First-line pLGG: comparison of tovorafenib with standard-of-care chemotherapy

“This is a 2-arm, randomized, open-label, multicenter, global, Phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy versus standard of care (SoC) chemotherapy in participants with pediatric low-grade glioma (LGG) harboring an activating rapidly accelerated fibrosarcoma (RAF) alteration requiring first-line systemic therapy.” (opens the source at this quote in a new tab)

“The primary objective is to compare the ORR of tovorafenib monotherapy (Arm 1) vs. investigator’s choice of SoC chemotherapy (Arm 2) as assessed by the IRC per RANO-LGG” (opens the source at this quote in a new tab)
“criteria in pediatric and young adult patients with LGG harboring an activating RAF alteration who require first-line systemic therapy.” (opens the source at this quote in a new tab)

Regulatory role: confirmatory trial for the relapsed or refractory accelerated approval

“To fulfill this PMR, the Applicant intends to submit data from FIREFLY-2, an ongoing randomized controlled trial comparing tovorafenib to standard of care chemotherapy in the front-line setting of RAF-altered pediatric LGG.” (opens the source at this quote in a new tab)

“In order to confirm the efficacy and safety of tovorafenib in the treatment of patients 6 months of age and older with paediatric low-grade glioma (LGG) harbouring a BRAF fusion or rearrangement, or BRAF V600 mutation, the MAH shall conduct and submit the final report of the phase III randomised, parallel-group, two-arm study (FIREFLY-2)” (opens the source at this quote in a new tab)

“As per post-marketing requirements, a study to verify the clinical benefit of tovorafenib, FIREFLY-2, is being conducted in the front-line setting and may inform expansion of the current indication.” (opens the source at this quote in a new tab)

Study start, sites, and countries

“The first site was activated on 12 December 2022, the consent of the first patient was on 08 February 2023 (study start date) and the first patient was dosed on 03 March 2023.” (opens the source at this quote in a new tab)

“It is being conducted at approximately 140 sites across the U.S., Canada, Europe, Australia, South America, Middle East and Asia, and in just over three years has enrolled approximately 400 participants who are receiving either tovorafenib once weekly or one of four standard of care (SoC) chemotherapy regimens.” (opens the source at this quote in a new tab)

Collaboration with the SIOPe Brain Tumour Group LOGGIC consortium

“The trial is being conducted in collaboration with the European Society for Paediatric Oncology (SIOPe) Brain Tumor Group LOGGIC Consortium (LOGGIC).” (opens the source at this quote in a new tab)

Timelines for primary analysis and regulatory reports

“Recruitment is progressing according to planned timelines, with a target completion of enrolment by Q1 2026, which is reassuring that the target completion can be achieved and that the interim study report (including the ORR primary analysis and the PFS interim analysis) can be projected to be available for submission in April 2028, with the final study report planned for April 2032.” (opens the source at this quote in a new tab)

Randomized, open-label, two-arm design with stratification and crossover

“LOGGIC/FIREFLY-2 ( NCT05566795 ) is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. SoC chemotherapy in patients with pLGG harboring an activating RAF alteration who require first-line systemic therapy.” (opens the source at this quote in a new tab)
“Randomization between treatment arms will be stratified by primary location of the tumor (supratentorial midline vs. other), type of genomic RAF alteration (fusion vs. mutation), CDKN2A status (deletion vs. wild-type/unknown), and infant chiasmatic-hypothalamic glioma (CHG) diagnosis (yes vs. no). Patients who experience progressive disease in Arm 2 can crossover to Arm 1 and receive tovorafenib.” (opens the source at this quote in a new tab)
“The total length of the study, from screening through to the end of the study is expected to be seven years.” (opens the source at this quote in a new tab)

Protocol amendment: RAPNO-LGG replaced RANO-LGG as the primary response criteria

“The FIREFLY-2 study protocol was amended to adopt the RAPNO-LGG criteria as primary endpoint for treatment response evaluation in paediatric low-grade glioma, replacing RANO-LGG.” (opens the source at this quote in a new tab)
“Furthermore, the change was implemented after 113/400 patients were recruited, such that the majority of the patients (~290/400) will have been enrolled after the change.” (opens the source at this quote in a new tab)

Independent data monitoring committee

“To ensure a high level of safety monitoring during this trial, an independent Data Monitoring Committee (DMC) has been established and will meet periodically to review safety and efficacy data across the entire tovorafenib program.” (opens the source at this quote in a new tab)

Registry inclusion and exclusion criteria

“Less than 25 years of age with LGG with known activating RAF alteration.” (opens the source at this quote in a new tab)
“Histopathologic diagnosis of glioma or glioneuronal tumor.” (opens the source at this quote in a new tab)
“Meet indication for first-line systemic therapy.” (opens the source at this quote in a new tab)
“Known or suspected diagnosis of NF-1/ neurofibromatosis Type 2 (NF-2).” (opens the source at this quote in a new tab)
“Prior or ongoing nonsurgical anticancer therapy for this indication (eg, chemotherapy, oral/IV targeted therapy) including radiation.” (opens the source at this quote in a new tab)

Indications for first-line systemic therapy and excluded molecular alterations

“Patients must be evaluable by RANO-LGG, that is, they must have at least one measurable lesion imaged up to 28 days prior to treatment initiation that can be defined by T2/FLAIR and reproducibly measured by MRI in at least two-dimensions of at least 10 mm in size, and visible on two or more axial slices that are preferably ≤ 5 mm apart with 0 mm skip.” (opens the source at this quote in a new tab)
“Patients < 16 years of age and patients ≥ 16 years of age, will be required to exhibit Lansky and Karnofsky performance status scores, respectively, of ≥ 70%.” (opens the source at this quote in a new tab)
“Patients with NF1 -driven tumors are excluded. Furthermore, patients with a tumor exhibiting activating molecular alterations in addition to activating RAF alterations are also ineligible for participation even if the tumors are histologically of a low-grade.” (opens the source at this quote in a new tab)

Exclusion of patients previously treated with dabrafenib plus trametinib

“However, there is some uncertainty in the fact that this study excludes patients previously treated with dabrafenib in combination with trametinib.” (opens the source at this quote in a new tab)

Arm 1: tovorafenib once weekly

“Patients randomized to Arm 1 receive tovorafenib at a dose of 420 mg/m 2 (not to exceed 600 mg), in the form of a tablet or liquid suspension, QW, continuously on days 1, 8, 15, and 22 of 28-day (four week) cycles.” (opens the source at this quote in a new tab)
“Patients may continue on tovorafenib even following radiographic progression at the investigator’s discretion if there is evidence that the patient is still deriving clinical benefit.” (opens the source at this quote in a new tab)

Arm 2: investigator’s choice of standard-of-care chemotherapy

“Participants will receive one of 4 SoC chemotherapy options selected by the treating Investigator: Children's Oncology Group - Vincristine/Carboplatin (COG-V/C) regimen, International Society for Paediatric Oncology - Low-Grade Glioma Vincristine/Carboplatin (SIOPe-LGG-V/C) regimen, vinblastine (VBL) regimen, or monthly carboplatin. The choice of SoC chemotherapy regimen will be selected prior to participant randomization.” (opens the source at this quote in a new tab)

