Abstract Background In the phase 2 FIREFLY-1 study, tovorafenib monotherapy achieved clinically meaningful, rapid, durable tumor responses in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG), supporting regulatory approval in the United States. This updated analysis provides longer follow-up and is based on a data cutoff of June 6, 2025. Methods Efficacy was assessed in patients with BRAF-altered pLGG (arm 1, n=77). Safety was assessed in a combined population that included an extension cohort (arm 2, n=60). Tovorafenib was administered at 420 mg/m2 (not to exceed 600 mg), once weekly, in 28-day cycles. After 26 cycles of treatment, patients could continue tovorafenib or enter a post-treatment observation period with an option of retreatment at progression. Results Median follow-up of patients in arm 1 was 40.6 months. Per Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO-LGG) criteria, overall response rate was 53%, median duration of response was 19.4 months, and median progression-free survival was 16.6 months. However, median time to next treatment was 42.6 months, tracking more closely with time to clinical progression than radiographic progression. For 39 patients who entered post-treatment observation (median follow-up of 16.0 months), median treatment-free interval was not reached; 31 patients remained off therapy with 30 (77%) treatment free for ≥12 months. No new safety signals were identified. Conclusions This updated analysis, with a median of 40.6 months of follow-up, confirmed the clinically meaningful activity of tovorafenib in the treatment of relapsed/refractory BRAF-altered pLGG and demonstrated prolonged clinical stability following completion of tovorafenib treatment. ClinicalTrials.gov ID: NCT04775485.

Abstract Tovorafenib is a selective, CNS-penetrant, type II RAF inhibitor that is FDA approved for patients aged ≥6 months with relapsed/refractory BRAF-altered pLGG, based on results from the ongoing FIREFLY-1 phase 2 study (NCT04775485). This updated analysis presents 3-year efficacy and safety data. After ≥26 28-day cycles in FIREFLY-1, patients could opt to stop tovorafenib and enter a post-treatment observation period. Tovorafenib could be reinitiated if disease progressed. As of June 6, 2025, 77 patients (aged 2–21 years) enrolled in the registrational arm. Median study duration was 40.6 months. Overall response rate per RAPNO criteria (n = 76 evaluable patients) was 53% (n = 40); median duration of response (DOR) was 19.4 months (95% CI 13.8–27.2); median time to response was 5.4 months (range 1.6–17.5). Median PFS by RAPNO was 16.6 months; however, median time to next treatment (TTNT) was 42.6 months. 44 patients (58%) remained on treatment for ≥26 cycles. 39 patients entered post-treatment observation; 77% (n = 30) remained treatment free for ≥12 months (median treatment free interval [TFI] not reached). 8/39 (21%) patients in the observation cohort were retreated with tovorafenib and remained on retreatment at data cutoff. Median change in tumor size during retreatment was 38%. Subgroup analyses demonstrated directionally longer TTNT and DOR in MAPK inhibitor naïve patients. Safety cohort data (N = 137) showed a favorable benefit-risk profile. Most patients in the observation period cohort were treatment free for ≥12 months after tovorafenib cessation. Median TTNT exceeded RAPNO PFS, suggesting that TTNT may be more clinically relevant than RAPNO PFS in guiding treatment decisions. Tumor rebound off treatment was minimal, and there was early evidence of retreatment activity. These results suggest prolonged clinical stability and durability beyond planned tovorafenib treatment.

Tovorafenib is a selective, CNS-penetrant, type II RAF inhibitor that is FDA approved for recurrent BRAF-altered pLGG based on results of the ongoing FIREFLY-1 (NCT04775485) phase 2 study. 77 patients enrolled in the registrational arm (Arm 1) of FIREFLY-1. After 26 or more cycles (28 days each), patients could stop tovorafenib (drug holiday) and reinitiate upon radiographic or clinical evidence of progressive disease (PD). As of May 10, 2024 data cutoff, objective response rate (ORR; RAPNO) for arm 1 (n=77) was 53%; median duration of response (DOR) was 18 months (range 12.0-22.8). 44 patients completed a 26-cycle course; 33/44 (75%) patients opted to enter drug holiday per protocol, with median follow-up since last dose of 4.4 months (range 0.2-11.6). 15/33 (45%) did not have radiographic PD prior to treatment cessation; PD events occurred in 5/15 patients by 6 months post treatment cessation. A more recent data extract (May 21, 2025) showed 5 additional patients entered drug holiday (n=38); median follow-up since last dose was 15.6 months (range 1.4-24.0). 30/38 (79%) remained clinically stable irrespective of radiographic response, with 28 (74%) remaining without retreatment ≥12 months from last dose. 2 patients exited study early, 7.7 months and 3 months from last dose. 8/38 (21%) were retreated with tovorafenib and remained on retreatment at time of extract. No new toxicities were reported with retreatment. Updated data from a prespecified data cut with approximately 36-month follow-up will be presented, including DOR, time to next treatment with ≥12 months off tovorafenib, and activity of tovorafenib at retreatment. Tovorafenib induces durable responses with evidence of clinical stability off treatment in patients with recurrent BRAF-altered pLGG. Progression can occur after cessation, but retreatment is feasible.

