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Tovorafenib produced deep, durable responses in pLGG, with long treatment-free intervals and minimal tumor rebound after therapy.
Patients with pediatric low-grade glioma (pLGG) who received tovorafenib (Ojemda) experienced deep and durable responses and were able to maintain disease control during extended periods off of therapy, according to updated data from the phase 2 FIREFLY-1 trial (NCT04775485) presented during the 2025 Society for Neuro-Oncology Annual Meeting.1
At a median follow-up of 40.6 months, tovorafenib elicited an objective response rate of 53% by independent radiology review committee (IRC) assessment and RAPNO criteria in evaluable patients in arm 1 (n = 76); the partial response (PR) rate was 39%, the minor response (MR) rate was 13%, the stable disease rate was 29%, the progressive disease rate was 17%, and 1% of patients were not evaluable (NE) for response. The median time to response (TTR) was 5.4 months (range, 1.6-17.5), and the median duration of response (DOR) was 19.4 months (95% CI, 13.8-27.2). The median change in tumor size was –47.3% (–97.3% to –162.0).
The prespecified secondary end point of progression-free survival (PFS) was also assessed by IRC and RAPNO criteria and was reported to be a median of 16.6 months (95% CI, 8.3-19.1). The median radiographic PFS was also 16.6 months (95% CI, 10.9-22.0). Notably, the median time to next treatment, which was defined as time from the first tovorafenib dose to the start of first subsequent anticancer therapy or date of death, was 42.6 months (95% CI, 36.7-NE).
A total of 39 patients entered a treatment-free observation period, and most of them (77%) were treatment free for at least 1 year. The median treatment-free interval, which was defined as the end of primary treatment with tovorafenib to the initiation of the next subsequent anticancer therapy or death, was not reached (95% CI, NE-NE). The median duration of treatment was 24.6 months (range, 16.0-38.7), and the median follow-up from last dose to subsequent anticancer treatment was 16.0 months (range, 1.4-24.5).
Tumor rebound was reported to be minimal in the first 6 months off therapy, with 31% of patients experiencing an increase in tumor size of at least 25% from the last scan before the last dose. Additionally, early evidence of retreatment activity was observed in those who were retreated with the agent (n = 8). At the time of data cutoff, all 8 patients were still on therapy, and the median tumor size was smaller than the size recorded before retreatment was started, with a median change of –38.3%. The median duration of retreatment was 9.0 months (range, 2.6-18.0), and the median number of cycles of tovorafenib received during retreatment was 10.5.
“All of [this] is further supporting the clinical benefit of utilizing tovorafenib as an effective therapy in children and young adults with recurrent/refractory low-grade glioma,” Cassie Kline, MD, MAS, director of clinical research in the Division of Neuro-Oncology at the Children’s Hospital of Philadelphia, in Pennsylvania, said in a presentation of the data. In a news release,2 she added, “This approach has the potential to offer patients and their families meaningful time away from treatment.”
The open-label, single-arm, FIREFLY-1 trial enrolled patients with relapsed or refractory pLGG harboring an activating BRAF alteration per local laboratory testing.3 To participate, patients needed to have at least 1 measurable lesion by RANO 2010 criteria, have received 1 or more prior lines of systemic therapy, and experienced radiographic progression. If patients had a known or suspected diagnosis of neurofibromatosis type 1 or had tumors harboring additional activating molecular alterations like IDH1/2 mutations or FGFR mutations, they were excluded.
Specifically, arm 1 was the registrational portion of the research, and included 77 children and young adults with recurrent or progressive pLGG and a known activating BRAF alteration, including BRAF V600E mutations or BRAF fusions.1 Arm 2 was the pLGG extension and comprised 60 children and young adults with recurrent or progressive pLGG and a known or expected activating RAF alteration, including BRAF or CRAF fusions or BRAF V600 mutations. Arm C included up to 20 patients with advanced solid tumors.
Participants were given tovorafenib at an approximate dose of 420 mg/m2 once weekly in 28-day cycles according to body surface area, with doses ranging from 290 mg/m2 to 476 mg/m2 and a maximum dose of 600 mg.1,3 The primary treatment period consisted of 26 cycles of tovorafenib equating to approximately 24 months;1 treatment continued until progressive disease or intolerable toxicity.3 Subsequently, patients were able to continue treatment with tovorafenib or opt into a post-treatment observation period.1
For arm 1, the primary end point was ORR by RANO-HGG criteria, and secondary end points included safety, ORR by RAPNO-LGG criteria, clinical benefit rate (CBR), TTR, DOR, and PFS based on RAPNO-LGG criteria. Exploratory end points were ORR and CBR by RANO-LGG criteria, time to next treatment, and treatment-free interval. Post-hoc analyses evaluated clinical and radiographic progression.
Earlier findings from FIREFLY-1 revealed that tovorafenib (n = 76) elicited an ORR of 51% (95% CI, 40%-63%), which comprised a PR rate of 37% and a MR rate of 14%.3 The median DOR was 13.8 months (95% CI, 11.3- NE); the 6- and 12-month DOR rates were 85% and 23%, respectively. Additionally, the median TTR was 5.3 months (range, 1.6-11.2).
In those with BRAF fusions or rearrangements (n = 64), the ORR achieved with tovorafenib was 52%; in those with BRAF V600E mutation (n = 12), this rate was 50%. Moreover, those who had prior exposure to MAPK-targeted therapy (n = 45) experienced an ORR of 49%, and those who had not previously received that kind of targeted therapy (n = 31) had a slightly higher ORR of 55%. The ORR by RANO-LGG 2011 criteria was 53% (95% CI, 41%-64%).
These data supported the FDA’s decision in April 2024 to grant accelerated approval to tovorafenib for pediatric patients aged 6 months and older with relapsed or refractory low-grade glioma and a BRAF fusion or rearrangement or a BRAF V600 mutation.4
At the time of the decision, Sarah E. S. Leary, MD, MS, of the University of Washington School of Medicine, further discussed the significance of the decision in an exclusive interview with OncLive®.5,6 “Pediatric low-grade gliomas are the most common tumors that we see in children. They are considered benign, but we believe that word is not appropriate when something is in the brain because it’s an essential part of how we function,” she said. “Low-grade glioma can be life threatening, and there were no FDA-approved medical therapies for low-grade glioma until tovorafenib—it’s the first drug to ever apply for FDA approval for this disease.”
In the safety analysis set, comprised of patients in arms 1 and 2 (n = 137), no new safety signals were observed with additional follow-up.1 Treatment-related adverse effects (TRAEs) occurred in 99% of patients, and 66% of these effects were grade 3 or higher. Moreover, TRAEs led to discontinuation for 13% of patients.
The most common grade 3 or higher TRAEs were decreased growth velocity (34%), anemia (14%), increased creatinine phosphokinase (11%), maculopapular rash (8%), and increased alanine aminotransferase level (5%).
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