“The Arm 2 VBL regimen comprises VBL (BSA ≥ 0.6 m 2 : 6 mg/m 2 /day, without exceeding 10 mg; BSA < 0.6 m 2 : BSA dose × 1/30 × body weight [kg]/day) administered IV QW in four-week cycles until completion of treatment at 70 weeks.” (opens the source at this quote in a new tab)

Primary endpoint in the current registry record

“ORR assessed per Response Assessment in Pediatric Neuro Oncology (RAPNO) criteria by Independent Review Committee (IRC), and defined as the proportion of participants with overall confirmed response of complete response (CR), partial response (PR), or minor response (MR).” (opens the source at this quote in a new tab)

Key secondary endpoints

“The primary endpoint of the trial is overall response rate (ORR), including duration of response (DOR), based upon Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO-LGG) criteria, with key secondary endpoints including progression-free survival (PFS) and event-free survival (EFS) per RAPNO-LGG, time to next treatment (TTNT), overall survival (OS) and other measures, including patient-reported outcomes.” (opens the source at this quote in a new tab)

Functional, visual, and patient-reported secondary endpoints

“Adaptive behavior Composite Score will be evaluated using domain scores collected from the comprehensive Vineland III Adaptive Behavior Scale (VABS).” (opens the source at this quote in a new tab)
“Visual progression-free survival is defined as the time from start of treatment to visual event for OPG participants aged ≥ 3 years.” (opens the source at this quote in a new tab)
“The Patient-Reported Outcomes Measurement Information System (PROMIS®) Pediatric/Parent Proxy Profile 49 v2.0 will be used to assess mental and social HRQoL.” (opens the source at this quote in a new tab)

Exploratory growth, neuropathy, and neuro-endocrine endpoints

“Comparison of changes in growth and development of patients between study arms” (opens the source at this quote in a new tab)
“Comparison of chemotherapy-induced peripheral neuropathy outcomes between study arms by pediatric-modified total neuropathy score in patients ≥ five years of age” (opens the source at this quote in a new tab)
“Comparison of neuro-endocrine morbidity between study arms” (opens the source at this quote in a new tab)

Original choice of RANO-LGG to align with the dabrafenib plus trametinib registrational trial

“As this is a registrational trial, the primary efficacy endpoint in this study is based on RANO-LGG criteria, the same criteria used in registrational study CDRB436G2201 ( NCT02684058 ) of dabrafenib in combination with trametinib in pediatric patients with pLGG harboring a BRAF V600 mutation” (opens the source at this quote in a new tab)
“In the context of pLGG being a chronic disease, in addition to radiologic responses, functional endpoints such as neurologic outcomes, visual function in OPG, and patient-reported outcomes are of extreme importance and will be assessed throughout this study.” (opens the source at this quote in a new tab)

Regulatory view of RAPNO-LGG as the criteria developed for pLGG

“On the other hand, RAPNO-LGG is developed specifically for pLGG, recognizing the biological and radiological differences from adult gliomas. RAPNO-LGG has in the meantime undergone international consensus development and validation efforts and is increasingly used in paediatric LGG clinical trials including the confirmatory FIREFLY 2 study.” (opens the source at this quote in a new tab)
“A detailed justification was given for the change of the primary and key secondary endpoints in phase 3 study FIREFLY-2, which can be followed.” (opens the source at this quote in a new tab)

“In alignment with current scientific consensus on the measurement of pLGG, FDA considered the RAPNO-LGG criteria, which assess response based on T2-weighted and T2-weighted fluid-attenuated inversion recovery imaging (T2/FLAIR signaling), most appropriate to evaluate efficacy in pLGG, which are variably non-contrast enhancing and frequently contain tumor cysts.” (opens the source at this quote in a new tab)

FDA acceptance of ORR and a PFS key secondary endpoint for verification of benefit

“Verification of benefit will be based on results from a randomized trial of tovorafenib compared to standard of care chemotherapy in patients with pediatric LGG with a primary endpoint of ORR and a key secondary endpoint of PFS.” (opens the source at this quote in a new tab)

“Efficacy will be assessed using a primary endpoint of ORR and key secondary endpoints of PFS and DoR as per LGG-specific criteria. Additionally, clinical outcome assessment data including evaluation of neurological function, visual function and health-related quality of life will be captured, which are particularly relevant for patients with pLGG given known tumor-related complications and the potentially indolent nature of the tumor.” (opens the source at this quote in a new tab)

Clinical relevance of minor responses included in the response rate

“However, review of these narratives provided clinical documentation of preliminary information suggesting that minor responses are clinically meaningful and that patients demonstrating tumor shrinkage, even if not meeting the criteria for a partial or complete response, may potentially derive benefit from treatment.” (opens the source at this quote in a new tab)

Limits of radiographic progression criteria and time to next treatment as a complementary endpoint

“While assessment per RAPNO may better capture biologically relevant tumor behavior in this disease, RAPNO progression criteria may not fully correlate with treatment benefit in slow-growing tumors.” (opens the source at this quote in a new tab)
“As such, evaluation of both PFS and TTNT is likely to provide a more accurate and meaningful assessment of treatment benefit in pLGG.” (opens the source at this quote in a new tab)

Power assumptions and hierarchical testing (design publication, RANO-LGG)

“To assess the ORR per the primary endpoint, the planned sample size of approximately 400 patients will provide around 85% power to detect a 15% improvement for the tovorafenib arm at a two-tailed level of significance of 0.05, assuming a 30% ORR in the control arm and a dropout rate of up to 10%. To assess PFS as per the key secondary endpoint, the planned sample size of approximately 400 patients will provide around 85% power to detect a hazard ratio of 0.67 for PFS at a two-tailed level of significance of 0.05, assuming the median PFS for the tovorafenib arm is 4.5 years versus a median of three years for the control arm.” (opens the source at this quote in a new tab)
“If this test meets the pre-specified boundary for statistical significance, then the key secondary endpoints will be tested. It should be noted that the statistical analysis plan for the LOGGIC/FIREFLY-2 trial may be subject to change based on emerging data from FIREFLY-1 trial.” (opens the source at this quote in a new tab)

Timing of the primary analysis

“The primary analysis is expected to occur approximately 12 months after the last patient is enrolled; preliminary insights are expected to be available in 2027.” (opens the source at this quote in a new tab)

Consistency of treatment effect before and after the endpoint amendment

“assessment of the consistency of the treatment effect before and after the change in terms of RAPNO-LGG ORR will be of interest when the final data are available as well as the respective effects for RAPNO-LGG.” (opens the source at this quote in a new tab)

Planned and enrolled participants

“Approximately 400 treatment-naïve LGG participants will be randomized 1:1 to either tovorafenib (Arm 1) or an Investigator's choice of SoC chemotherapy (Arm 2).” (opens the source at this quote in a new tab)

“As of 15 January 2025, there are currently 110 active sites and 169 randomized patients.” (opens the source at this quote in a new tab)

Participants analyzed

No evidence found.

Enrollment completion

“Day One Biopharmaceuticals, Inc., now part of Servier Group, today announced that it has completed enrollment in the FIREFLY-2 clinical trial, which is evaluating the efficacy, safety and tolerability of tovorafenib vs standard of care chemotherapy in the front-line setting of therapy for patients aged 6 months to 25 years with low-grade glioma.” (opens the source at this quote in a new tab)

Participant disposition by arm

No evidence found.