Background Due to their anatomical locations, optic pathway gliomas (OPGs) can rarely be cured by resection. Given the importance of preserving visual function, we analyzed radiological and visual acuity (VA) outcomes for the type II RAF inhibitor tovorafenib in the OPG subgroup of the phase 2 FIREFLY-1 trial.Methods FIREFLY-1 investigated the efficacy (arm 1, n = 77), safety, and tolerability (arms 1/2) of tovorafenib (420 mg/m2 once weekly; 600 mg maximum) in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG). In this post hoc analysis, anti-tumor activity and VA were analyzed in arm 1 patients with OPG. Anti-tumor activity was independently assessed per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG), Response Assessment in Pediatric Neuro-Oncology-LGG (RAPNO), and RANO-LGG criteria. The data cutoff was June 5, 2023.Results Forty-two of 77 patients had OPGs; 35 of 42 had >= 2 VA assessments. The overall response rate in the OPG subgroup according to RANO-HGG, RAPNO, and RANO-LGG criteria were 64%, 50%, and 55%, with clinical benefit rates of 95%, 88%, and 90%, respectively. VA per patient was preserved for 80% of patients; 31% demonstrated improved VA; VA per eye was preserved in 87%, with 27% improving. The safety profile in the arm 1 OPG subgroup was similar to the overall FIREFLY-1 safety analysis set.Conclusions Tovorafenib demonstrated anti-tumor activity in relapsed/refractory BRAF-altered OPG across radiological assessment criteria and was generally well tolerated. Importantly, vision remained stable or improved in most patients.

Abstract BACKGROUND Tovorafenib, a selective, CNS-penetrant, type II RAF inhibitor, received US FDA accelerated approval for r/r BRAF-altered pLGG. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) in this population showed clinically meaningful tumor responses and a manageable safety profile. METHODS Patients in FIREFLY-1 treated for ≥26 cycles (~24 months) who entered a DH period were routinely assessed every 3 cycles; once-weekly tovorafenib 420 mg/m2 (not to exceed 600 mg) could be restarted if there was radiographic and/or clinical evidence of new disease progression. RESULTS As of the April 19, 2024 data cutoff, 26 patients (BRAF fusion: 22; BRAF V600E mutation: 4) (33.8%) of 77 patients in arm 1 (pLGG registrational) had completed 2 years of treatment and started a DH. No patients on a DH withdrew. Twenty-four patients (92.3%) remain on a DH, of which 22 were evaluable for response (duration range: 0.6-10.9 months); duration of response off-treatment ranged from 0.0-8.5 months. (Ranges exclude 2 non-evaluable patients treated beyond radiographic progression who remained on treatment in first 26 cycles due to ongoing clinical benefit; both remain on DH without clinical progression.) Two patients had tumor progression while on a DH and restarted treatment; 1 patient with a BRAF V600E mutation progressed (≥25% in tumor size) after 1 month (rebound growth per O’Hare P., et al. Neuro-Oncol. 2024: ≥25% increase [per RANO-LGG] w/in 6 months of stopping treatment) and has been on retreatment for 4 months; 1 patient with a BRAF fusion progressed after 9 months and has been on retreatment for 3 months. Treatment-related adverse events of any grade experienced by patients on retreatment were alopecia and rash (1 each). Independent radiographic analysis for response during retreatment is ongoing. CONCLUSIONS Tovorafenib provided durable tumor responses off-treatment in patients with r/r pLGG on a DH in FIREFLY-1.

