Tovorafenib Elicits Responses in Recurrent or Progressive Pediatric Low-Grade Glioma

Tovorafenib (DAY101) monotherapy generated responses in patients with recurrent or progressive pediatric low-grade glioma, according to topline data from the pivotal phase 2 FIREFLY-1 trial (NCT04775485).¹

Findings showed that patients evaluable by Response Assessment for Neuro-Oncology (RANO) criteria (n = 69) achieved an overall response rate (ORR) of 64%, including a complete response rate of 4% and a partial response rate of 59%. Additionally, 28% experienced stable disease, and the clinical benefit rate was 91%.

“Based on the efficacy and safety profile of tovorafenib observed to date from the FIREFLY-1 trial population, we plan to submit a new drug application in the first half of [2023] that will include additional follow up from the full study population,” Jeremy Bender, PhD, chief executive officer of Day One, stated in a press release. “We look forward to continuing our discussions with regulatory authorities with the hope of bringing this therapy to children in need of new options as soon as possible.”

Tovorafenib is an investigational, oral, brain-penetrant, highly selective type II pan-RAF kinase inhibitor designed to target a key enzyme in the MAPK signaling pathway, which is being investigated in primary brain tumors or brain metastases of solid tumors.

The ongoing FIREFLY-1 trial is evaluating tovorafenib monotherapy in patients aged 6 months to 25 years with recurrent or progressive pediatric low-grade glioma. The trial is being conducted in collaboration with the Pacific Pediatric Neuro-Oncology Consortium and is designed to support the potential regulatory approval of tovorafenib.

Arms 1 and 2 of the trial are enrolling patients with low-grade glioma, and arm 3 includes patients with advanced solid tumors.²

For arms 1 and 2, patients are required to have relapsed or progressive low-grade glioma with documented known activating BRAF alteration, at least 1 prior line of systemic therapy with evidence of radiographic progression, and at least 1 measurable lesion as defined by RANO criteria.

Key exclusion criteria include the presence of previously known activating molecular alterations, symptoms of clinical progression in the absence of radiographic progression, or a known or suspected diagnosis of neurofibromatosis type 1.

Enrolled patients are receiving oral tovorafenib administered at the recommended phase 2 dose of 420 mg/m² orally (not to exceed 600 mg) once weekly for each 28-day treatment cycle. Treatment is planned for 26 cycles over approximately 24 months, or until patients experience disease progression or unacceptable toxicity.

ORR per RANO criteria as assessed by blinded independent central review (ICR), safety and tolerability, and ORR by RECIST v1.1 criteria as assessed by blinded ICR, are the primary end points. Secondary end points include ORR per investigator assessment, progression-free survival, duration of response, time to response, CBR, and pharmacokinetics,

Among 77 patients who received treatment with tovorafenib, the median number of prior lines of therapy was 3 (range, 1-9). Additionally, 60% of patients (n = 46) received prior treatment with at least 1 MAPK inhibitor. In RANO-evaluable patients, 86% (n = 59) harbored a BRAF fusion alteration, and 14% (n = 10) had a BRAF mutation.

The median duration of treatment duration with tovorafenib was 8.4 months, and 77% of patients (n = 59) remained on treatment at data cutoff.

Safety data from these 77 patients showed that tovorafenib was well tolerated. The most common adverse effects related to the agent included change in hair color (75%), increase creatine phosphokinase (64%), anemia (46%), fatigue (42%), and maculopapular rash (42%).

References

• Day One announces topline data from pivotal phase 2 FIREFLY-1 trial demonstrating meaningful responses with tovorafenib (DAY101) in recurrent or progressive pediatric low-grade glioma. News release. Day One. January 8, 2023. Accessed January 9, 2023. https://bit.ly/3VR4id7
• 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 October 3, 2022. Accessed January 9, 2023. https://clinicaltrials.gov/ct2/show/NCT04775485