Status of efficacy results as of September 2026

“Trial aims to extend OJEMDA's indication beyond relapsed/refractory setting to address significant unmet need; topline data expected by mid-2027” (opens the source at this quote in a new tab)

Comparative ORR, PFS, and visual outcomes

No evidence found.

Planned patient-reported outcome assessments

“PedsQL-Core, PedsQL-Cancer and PROMIS ® are being assessed at Screening, every 52 weeks from week 5 to end of treatment, and at year 5 as part of the LTFU. Arm 2 has an additional assessment at year 2 in the LTFU.” (opens the source at this quote in a new tab)

Patient-reported outcome results

No evidence found.

Planned growth and development monitoring

“Growth data collection, including Tanner stage and bone age, is ongoing in the LOGGIC/FIREFLY-2 (NCT05566795)” (opens the source at this quote in a new tab)
“trial to further characterize the growth and development in patients during and after tovorafenib treatment and will provide important insights into risk factors for not achieving growth recovery.” (opens the source at this quote in a new tab)

“Additional safety data from FIREFLY-2 will also be submitted as PMRs to further inform the safety profile of tovorafenib in the intended population, including the long-term adverse effects of tovorafenib on growth and development of pediatric patients, and the potential for gonadal toxicity.” (opens the source at this quote in a new tab)

Comparative safety results

No evidence found.

Summary: design limitations and evidence gaps for the first-line indication

LOGGIC/FIREFLY-2 is the only randomized trial of tovorafenib and the only trial in the first-line setting. As of September 2026, no efficacy, safety, or patient-reported outcome results have been reported; enrollment of approximately 400 participants (418 in the registry record) was completed in May 2026, and topline data are expected by mid-2027, with the interim report projected for April 2028 and the final report for April 2032.

The trial is open label, so investigator-assessed outcomes and patient-reported outcomes are susceptible to assessment bias; the primary endpoint relies on independent review. The primary response criteria were changed from RANO-LGG to RAPNO-LGG after 113 of 400 participants were recruited, and the EMA noted interest in the consistency of the treatment effect before and after this change. The design paper stated that the statistical analysis plan may change based on FIREFLY-1 data.

The comparator is investigator's choice among four chemotherapy regimens (two vincristine/carboplatin schedules, vinblastine, or monthly carboplatin), and participants with progression on chemotherapy may cross over to tovorafenib, which may affect interpretation of overall survival and time-to-event endpoints. ORR is a surrogate endpoint; PFS is the key secondary endpoint. The comparator does not include dabrafenib plus trametinib for BRAF V600E-mutated tumors, and participants with NF1, additional activating alterations, or prior nonsurgical therapy are excluded, which limits generalizability to these groups.

Relapsed or refractory pLGG and advanced solid tumors

“The phase 2 FIREFLY-1 (PNOC026; NCT04775485 ) trial objective was to evaluate the safety and efficacy of tovorafenib monotherapy in children, adolescents and young adults with RAF -altered, relapsed/refractory pLGG or advanced solid tumors.” (opens the source at this quote in a new tab)

Updated analysis objectives: long-term outcomes, treatment-free interval, and retreatment

“Herein we provide the first report of long-term outcomes of patients treated with tovorafenib, including patients with ≥12 months off therapy following completion of planned treatment, and the first evaluation of tovorafenib retreatment.” (opens the source at this quote in a new tab)

Sites, countries, and enrollment period

“This multicenter study is conducted at 32 study sites that enrolled patients in 11 countries. The countries with the highest percentage of enrolled patients were the United States (36.5%) and Australia (19.0%).” (opens the source at this quote in a new tab)

“Between 22 April 2021 and 26 January 2023, 137 patients were enrolled to arms 1 and 2 and received tovorafenib—77 in arm 1 and 60 in arm 2.” (opens the source at this quote in a new tab)

Data cutoffs of the primary, regulatory, and 3-year analyses

Analysis	Quoted data cutoff
Primary publication and FDA review	“as of a 5 June 2023 datacut”

“The data cutoff is 10 May 2024, which is 24 months after the last patient was enrolled to Arm 1.” (opens the source at this quote in a new tab)

“This updated analysis provides longer follow-up and is based on a data cutoff of June 6, 2025.” (opens the source at this quote in a new tab)

Single-arm, open-label phase 2 trial with three arms

“FIREFLY-1 (PNOC026; NCT04775485; first registered February 3, 2021) is an ongoing, phase 2, multicenter, international, open-label study evaluating tovorafenib monotherapy in children and young adults with RAF-altered pLGG or advanced solid tumors who had received at least 1 prior systemic anticancer therapy.” (opens the source at this quote in a new tab)
“The trial consists of 3 treatment arms: arm 1 (registrational), arm 2 (a pLGG expansion cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure), and arm 3, which enrolled patients with advanced solid tumors harboring an activating RAF fusion (data not included).” (opens the source at this quote in a new tab)

Blinded independent central review by three response criteria

“As per the trial design, patients were initially enrolled based on investigator assessment of eligibility per RANO-HGG criteria. Investigator response assessments per RANO-HGG were also the criteria on which cessation of treatment due to PD were based. Response was subsequently analyzed per all three criteria by blinded independent central review.” (opens the source at this quote in a new tab)

Planned treatment duration, post-treatment observation, and retreatment

“Treatment duration was planned for a period of 26 cycles (approximately 24 months), after which patients could continue tovorafenib treatment or, at any point thereafter, enter a predefined post-treatment observation period. During this observation period, patients could be retreated with tovorafenib for radiographic or clinical evidence of disease progression.” (opens the source at this quote in a new tab)

Arm 1 inclusion criteria

“In brief, eligible patients in arm 1 were aged 6 months to 25 years, inclusive, with a histopathologically verified pLGG, which had previously been treated with at least one line of prior systemic therapy with evidence of radiographic progression, a documented known activating BRAF alteration and measurable disease as defined by RANO-HGG criteria, a Lansky (aged <16 years) or Karnofsky (aged ≥16 years) performance score of ≥50 and adequate organ function.” (opens the source at this quote in a new tab)

Exclusion criteria

“Patients were excluded if their tumor harbored an additional previously known or expected-to-be activating molecular alteration (including but not limited to an IDH1/2 mutation, FGFR mutation or fusion, or MYBL alteration), if they had symptoms of clinical progression without radiographic PD, or if they had a known or suspected diagnosis of neurofibromatosis type 1 (NF-1).” (opens the source at this quote in a new tab)

Tovorafenib dose and schedule

“Tovorafenib was administered at the protocol-specified dose of 420 mg/m2 (not to exceed 600 mg) by mouth (tablet or liquid formulation), once weekly, with or without food, in 28-day cycles.” (opens the source at this quote in a new tab)
“Patients who had radiographic evidence of PD were allowed to continue tovorafenib treatment if, in the opinion of the investigator and approved by the sponsor, the patient was deriving clinical benefit from continuing treatment.” (opens the source at this quote in a new tab)

Formulation received

“Seven (9%) patients in arm 1 and 21 (35%) patients in arm 2 received tovorafenib as a liquid formulation; all other patients received the tablet formulation.” (opens the source at this quote in a new tab)