Abstract BACKGROUND Despite favorable long-term survival, ongoing disease and treatment-related morbidity substantially impact the HRQOL of patients with pLGG. Tovorafenib is a selective, CNS-penetrant, type II RAF inhibitor. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) showed clinically meaningful responses and a manageable safety profile in pLGG. Vision remained stable or improved in 89% of evaluable patients with optic pathway gliomas (Nysom K, et al. Neuro-Oncol. 2023). METHODS FIREFLY-1 arm 1 patients 6 months–25 years of age with RAF-altered r/r pLGG received tovorafenib 420 mg/m2 weekly (600 mg max) in 28-day cycles. Exploratory measures included longitudinal assessment of PedsQL in patients ≥2 years of age. PedsQL 3.0 Cancer Module child self-reports Total Score and 8 subscales were used to assess HRQOL from 0 (worst)–100 (fewer problems/symptoms) (as of December 22, 2022) baseline (BL) to cycle 13 (C13) in patients ≥5 years of age. RESULTS For the PedsQL 3.0 Cancer Module, 51 completed self-reports at BL, and 32 at C13 due to continued attrition over time. Median Total Score was 81.5 (range: 46.3-100) at BL and 85.2 (range: 50-100) at C13. At C4, 16% worsened (decrease >10 points) and 11% improved (increase >10 points); by C13, 11% worsened and 33% improved. For Cognitive Problems, patients scored a median of 75 (range: 5-100) at BL and 85 (range: 20-100) at C13, with 11% and 26% improved at C4 and C13, respectively. A similar trend was seen with Nausea. Pain and Hurt remained even throughout (median: 87.5). Treatment Anxiety was not a major concern (median: 100, C1-C13); Procedural Anxiety improved over time (median: 58.3 BL; 79.2 at C13). CONCLUSIONS HRQOL generally remained stable, or improved, in the majority of patients with r/r pLGG during the first year of treatment with tovorafenib.

TPS10067 Background: Pediatric low-grade gliomas (pLGGs) are the most common CNS tumors of childhood. Genomic alterations of BRAF are oncogenic drivers in almost all pLGGs. Approximately 50%‒60% of pLGGs harbor a KIAA1549-BRAF fusion and 5%‒15% a BRAF V600E mutation. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan-RAF inhibitor. The registrational, phase 2 FIREFLY-1 (NCT04775485) study of tovorafenib in pediatric patients with recurrent/progressive LGG is ongoing and interim analysis has shown encouraging anticancer activity. Methods: LOGGIC/FIREFLY-2 (NCT05566795) is a registrational, 2-arm, randomized, multicenter, global (~100 sites across Australia, Canada, Europe, New Zealand, Singapore, South Korea, and USA), phase 3 trial being conducted in collaboration with the SIOPe Brain Tumor Group LOGGIC Consortium. The study is evaluating the efficacy, safety, and tolerability of tovorafenib vs. standard of care (SoC) chemotherapy in patients < 25 years old with pLGG harboring an activating RAF-alteration and requiring first-line systemic therapy. Approximately 400 patients will be randomized 1:1 to receive oral tovorafenib, 420 mg/m 2 (≤600 mg) once weekly (tablet or liquid suspension), or an investigator’s choice of SoC chemotherapy: COG-V/C regimen (60 weeks), SIOPe-LGG-V/C regimen (81 weeks), or single-agent vinblastine (70 weeks). Tovorafenib will be continued until the occurrence of radiographic progression (based on Response Assessment in Neuro-Oncology [RANO] criteria as determined by the investigator and confirmed by independent review) or unacceptable toxicity; patients with radiographic progression may be allowed to continue tovorafenib if, in the opinion of the treating investigator, they are deriving clinical benefit from study treatment. Patients who progress in the SoC arm during or after completion of chemotherapy are eligible to cross-over to receive tovorafenib. The primary endpoint is the objective response rate based on RANO criteria, as determined by independent review. Key secondary endpoints are progression-free survival and duration of response per RANO criteria by independent review and overall survival. Other secondary endpoints include efficacy assessments per Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria, changes in neurological and visual function, and safety and tolerability. Exploratory endpoints include efficacy assessments per investigator, tumor volume, adaptive behavior and quality of life. Prognostic and predictive molecular biomarkers, including senescence profiles for treatment outcome, response prediction, and treatment resistance, will be explored in parallel studies. Clinical trial information: NCT05566795 .

