Nivens - stock.adobe.com

Human brain © Sergey Nivens - stock.adobe.com

FIREFLY-1 is an ongoing, multicenter, single-arm, open-label trial where patients aged 6 months to 25 years with relapsed or progressive pediatric low-grade glioma are being treated with tovorafenib as once-weekly monotherapy. Enrollment in the study is open to patients who have a known activating BRAF alteration, received at least 1 line of systemic therapy, have evidence of radiographic progression, and at least 1 measurable lesion, as defined by RANO in arms 1 and 2 of the study, or RECIST v1.1 criteria in arm 3.2

In arms 1 and 2, patients with relapsed or progressive low-grade glioma with a documented known activating BRAF alteration will be enrolled, while those in arm 3 will include patients with locally advanced or metastatic solid tumors that have a documented known or suspected activating RAF fusions.

Treatment of tovorafenib is being administered to patients orally at the recommended phase 2 dose of 420 mg/m2 once a week for each 28-day treatment cycle. At the end of every third cycle, patients will undergo radiographic evaluation of their disease. Treatment will continue until radiographic evidence of disease progression by RANO or RECIST v1.1 criteria as determined by the investigator, unacceptable toxicity, withdrawal of consent, or death.

The primary end point of the study is ORR by RANO-HGG criteria, and secondary end points include ORR by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO-LGG) criteria, progression-free survival (PFS), DOR, time to response, clinical benefit rate (CBR), and safety.

At the data cutoff date of June 5, 2023, results of the study showed that in patients evaluable per RAPNO-LGG criteria (n = 76), the ORR was 51% and the CBR was 82%. The rates of PR, minor response (MR), and SD were 37%, 14%, and 30%, respectively. The median DOR was 13.8 months (95% CI, 11.3-NE).1

Findings from an exploratory analysis demonstrated that in the 76 patients evaluable per RANO-LGG criteria, the ORR was 53% with a CBR of 83%. For these patients, the PR, MR, and SD rates were 26%, 26%, and 30%, respectively, and the median DOR was 14.4 months (95% CI, 11.0-NE).

In arms 1 and 2, 137 patients were evaluable for safety. Here, treatment was generally well-tolerated with most of the adverse events (AEs) being grade 1 or grade 2. Treatment-related AEs which were seen most frequently in patients were change in hair color (76%), fatigue (44%), maculopapular rash (41%), dry skin (33%), and dermatitis acneiform (30%).

Moreover, commonly reported treatment-related lab abnormalities included creatinine phosphokinase elevation, lactate dehydrogenase elevation, anemia, hypophosphatemia, and aspartate transaminase elevation. The majority of lab abnormalities had no clinical manifestations, and they did not require clinical intervention or change in study treatment.

  1. Day One announces updated FIREFLY-1 data for tovorafenib and completion of rolling NDA submission to FDA for relapsed or progressive pediatric low-grade glioma (pLGG). News release. Day One Biopharmaceuticals. September 11, 2023. Accessed September 14, 2023. https://tinyurl.com/yt27stv7
  2. A study to evaluate DAY101 in pediatric and young adult patients with relapsed or progressive low-grade glioma and advance solid tumors (FIREFLY-1). ClinicalTrials.gov. Updated January 11, 2023. Accessed September 14, 2023. https://clinicaltrials.gov/study/NCT04775485
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