Primary and secondary endpoints

“The primary endpoint in arm 1 was ORR, defined as the proportion of patients with a confirmed response of CR or PR according to RANO-HGG criteria, as assessed by an IRC. Secondary endpoints for arm 1 included CBR, PFS, DOR and TTR, as assessed by the IRC using RANO-HGG criteria.” (opens the source at this quote in a new tab)
“ORR, CBR, PFS, DOR and TTR were also assessed by the IRC according to RAPNO criteria.” (opens the source at this quote in a new tab)
“Post hoc exploratory endpoints for arm 1 included ORR and CBR according to RANO-LGG criteria by IRC assessment. For RAPNO and RANO-LGG ORR assessments, patients with confirmed MRs were considered responders in accordance with published guidelines. Changes in quality of life and health utilities measures were exploratory objectives.” (opens the source at this quote in a new tab)

Time to next treatment and treatment-free interval

“TTNT was a composite endpoint defined as the time from the date of the first tovorafenib dose to the start date of the first subsequent anticancer therapy (including retreatment with tovorafenib), or date of death, whichever was earlier. TFI was also a composite endpoint, defined as the time from the last dose of primary tovorafenib treatment to the start of subsequent treatment or death, whichever was earlier.” (opens the source at this quote in a new tab)
“Tumor rebound after the last dose of primary tovorafenib treatment was assessed per the definition established by the International Pediatric Low-Grade Glioma Coalition (R3): a change in tumor size of ≥25% in the first 6 months, compared with the scan immediately prior to stopping therapy.” (opens the source at this quote in a new tab)

Sponsor rationale for RANO-HGG at trial initiation

“The primary endpoint of overall response rate (ORR) was assessed per independent radiology review committee (IRC) according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria” (opens the source at this quote in a new tab)
“as these were considered the only validated assessment criteria at the time of trial initiation.” (opens the source at this quote in a new tab)
“According to RANO-HGG criteria, the FIREFLY-1 trial met its primary endpoint by rejecting the null hypothesis ORR of 21% observed for single-agent vinblastine in this setting” (opens the source at this quote in a new tab)
“RAPNO criteria focus on T2-weighted fluid-attenuated inversion recovery (FLAIR) imaging for assessing response in pLGG rather than changes in contrast-enhancing disease.” (opens the source at this quote in a new tab)

FDA: T2/FLAIR-based criteria preferred and RAPNO-LGG used for the regulatory analysis

“Notable discussion at this meeting included the FDA’s recommendation to evaluate efficacy in FIREFLY-1 using response criteria specifically devised for LGG (i.e., RAPNO-LGG and RANO-LGG), which are preferred over RANO-HGG as LGG is a radiographically distinct tumor from HGG.” (opens the source at this quote in a new tab)
“As such, the FDA’s evaluation of efficacy in FIREFLY-1 is based upon RAPNO-LGG criteria inclusive of observed minor response, partial response, and complete response rates.” (opens the source at this quote in a new tab)
“The FDA considers ORR and DOR to be endpoints that are reasonably likely to predict clinical benefit in patients with relapsed or refractory pediatric LGG with BRAF fusions or rearrangements, or BRAF V600 mutations.” (opens the source at this quote in a new tab)

“Unlike the RANO-HGG and RANO-LGG criteria, RAPNO criteria do not consider change in contrast enhancement in the measurement of response due to spontaneous changes in contrast uptake in pLGG in the absence of clinical progression, and also incorporate parameters to define a response for cysts” (opens the source at this quote in a new tab)

EMA: RANO-HGG considered unsuitable for pLGG

“However, considering that the RANO-HGG criteria are not suitable for assessing LGG, and in particular pLGG, benefit assessment in this application is primarily focused on the analysis of ORR using the RAPNO-LGG criteria, despite being a secondary endpoint according to the protocol.” (opens the source at this quote in a new tab)
“Although imaging response measures are suitable endpoints in a single arm trial as these can isolate a treatment effect, it is more difficult to assess in terms of clinical benefit. Regulatory experience in the present setting is limited.” (opens the source at this quote in a new tab)
“The inclusion of MR in the FIREFLY-1 study aligns with updated RAPNO-LGG and RANO-LGG guidelines, which recognize MR as a meaningful indicator of therapeutic benefit in paediatric low-grade glioma.” (opens the source at this quote in a new tab)

Minor responses and clinical improvement in case narratives

“In the FIREFLY-1 efficacy population, 22 patients demonstrated an MR by either RANO-LGG or RAPNO criteria. Reported clinical changes included improvement in headaches, neurocognitive function, mobility, motor and verbal developmental delays, and fatigue; improvement of tumor-related medical complications including endocrinopathies; ability to attend or perform in school; and ability to engage in other age-appropriate activities of daily living.” (opens the source at this quote in a new tab)
“This information was not collected in a sufficiently standardized or comprehensive manner to support an assessment of direct clinical benefit of tovorafenib; however, it provided preliminary substantiation of the clinical meaningfulness of MRs in pLGG.” (opens the source at this quote in a new tab)

Radiographic response and visual acuity in optic pathway glioma

“Furthermore, improvements in VA occurred in some patients with only small maximal changes in tumor size.” (opens the source at this quote in a new tab)

Radiographic progression-free survival compared with clinical progression and time to next treatment

“Deconstructing the RAPNO PFS endpoint into its radiographic and clinical components demonstrated that RAPNO PFS (median 16.6 months, 95% CI 8.3-19.1) tracked closely with radiographic PFS (median 16.6 months, 95% CI 10.9-22.0) but showed a marked separation from clinical PFS, indicating that RAPNO PFS events were driven predominantly by radiographic-only changes.” (opens the source at this quote in a new tab)

Sample size and statistical methods

“A sample size of 60 patients in the evaluable population was considered to provide 88% power to reject the null hypothesis ORR of 21%, at the two-sided 0.05 level, assuming that the true underlying ORR of tovorafenib was 40% in this disease population. An exact binomial test was used for hypothesis testing.” (opens the source at this quote in a new tab)
“The ORR and CBR were calculated with 95% CIs determined using the Clopper–Pearson method. PFS and DOR were estimated by the Kaplan–Meier method and were summarized along with the corresponding two-sided 95% CI.” (opens the source at this quote in a new tab)

Time-to-event endpoints considered descriptive in a single-arm trial

“However, the single-arm design of this trial limits the interpretability of certain results (i.e., time to event endpoints such as PFS and OS), given the absence of an active control or comparison to the natural history of disease. Therefore, these reported results are considered descriptive only.” (opens the source at this quote in a new tab)

Enrolled and evaluable participants in arms 1 and 2

“The IRC deemed 69 patients in arm 1 who received ≥1 dose of tovorafenib to have measurable disease at baseline per RANO-HGG criteria. Seventy-six patients in arm 1 were deemed evaluable for efficacy by the IRC per RAPNO and RANO-LGG criteria, which use T2-weighted imaging for response assessment. Safety was analyzed in all patients in arms 1 and 2 who received ≥1 dose of tovorafenib ( n = 137).” (opens the source at this quote in a new tab)

Efficacy and safety analysis sets

“The primary endpoint analysis was performed in the arm 1 evaluable population, which included all enrolled patients who received at least one dose of tovorafenib and had measurable disease at baseline per RANO-HGG criteria as determined by the IRC.” (opens the source at this quote in a new tab)
“For this report, safety was assessed in the arm 1 and 2 safety analysis set, which comprised all enrolled patients who received at least one dose of trial treatment.” (opens the source at this quote in a new tab)