Background Despite high long-term survival rates, pediatric low-grade gliomas (pLGGs) are linked with significant tumor- and treatment-associated morbidities that may persist throughout life. The aims of this descriptive cross-sectional pilot study were to characterize health conditions among a cohort of patients with pLGG and explore the feasibility of quantifying disease burden and healthcare resource utilization (HRU).Methods Optum (R) Market Clarity Data were used to identify patients aged <= 18 years with an ICD-10 code for brain neoplasm, >= 1 physician notes, and with evidence of pLGG recorded between January 1, 2017 and June 30, 2018. Outcomes including health characteristics, HRU, medications, and procedures were assessed at 6-month intervals over 36 months.Results One hundred and fifty-four patients were identified with pLGG and over half experienced headache/migraine, respiratory infection, pain, or behavioral issues during the 36-month study period. The most common comorbidities were ocular/visual (including blindness), mental health disorders, seizures, and behavioral/cognition disorders. Most symptoms and comorbidities persisted or increased during the study period, indicating long-term health deficits. HRU, including speciality care visits, filled prescriptions, and administered medications, was common; 74% of patients had prescriptions for anti-infectives, 56% antiemetics, and 52% required pain or fever relief. Sixty-five percent of patients underwent treatment to control their pLGG, the most common being brain surgery. Little decline was observed in medication use during the study period.Conclusions Patients with pLGG have complex healthcare needs requiring high HRU, often over a long time. Patients need to be optimally managed to minimize disease- and treatment-related burden and HRU.

Abstract BACKGROUND: Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. The ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) of tovorafenib in BRAF-altered pLGG resulted in antitumor activity and manageable safety. Decreased growth velocity (GV) was observed; this is an update on GV changes in skeletally immature children receiving tovorafenib. Methods A planned safety analysis was completed on August 8, 2023 on 137 patients (Arm 1: 77 & Arm 2: 60). Additional follow-up on all cases of decreased GV (an AESI) reported to the global safety database (GSDB) as of January 19, 2024 is provided. Results Overall, 29% had decreased GV from baseline (BL); 19% had ≥50% decrease. Of the 40 with this AESI, 75% had pre-existing neuromuscular or endocrine comorbidities potentially affecting normal growth, including 6 on GnRH-analogues for precocious puberty and 9 with BL heights 2 SDs above/below average for age and sex. Nineteen had on-treatment bone age assessments; none showed bone age advancement from BL or premature growth plate closure. No osteopenia or abnormal fractures reported. All 10 who discontinued or interrupted tovorafenib for ≥3 months for any reason (mean follow-up: 5.8 months), with off-treatment growth measurements available, showed post-treatment annualized GV (AGV) recovery (average AGV: on-treatment, 1.1 cm/y; off-treatment, 8 cm/y), with some exceeding expected average AGV for age. A 4-year-old boy with 1.2 cm/y AGV on-treatment had 12.3 cm/y AGV off-treatment (follow-up: 2 months). Five additional events of decreased GV in patients not on study FIREFLY-1 were reported to the GSDB; 4 of 5 had ≥3 months of off-treatment follow-up, all 4 recovered GV. Conclusions Decreased GV has been observed in patients on tovorafenib. Preliminary follow-up data in those who interrupted treatment show consistent evidence of GV recovery and preservation of growth potential on bone age studies.

