Tovorafenib Leads to Durable Off-Treatment Responses in Pediatric BRAF-Altered R/R Low-Grade Glioma

Treatment with the type II RAF inhibitor tovorafenib (Ojemda) led to durable responses in pediatric patients with BRAF-altered relapsed/refractory low-grade glioma who entered a drug holiday during the phase 2 FIREFLY-1 trial (NCT04775485), according to findings shared in a poster presentation during the 2024 Society for Neuro-Oncology Annual Meeting.¹

At a data cutoff date of May 10, 2024, among patients who entered a drug holiday (n = 33), 97% experienced no signs of clinical progression and 15% achieved additional tumor shrinkage of at least 25%. Additionally, 91% of patients remained on a drug holiday, and 1 patient had signs of clinical progression. The safety profile of tovorafenib among patients who were rechallenged with tovorafenib (n = 3) following a drug holiday was consistent with the known safety profile of the agent. The median duration of treatment was 24 months (range, 16-29), and the median follow-up since the end of treatment was 3.4 months (range, 0.3-10.6).

FIREFLY-1 Design and Implications

In April 2024, the FDA granted accelerated approval to tovorafenib for the treatment of pediatric patients 6 months of age and older with relapsed or refractory low-grade glioma harboring a BRAF fusion or rearrangement, or a BRAF V600 mutation.² The regulatory decision was supported by prior data from FIREFLY-1 and represented the first systemic therapy indication for pediatric patients with low-grade glioma with BRAF rearrangements, including fusions.

FIREFLY-1 is an ongoing multicenter, open-label trial that is examining the safety and efficacy of tovorafenib in pediatric, adolescent, and young adult patients with recurrent or progressive low-grade glioma or advanced solid tumors harboring a known RAF alteration.³ The study consists of 3 treatment arms. Arm 1 is enrolling patients ages 6 months to 25 years withrecurrent or progressive low-grade glioma harboring an activating BRAF alteration, including BRAF V600 mutations and KIAA1549:BRAF fusions; arm 2 includes patients ages 6 months to 25 years with recurrent or progressive low-grade glioma harboring a known or expected activating RAF alteration; and arm 3 includes patientsages 6 months to 25 years with advanced solid tumors harboring a known or expected activating RAF fusion. Other inclusion criteria include radiographic disease progression following at least 1 line of systemic therapy and a minimum of 1 measurable lesion per Response Assessment in Pediatric Neuro-Oncology (RANO; arms 1 and 2) or RECIST 1.1 (arm 3) criteria.

Patients receive oral tovorafenib at the recommended phase 2 dose of 420 mg/m² once weekly, not exceeding 600 mg, for each 28-day treatment cycle. Tovorafenib is administered for a planned period of 26 cycles over approximately 24 months. Treatment cycles repeat in the absence of disease progression or unacceptable toxicity. Treatment with tovorafenib continues until investigator-assessed disease progression by RANO (arms 1 and 2) or RECIST 1.1 (arm 3) criteria, unacceptable toxicity, withdrawal of patient consent, or death.

The primary end point in arms 1 and 3 is overall response rate (ORR) by independent radiology review committee (IRC) based on RANO criteria. In arm 2, the primary end point is safety and tolerability. Secondary end points include pharmacokinetics, investigator-assessed ORR, progression-free survival, duration of response, time to response (TTR), and clinical benefit rate.

The objectives of the drug holiday analysis were to assess the stability of response and need for additional treatment in patients in arm 1 who entered a drug holiday and to determine whether patients can be rechallenged with tovorafenib following disease progression when on a drug holiday.¹ The analysis included patients on a drug holiday who had received at least 2 years of tovorafenib treatment.

Additional Drug Holiday Analysis Findings

The median age of patients who entered a drug holiday was 8 years (range, 3-16). Most patients were male (58%); BRAF alterations included BRAF fusions (88%), comprised of KIAA 1549:BRAF fusions (73%) and other BRAF fusions (15%), as well as BRAF V600E mutations (12%). The median number of prior lines of systemic therapy was 2 (range, 1-7), with patients having received 1 (21%), 2 (30%), or 3 or more (49%) prior lines of treatment.

Additional findings from the drug holiday analysis showed that a 15-year-old patient with a BRAF V600E–mutated mid-brain, dorsal pons tumor who initiated treatment with tovorafenib at a weekly dose of 600 mg for 24.6 months achieved a partial response (PR) as their best overall response (BOR) on primary treatment; the response led to tumor shrinkage by 67.1%. The median TTR was 2.73 months. Clinically relevant treatment-related adverse effects (TRAEs) in this patient included grade 2 keratosis pilaris, hypophosphatemia, and hypokalemia; as well as grade 1 increased creatine phosphokinase (CPK) levels, hair color change, rash, anemia, and hypocalcemia.

The 15-year-old patient was rechallenged with tovorafenib at a dose of 600 mg weekly and achieved a subsequent clinical status of stable disease. Retreatment was ongoing for longer than 1 month at the data cutoff, and the patient will be evaluated for response at 3 months. Notably, no TRAEs were reported during retreatment with tovorafenib in this patient.

Another patient highlighted in the poster presentation, a 6-year-old patient with BRAF fusion–positive optic pathway glioma, initiated treatment with tovorafenib at a weekly dose of 400 mg for 23.7 months and achieved a PR as their BOR; the response led to tumor shrinkage by 55.0%, and the median TTR was 2.76 months. Clinically relevant TRAEs in this patient included grade 2 rash, increased CPK levels, and decreased growth velocity; as well as grade 1 hair color change, dermatitis, facial and limb edema, hypocalcemia, hypophosphatemia, increased liver function test levels, alopecia, anemia, paronychia, and cheilitis.

During the drug holiday period, this patient had disease progression after 8.5 months, with a tumor size increase of 28%. The patient was rechallenged with tovorafenib at a weekly dose of 500 mg. At first assessment, the patient’s tumor size decreased by 1.1%, and there were no signs of clinical progression. Retreatment was ongoing for over 3 months at data cutoff, and the patient will be evaluated for response at 6 months. At the time of the analysis, no AEs had been reported since retreatment with tovorafenib was initiated in this patient.

References

1. Perreault S, Khuong-Quang DA, Kilburn LB, et al. Type II RAF inhibitor tovorafenib in relapsed/refractory (r/r) pediatric low-grade glioma (pLGG): results from patients on a drug holiday (DH) in the phase 2 FIREFLY-1 trial. Presented at: 2024 SNO Annual Meeting; November 21-24, 2024; Houston, TX. Abstract CTNI-09.
2. FDA grants accelerated approval to tovorafenib for patients with relapsed or refractory BRAF-altered pediatric low-grade glioma. FDA. April 23, 2024. Accessed November 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tovorafenib-patients-relapsed-or-refractory-braf-altered-pediatric
3. 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 December 27, 2023. Accessed November 23, 2024. https://clinicaltrials.gov/study/NCT04775485