EMA assessment of the exclusion of participants without measurable disease

“While this exclusion departs from the ITT principle, this deviation should have almost no effects on the results based on RAPNO or RANO-LGG (as the difference between the 2 analysis sets is only 1 participant), and minor effects on the results based on RANO-HGG.” (opens the source at this quote in a new tab)

Primary analysis (5 June 2023)

“Patients in arm 1 had received a median of 18 treatment cycles (range, 1–26), with median treatment compliance of 100% (range, 93–100)” (opens the source at this quote in a new tab)
“The median duration of treatment (DOT) was 15.8 months (range, 0.7–23.7), with 66% ( n = 51) continuing treatment.” (opens the source at this quote in a new tab)

Regulatory data cutoff (10 May 2024)

“The most common reason for primary treatment discontinuation in Arm 1 was drug holiday (33 patients (42.9%)). Ten patients (13.0%) discontinued study early, either due to death (5.2%) or withdrawal by patient (3.9%) or parent/guardian (3.9%).” (opens the source at this quote in a new tab)
“Thirty-five (45.5%) patients had major protocol deviations, and most included informed consent (twenty-two [28.6%]) and missing laboratory analytes (seventeen [22.1%]).” (opens the source at this quote in a new tab)

Three-year analysis (6 June 2025)

“The median study duration for patients in arm 1 was 40.6 months (range 1.1-49.1). At data cutoff, 4 patients (5%) were still receiving primary tovorafenib treatment and 73 (95%) had discontinued therapy, of whom 40 (55%) had completed planned therapy of ≥26 cycles (Figure S2). Thirty-nine patients (51%) entered a post-treatment observation period, including 35 who had received ≥26 cycles of treatment and 4 who had received <26 cycles (18, 22, 24, and 24 cycles) due to discontinuation related to decreased growth velocity. The most common reasons for treatment discontinuation in the remaining patients were PD (n = 10, 13%) and adverse events (n = 8, 10%).” (opens the source at this quote in a new tab)
“Thirty-one patients (52%) in arm 2 entered a post-treatment observation period. The most common reasons for treatment discontinuation in the remaining patients were adverse events (n = 11, 18%) and PD (n = 7, 12%).” (opens the source at this quote in a new tab)

Arms 1 and 2 combined

“In the combined population, the median age was 9 years (range 1-24); 68 patients (50%) had disease in the optic pathway and 20 (15%) in deep midline structures. The median number of prior lines of systemic anticancer therapy was 3 (range 1-10) and 83 patients (61%) had previously received MAPK pathway-targeted therapy (Table 1).” (opens the source at this quote in a new tab)

Selected baseline characteristics by arm

Characteristic	Arm 1 (n = 77)	Arm 2 (n = 60)	Total (n = 137)
Age, years, median (range)	“8 (2-21)”	“9.5 (1-24)”	“9 (1-24)”
Optic pathway primary location, n (%)	“39 (51)”	“29 (48)”	“68 (50)”
KIAA1549::BRAF fusion, n (%)	“56 (73)”	“45 (75)”	“101 (74)”
BRAF V600E mutation, n (%)	“13 (17)”	“9 (15)”	“22 (16)”
Three or more prior lines, n (%)	“39 (51)”	“33 (55)”	“72 (53)”
Prior MEK and/or BRAF inhibitor, n (%)	“46 (60)”	“37 (62)”	“83 (61)”
Prior radiotherapy, n (%)	“2 (3)”	“3 (5)”	“5 (4)”

No participants younger than 2 years in arm 1

“No patient was in the 6 months to < 2 years of age group. However, the claimed indication includes patients from 6 months of age.” (opens the source at this quote in a new tab)

Relapsed or refractory pLGG: ORR by three response criteria at the primary analysis (5 June 2023)

Response	RANO-HGG (N = 69)	RAPNO-LGG (N = 76)	RANO-LGG (N = 76)
Complete response, n (%)	“12 (17.4)”	“0”	“0”
Partial response, n (%)	“34 (49.3)”	“28 (36.8)”	“20 (26.3)”
Minor response, n (%)	“-”	“11 (14.5)”	“20 (26.3)”
Stable disease, n (%)	“18 (26.1)”	“23 (30.3)”	“23 (30.3)”
Progressive disease, n (%)	“4 (5.8)”	“13 (17.1)”	“11 (14.5)”
Patients with confirmed response	“46”	“39”	“40”
ORR, % (95% CI)	“66.667 (54.288, 77.563)”	“51.316 (39.569, 62.957)”	“52.632 (40.844, 64.208)”

Relapsed or refractory pLGG: duration of response, PFS, and time to response by criteria (5 June 2023)

“The median IRC-assessed DOR was 16.6 months (95% CI: 11.6, NE) based on RANO-HGG criteria, 13.8 months (95% CI: 11.3, NE) based on RAPNO criteria, and 14.4 months (95% CI: 11.0, NE) based on RANO-LGG criteria.” (opens the source at this quote in a new tab)
“The median estimated IRC-assessed PFS was 19.4 months (95% CI: 16.9, NE) based on RANO-HGG criteria, 13.8 months (95% CI: 8.3, 16.9) based on RAPNO criteria, and 13.9 months (95% CI: 11.1, 19.1) based on RANO-LGG criteria.” (opens the source at this quote in a new tab)
“The median IRC-assessed TTR was 3.0 months to 5.5 months (overall range: 1.6 to 16.6 months) depending on which tumor assessment criteria was used.” (opens the source at this quote in a new tab)
“Of note, there were 39 responders by RAPNO-LGG criteria, while 40 patients were considered responders by RANO-LGG criteria. Of these patients, 32 were considered responders by both RAPNO-LGG and RANO-LGG criteria.” (opens the source at this quote in a new tab)

Relapsed or refractory pLGG: clinical benefit rate and subgroups (5 June 2023)

“The ORR per RANO-HGG criteria (primary endpoint) in patients with response-evaluable disease was 67% (95% confidence interval (CI): 54–78), including 12 (17%) patients with a complete response (CR) and 34 (49%) patients with a partial response (PR). Eighteen (26%) patients had a best overall response (BOR) of stable disease (SD), giving a CBR of 93%” (opens the source at this quote in a new tab)
“The ORR was similar in patients with tumors harboring BRAF fusions (52%; 95% CI: 39–64) and BRAF V600E mutations (50%; 95% CI: 21–79) and in patients who had received prior MAPKi therapy (49%; 95% CI: 34–64) and those who had not (55%; 95% CI: 36–73)” (opens the source at this quote in a new tab)
“For RANO-HGG criteria, 33% (n = 15) of patients who had progressed on a MAPKi as their most recent prior therapy had a CR or a PR to tovorafenib” (opens the source at this quote in a new tab)

Relapsed or refractory pLGG: regulatory data cutoff (10 May 2024)