10036 Background: Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (1) in BRAF-altered pLGG showed clinically meaningful tumor responses and a manageable safety profile with tovorafenib monotherapy. Decreased growth velocity (GV) was observed; this is an update on changes in GV in skeletally immature children receiving tovorafenib. Methods: A planned safety analysis was completed on August 8, 2023 and included 137 patients (Arm 1: 77 & Arm 2: 60) treated with ≥1 dose of tovorafenib in FIREFLY-1. This report provides additional follow-up on all cases of decreased growth velocity (GV), an adverse event of special interest (AESI), reported to the Sponsor’s global safety database (GSDB) as of January 19, 2024. Results: Decreased GV was reported in 40 (29.2%) of 137 patients; 26 (19%) had GV reduction ≥50% from baseline (BL). Of those with decreased GV, 30 (75.0%) had pre-existing neuromuscular or endocrine comorbidities that may affect normal growth, including 6 (15%) with precocious puberty being treated with a gonadotropin-releasing hormone analogue, and 9 (22.5%) with BL heights 2 standard deviations above or below average for age and sex. Nineteen of the 40 patients with this AESI had on-treatment bone age assessments; none showed advancement of bone age from BL or premature closure of growth plates. No osteopenia or abnormal fractures were reported. Of the 35 patients with growth hormone (GH) testing, only 2 had signs of GH deficiency (both had optic pathway tumors; 1 had GH deficiency at BL, the other, a new tumor-associated GH deficiency). Post-treatment heights ≥3 months off treatment were reported for 10 of 40 patients who had interrupted or discontinued treatment for any reason (mean follow up: 5.8 months), including 2 (1.5%) permanent discontinuations and 3 (2.2%) interruptions due to decreased GV. All 10 showed post-treatment recovery in annualized GV (AGV) (average on-treatment AGV 1.1 cm/y vs. average post-treatment AGV 8 cm/y), in some cases exceeding expected average AGV for age. One additional 4-year-old boy with on-treatment AGV of 1.2 cm/y had an off-treatment AGV of 12.3 cm/y after 2 months of off-treatment follow-up. Decreased GV was reported to the GSDB for 5 (11.4%) of 44 patients who received above the maximum dose of tovorafenib used in FIREFLY-1 in an ongoing investigator-initiated study. Four of the 5 patients from this study had ≥3 months of off-treatment follow-up reported; all 4 showed evidence of GV recovery. Conclusions: Decreased GV has been observed in patients treated with tovorafenib. Early follow-up data from patients whose treatment was interrupted show consistent evidence for GV recovery and preservation of growth potential on bone age studies. 1. Kilburn LK, et al. Nat Med.2023. Clinical trial information: NCT04775485 .

This pilot study investigated the long-term impact of a surgery-only treatment (no exposure to other treatments, such as chemotherapy and radiation) for pediatric cerebellar low-grade gliomas on executive function, anxiety, and fear of pain (FOP) beliefs. Twelve patients who underwent surgical glioma resection during childhood (surgery age was 4-16 years, study visit age was 10-28 years), and 12 pain-free controls matched for age, sex, race, and handedness were tested. The spatial extent of resection was precisely mapped using magnetic resonance imaging (MRI). Executive function, anxiety, and FOP were assessed using validated self-report age-appropriate questionnaires for children and adults. Structured clinical interviews at a post-surgery follow-up visit were completed (average: 89 months, range: 20-99). No significant differences in FOP (FOPQ-C t[14 = 1.81, p = 0.09; FOPQ-III t[4] = 0.29, p = 0.79), executive function scores (BRIEF t[20] = 0.30, p = 0.28), or anxiety scores (MASC t[16] = 0.19, p = 0.85; MAQ t[4] = 1.80, p = 0.15) were found in pediatric or adult patients compared to pain-free controls. Clinical interviews mainly categorized pediatric patients as not anxious. One participant reported mild/subclinical anxiety, and one had moderate clinical anxiety. Neither psychologists nor patients endorsed impairments to executive functioning, anxiety, or FOP. Our pilot results suggest that pediatric cerebellar tumor survivors treated with surgery-only have favorable long-term functioning related to these themes. While these results are promising, they will need to be replicated in a larger patient sample.

Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia-mutated (ATM) kinase, and preclinical studies have identified ATRi-sensitizing alterations in other DNA damage response (DDR) genes. Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors harboring LOF alterations in DDR genes, predicted by chemogenomic CRISPR screens to sensitize tumors to ATRi. Primary objectives were to determine safety and propose a recommended phase 2 dose (RP2D). Secondary objectives were to assess preliminary anti-tumor activity, to characterize camonsertib pharmacokinetics and relationship with pharmacodynamic biomarkers and to evaluate methods for detecting ATRi-sensitizing biomarkers. Camonsertib was well tolerated; anemia was the most common drug-related toxicity (32% grade 3). Preliminary RP2D was 160 mg weekly on days 1-3. Overall clinical response, clinical benefit and molecular response rates across tumor and molecular subtypes in patients who received biologically effective doses of camonsertib (>100 mg d(-1)) were 13% (13/99), 43% (43/99) and 43% (27/63), respectively. Clinical benefit was highest in ovarian cancer, in tumors with biallelic LOF alterations and in patients with molecular responses. ClinicalTrials.gov registration: NCT04497116.

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 ( n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system–penetrant, type II RAF inhibitor tovorafenib (420 mg m − 2 once weekly; 600 mg maximum) in patients with BRAF -altered, relapsed/refractory pLGG. Arm 2 ( n = 60) is an extension cohort, which provided treatment access for patients with RAF -altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF -altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 .