“IRC-assessed ORR (CR, PR, or MR) was 52.6% (95% CI: 40.8, 64.2). No patients had a CR, 29 (38.2%) patients had a PR, 11 (14.5%) patients had an MR, and 22 (28.9%) patients had stable disease.” (opens the source at this quote in a new tab)
“Median IRC-assessed DOR was 18.0 months (95% CI: 12.0, 22.8). The Kaplan-Meier estimate of the probability of continued response was 65.0% (95% CI: 48.2, 77.6) at 12 months, 50.0% (95% CI: 33.8, 64.2) at 18 months, and 25.6% (95% CI: 11.4, 42.6) at 24 months.” (opens the source at this quote in a new tab)
“IRC-assessed ORR (CR, PR, or MR) was 53.9% (95% CI: 42.1, 65.5). No patients had a CR, 23 (30.3%) patients had a PR, 18 (23.7%) patients had an MR, and 22 (28.9%) patients had stable disease.” (opens the source at this quote in a new tab)
“Although considered exploratory, outcomes of ORR based on RANO-HGG criteria are very discordant between the assessment made by the IRC (71.0% (95% CI: 58.8, 81.3)) and the investigators (49.3% (95% CI: 37.0, 61.6)).” (opens the source at this quote in a new tab)

Relapsed or refractory pLGG: 3-year update per RAPNO-LGG (6 June 2025)

Parameter (RAPNO-evaluable, arm 1, n = 76)	Quoted value
ORR, n (%)	“40 (53)”
CBR, stable disease of any length, n (%)	“62 (82)”
CBR, stable disease ≥12 months, n (%)	“44 (58)”
Partial response, n (%)	“30 (39)”
Minor response, n (%)	“10 (13)”
Progressive disease, n (%)	“13 (17)”
Median DOR, months (95% CI)	“19.4 (13.8-27.2)”
Median TTR, months (range)	“5.4 (1.6-17.5)”
Median PFS, months (95% CI)	“16.6 (8.3-19.1)”
PFS rate at 24 months, % (95% CI)	“32 (21-42)”
PFS rate at 36 months, % (95% CI)	“20 (12-30)”
Median TTNT, months (95% CI)	“42.6 (36.6-NE)”

“The median DOR was 19.4 months (95% CI 13.8-27.2) overall, 16.6 months (95% CI 12.0-19.8) in patients previously treated with MAPK pathway inhibitors and 24.0 months (95% CI 10.9-not evaluable [NE]) in patients naïve to such agents (Table 2).” (opens the source at this quote in a new tab)
“Efficacy outcomes per RANO-HGG and RANO-LGG criteria are summarized in Table S1.” (opens the source at this quote in a new tab)

Relapsed or refractory pLGG: treatment beyond progression

“Thirty-eight patients (50%) with RAPNO-defined PD continued primary tovorafenib treatment beyond IRC assessment of PD, either due to the absence of PD as determined by investigators per RANO-HGG or to perceived ongoing clinical benefit (Figure S3).” (opens the source at this quote in a new tab)
“In most cases (37/58 patients, 64%), tumor size at PD (orange X, Figure 2) remained below baseline.” (opens the source at this quote in a new tab)

Relapsed or refractory pLGG: treatment-free interval and rebound after stopping treatment

“Thirty-one patients (79%) remained off therapy at the data cutoff. Thirty of 39 patients (77%) were treatment free for ≥12 months (1 patient had <12 months follow-up after treatment cessation), with 12 patients (31%) off therapy for as long as 18 months. Median TFI was not reached.” (opens the source at this quote in a new tab)
“Twelve of 39 patients (31%) met the criteria (as defined in the methods) for rebound tumor growth (Figure 3A) after discontinuing tovorafenib.” (opens the source at this quote in a new tab)
“Ten of the 12 (83%) patients who qualified as having tumor rebound had tumor sizes that remained below the size observed at baseline and 9 (75%) patients had either further reductions or stabilization of tumor size (without intervention) after the initial rebound scan. Among the 6 patients in the observation period with tumors harboring BRAF V600E mutations, 4 (67%) displayed rebound tumor growth.” (opens the source at this quote in a new tab)

Relapsed or refractory pLGG: retreatment after the observation period

“All 8 patients were retreated with tovorafenib, were still on treatment at data cutoff, and had been retreated for a median of 10.5 cycles (range 2-20) and a median duration of 9.0 months (range 2.6-18.0).” (opens the source at this quote in a new tab)
“The median change in tumor size from the last scan before retreatment was −38% (range −81 to 0).” (opens the source at this quote in a new tab)

Relapsed or refractory pLGG: prior-therapy subgroups at 3 years

“Subgroup analyses demonstrated directionally longer TTNT and DOR in MAPK inhibitor naïve patients.” (opens the source at this quote in a new tab)

Relapsed or refractory optic pathway glioma: radiographic and visual acuity outcomes

“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.” (opens the source at this quote in a new tab)

“While changes of ≥ 0.2 logMAR occurred, with decreases from baseline more commonly reported than increases, the clinical relevance of visual acuity assessments cannot robustly be interpreted in a single-arm study.” (opens the source at this quote in a new tab)

PedsQL 3.0 Cancer Module during the first year of treatment

“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.” (opens the source at this quote in a new tab)
“CONCLUSIONS HRQOL generally remained stable, or improved, in the majority of patients with r/r pLGG during the first year of treatment with tovorafenib.” (opens the source at this quote in a new tab)

Quality-of-life data not included in the EU application

“Therefore, although quality-of-life and health utilities measures using the PedsQL-Core, PedsQL-Cancer, and PROMIS® assessment, and improvement in motor function measured by changes from baseline in the Vineland 3 Adaptive” (opens the source at this quote in a new tab)
“Behavior Scales were collected as exploratory endpoints in the FIREFLY-1 study, they are not presented nor discussed in the current application.” (opens the source at this quote in a new tab)

Treatment-emergent and treatment-related adverse events at 3 years (arms 1 and 2, n = 137)

Preferred term	TEAE, any grade, n (%)	TEAE, grade ≥3, n (%)	TRAE, any grade, n (%)	TRAE, grade ≥3, n (%)
Any adverse event	“137 (100)”	“113 (82)”	“136 (99)”	“91 (66)”
Hair color changes	“106 (77)”	“0”	“106 (77)”	“0”
Elevated CPK	“85 (62)”	“16 (12)”	“82 (60)”	“15 (11)”
Fatigue	“84 (61)”	“6 (4)”	“68 (50)”	“6 (4)”
Anemia	“83 (61)”	“20 (15)”	“69 (50)”	“19 (14)”
Maculopapular rash	“69 (50)”	“11 (8)”	“63 (46)”	“11 (8)”
Decreased growth velocity	“61 (45)”	“46 (34)”	“60 (44)”	“46 (34)”
Increased ALT	“33 (24)”	“8 (6)”	“24 (18)”	“7 (5)”
Epistaxis	“44 (32)”	“1 (1)”	“28 (20)”	“0”

Serious adverse events, deaths, discontinuations, and dose modifications at 3 years

“Serious TEAEs were reported in 77 patients (56%), with the most common being pyrexia (n = 15, 11%), hydrocephalus (n = 11, 8%), decreased growth velocity, and vomiting (n = 9 each, 7%). Serious TRAEs occurred in 29 patients (21%), with the most common being decreased growth velocity (n = 9, 7%) and tumor hemorrhage (n = 5, 4%). Five patients (4%) had grade 5 TEAEs assessed by the investigator as not related to tovorafenib—2 in arm 1, and 3 in arm 2.” (opens the source at this quote in a new tab)
“Eighteen patients (13%) had TRAEs leading to tovorafenib discontinuation. The most common of these were decreased growth velocity (n = 6, 4%) and ITH (n = 5, 4%). TRAEs leading to dose reduction were reported in 45 patients (33%), with the most common being maculopapular rash (n = 7, 5%), fatigue (n = 6, 4%), and decreased appetite (n = 4, 3%). TRAEs leading to dose interruption occurred in 58 patients (42%), with the most common being maculopapular rash (n = 13, 9%), elevated alanine aminotransferase, decreased growth velocity, and vomiting (n = 6 each, 4%).” (opens the source at this quote in a new tab)

Primary analysis safety (5 June 2023)

“Grade ≥3 TEAEs occurred in 63% of patients, the most common being elevated CPK (12%), anemia (11%) and maculopapular rash (8%).” (opens the source at this quote in a new tab)
“Nine (7%) patients had TRAEs leading to tovorafenib discontinuation, the most common being tumor hemorrhage (three patients) and decrease in growth velocity (two patients). TRAEs leading to dose reduction were seen in 33 (24%) patients, the most common being maculopapular rash (4%) and decreased appetite (3%).” (opens the source at this quote in a new tab)
“No signs of ocular toxicity, adverse impact on cardiac function or abnormal weight gain were observed in children treated with tovorafenib, unlike those observed with MEK inhibitors” (opens the source at this quote in a new tab)

Intratumoral hemorrhage

“With longer follow-up, in this analysis, 21 (15%) of 137 patients with reported events of ITH (preferred terms: tumor hemorrhage or intracranial tumor hemorrhage) is numerically greater than the 15 patients with ITH described at the time of the primary analysis. However, the exposure-adjusted incidence of ITH has remained stable over time. Serious TEAEs of ITH occurred in 8 patients (6%), 5 of whom experienced grade ≥3 events.” (opens the source at this quote in a new tab)

Growth velocity on treatment and recovery after stopping

“Median AGV increased from 1.40 cm/year (IQR 0.86, 2.72) during treatment to 7.23 cm/year (IQR 3.50, 10.06) after treatment. Of the 74 (91%) patients in this analysis who had a reduction in growth velocity while on treatment, 67 (91%) had growth recovery, with 53 (72%) demonstrating catch-up growth (Table S2).” (opens the source at this quote in a new tab)
“At the time of data cutoff, no treatment-related fractures, acceleration of bone age advancement, or premature growth plate fusions had been observed.” (opens the source at this quote in a new tab)

“Seventy-four out of 81 children (91.4%) experienced growth suppression on treatment, with median height percentile decreasing from 44.3 (interquartile range [IQR] 50.3) at baseline to 12.9 (IQR 31.7) at end of treatment.” (opens the source at this quote in a new tab)

Long-term safety uncertainty noted by the EMA

“With respect to safety, follow-up remains limited and the long-term safety profile, including the risk for late-onset ADRs has not yet been fully characterised. This is particularly relevant given the potential for prolonged treatment in a paediatric population and the possible impact on growth, development and long-term health outcomes.” (opens the source at this quote in a new tab)

Summary: limitations of FIREFLY-1 as evidence for the first-line indication

FIREFLY-1 enrolled only participants with relapsed or refractory pLGG who had received a median of 3 prior lines of systemic therapy (range 1 to 10), and 61% had received a MEK and/or BRAF inhibitor; it provides no direct evidence in the treatment-naive, first-line population that is the subject of this report. It is a single-arm trial without a comparator, and the authors, the FDA, and the EMA identified this as the main limitation; PFS, OS, time to next treatment, visual acuity, and quality-of-life results are descriptive.

The protocol primary endpoint (RANO-HGG ORR, 67%) was not used by regulators: the FDA and EMA based their assessments on RAPNO-LGG ORR (51% at June 2023; 52.6% at May 2024; 53% at June 2025 in 76 evaluable participants), a protocol secondary endpoint, with minor responses included. RANO-LGG was added post hoc at regulatory request. IRC-assessed and investigator-assessed RANO-HGG ORR differed (71.0% vs 49.3% at May 2024), and treatment decisions were based on investigator RANO-HGG assessments, so 38 participants (50%) continued treatment beyond RAPNO-defined progression. Median RAPNO PFS (16.6 months) was shorter than median time to next treatment (42.6 months).

Arm 1 included no participants younger than 2 years, 51% had optic pathway tumors, 74% had KIAA1549::BRAF fusions, and participants with NF1 or additional activating alterations were excluded. Race and ethnicity diversity was limited. Only 3 participants with BRAF V600E mutations had received dabrafenib plus trametinib. Quality-of-life data are available only as a congress abstract with attrition from 51 to 32 respondents by cycle 13. The growth analysis required at least 6 months of treatment and off-treatment height data, and adult height outcomes are not yet known. Evidence on retreatment is limited to 8 participants.

Single-arm design

“The major limitation of this study is the lack of a comparator arm, although this design was appropriate at the time the study was initiated since no approved treatment for patients with BRAF-altered relapsed/refractory pLGG was available.” (opens the source at this quote in a new tab)

“Due to the limitations of the pivotal study design, including the lack of a randomised comparator arm and the limited sample size, the available data are not considered comprehensive within the meaning of the CMA legislation.” (opens the source at this quote in a new tab)

Post hoc visual acuity analysis

“The main limitation of this analysis of VA outcomes in patients with OPG enrolled in arm 1 of the FIREFLY-1 trial is that it is a post hoc investigation, conducted in the absence of power calculations; analyses are consequently not powered to allow the drawing of definitive conclusions.” (opens the source at this quote in a new tab)

Maximum tolerated or recommended phase 2 dose in children with recurrent MAPK-altered tumors

“The primary objective of this study was to determine the maximal tolerated dose (MTD) or recommended phase II dose (RP2D) of tovorafenib administered once every week to children and adolescents with radiographically recurrent or progressive MAPK pathway-activated tumors.” (opens the source at this quote in a new tab)

Treatment periods

“We treated nine eligible patients with primary CNS tumors at 280 (n = 3), 350 (n = 3), and 420 (n = 3) mg/m2 from February 2018 through November 2021.” (opens the source at this quote in a new tab)
“Patients were treated from June 2020 through November 2023.” (opens the source at this quote in a new tab)

Participating sites

No evidence found.

Registry record: sponsor, study status, and actual start and completion dates

Field	Registry record
Sponsor	“Karen D. Wright, MD”
Responsible party	“Karen D. Wright, MD, Dana-Farber Cancer Institute”
Study status	“Completed”
Study start (actual)	“2018-02-27”
Primary completion (actual)	“2025-12-31”
Study completion (actual)	“2025-12-31”
Last update posted	“2026-02-19”

Phase IA 3 + 3 escalation and phase IB subgroup-specific design

“The first phase (IA) followed a 3 + 3 design. Based on initial observed responses and pharmacokinetic data, the trial was modified to include phase IB using a subgroup-specific time to event (Sub-TITE) design to better determine dosing within two subgroups defined by body surface area (BSA ≤1.5 m2 and >1.5 m2).” (opens the source at this quote in a new tab)
“With that information, the decision was made to re-evaluate dosing in the context of BSA and exclude patients with NF1.” (opens the source at this quote in a new tab)

Inclusion and exclusion criteria

“Eligible patients were between age 1 and 25 years with a confirmed diagnosis of radiographically recurrent or progressive CNS or solid tumors with associated activation of the MAPK pathway. Patients had to have received prior standard therapy.” (opens the source at this quote in a new tab)
“Exclusion criteria included patients having been treated with tovorafenib previously, receiving any other anticancer or experimental therapy, with unstable systemic diseases, pregnant or lactating, or having any condition that potentially hindered compliance with study protocol and the follow-up schedule.” (opens the source at this quote in a new tab)

Dose levels and treatment duration

“Based on the adult oral RP2D of 350 mg/m2 given once every week (using a typical adult BSA of 1.7 m2), the starting dose for the phase IA study was 80% of the adult RP2D, which is 280 mg/m2.” (opens the source at this quote in a new tab)
“Patients received tovorafenib for 12 cycles from the time of study entry but could continue up to a total treatment period of 24 cycles. Patients progressing off therapy within 6 months could resume drug for an additional 12-24 cycles.” (opens the source at this quote in a new tab)

Primary endpoint, toxicity grading, and response assessment

“Toxicities were graded according to Common Terminology Criteria for Adverse Events version 5. Response was classified as complete response (CR), partial response (PR), or stable disease (SD).” (opens the source at this quote in a new tab)
“Magnetic resonance imaging or computed tomography depending on CNS or non-CNS tumor type, respectively, was assessed within 28 days of treatment start and at the end of every 2-3 cycles using RANO or RECIST criteria, as appropriate.” (opens the source at this quote in a new tab)

Bayesian subgroup-specific dose finding

“We used a modified Bayesian adaptive Sub-TITE design to allow separate determination of a MTD or RP2D in the two BSA subgroups, BSA ≤1.5 m2 and BSA >1.5 m2, starting at the prior tolerable dose of 420 mg/m2/dose once every week (Fig 1).” (opens the source at this quote in a new tab)
“For BSA ≤1.5 m2, the posterior mean toxicity probability that was closest to the 20% target toxicity rate was 0.19 at dose level 2.” (opens the source at this quote in a new tab)

Treated and evaluable participants

“We treated 44 eligible patients (phase IA: 9; phase IB: 35) with high-(n = 6) or low-grade (n = 38) tumors.” (opens the source at this quote in a new tab)
“For dose finding, 30 (n = 16 for BSA ≤1.5 m2; n = 14 for BSA >1.5 m2) of 35 patients were evaluable for the DLT observation period.” (opens the source at this quote in a new tab)
“Of the 35 eligible patients enrolled, 31 met evaluability criteria for objective response. Four patients did not complete cycle 1 of therapy and were unevaluable for response.” (opens the source at this quote in a new tab)

Toxicity and response-evaluable sets

“All 35 patients received at least one dose of tovorafenib and were evaluable for the toxicity analysis.” (opens the source at this quote in a new tab)
“Of the 31 evaluable patients, 30 patients had known response data from institutional imaging evaluation and 27 patients had known response data from central review imaging assessment using RANO criteria.” (opens the source at this quote in a new tab)

Deaths during follow-up

“Figure 2 highlights the swimmers plot for duration of follow-up, timing of PD, first response, and 5 deaths starting from study enrollment. All deaths were unrelated to treatment.” (opens the source at this quote in a new tab)

Diagnoses and molecular alterations

“Pilocytic astrocytoma (n = 19) was the most common diagnosis; KIAA1549:BRAF fusion was the most common molecular alteration (n = 27).” (opens the source at this quote in a new tab)

Pediatric LGG population described in the FDA review

“The study enrolled 34 patients with pediatric LGG with an activating BRAF alteration, of which 29 patients harbored a RAF fusion (24/29 patients had the KIAA1549:BRAF fusion).” (opens the source at this quote in a new tab)

Relapsed or recurrent pLGG and other MAPK-altered tumors: phase IA and IB responses

“Independent central radiology review by a single radiologist not involved in study conduct for the phase IA was notable for 2 complete response (CR), 3 partial response (PR), 2 stable disease (SD), and 2 median time to response of 10.5 weeks (range, 8-32 weeks).” (opens the source at this quote in a new tab)
“At approximately 5 years after completion of therapy, only 1 CR and 1 PR persist.” (opens the source at this quote in a new tab)
“For the 27 patients with centrally reviewed imaging, 25 (93%) were responders with CR/PR/SD. The median duration of response was 11.3 months (range, 0.03-35.4 months; Table 4). Of 10 patients treated at RP2D, 8 (80%) responders had median duration of response of 24.1 months (range, 11-35.4 months).” (opens the source at this quote in a new tab)

FDA consideration as confirmatory evidence

“In these 31 patients, 3 had a complete response and 10 had a partial response. The demonstration of responses in a heavily pre-treated patient population constitutes confirmatory evidence of the effectiveness of tovorafenib in the intended population.” (opens the source at this quote in a new tab)

Dose-limiting toxicities and recommended phase 2 dose

“Phase IB included 6 DLTs: three in each BSA subgroup, all at 530 mg/m2/dose, all grade 3.” (opens the source at this quote in a new tab)
“Based on this information, the principal investigators chose 420 mg/m2/dose (dose level 1) for the RP2D in each BSA subgroup.” (opens the source at this quote in a new tab)

Common adverse events and laboratory abnormalities

“The most common adverse reactions (approximately 20%) were skin and subcutaneous disorders, which included rash and hair color changes, followed by GI disorders (10%), and blood and lymphatic system disorders (6%).” (opens the source at this quote in a new tab)
“The top three most common laboratory abnormalities were decreased phosphorus, increased creatinine phosphokinase, and increased AST. The most common grade 3 and 4 laboratory abnormality was low phosphorus.” (opens the source at this quote in a new tab)
“Three patients treated on phase IB experienced this event, with two grade 1 hemorrhages being deemed possibly related.” (opens the source at this quote in a new tab)

Growth suppression

“Eleven of 12 patients (92%) on drug for more than 6 months and not postpubertal experienced grade 3 growth suppression.” (opens the source at this quote in a new tab)
“For patients who received treatment for more than 6 months (n = 19), the average growth velocity was 0.94 cm/year (range: 0-3.6).” (opens the source at this quote in a new tab)
“Within the limits of our data, all patients except for one, for whom we do not have follow-up data to make the determination, recovered near-normal or normal growth rates within 12 months of drug discontinuation.” (opens the source at this quote in a new tab)

Summary: limitations of PNOC014

PNOC014 was a phase 1, nonrandomized, dose-finding study in 44 participants aged 1 to 25 years with recurrent or progressive MAPK pathway-altered tumors (38 low-grade and 6 high-grade tumors) at 15 US sites; it did not include treatment-naive participants. The design was changed mid-study from a 3 + 3 escalation to a Bayesian subgroup-specific design, and doses ranged from 280 to 530 mg/m2, so response data are pooled across dose levels. Responses were reported with stable disease counted as response (25 of 27 centrally reviewed participants, 93%), central and institutional assessments were discordant in 13 of 31 participants, and pharmacokinetic sampling in phase IB was disrupted by COVID-19 travel restrictions. The FDA stated that limited data from this study precluded its acceptance as a second adequate and well-controlled trial.

Authors’ discussion of heterogeneity of response

“We did not observe the same degree of response even among patients with the same genetic alteration.” (opens the source at this quote in a new tab)

First-in-human study in adults with advanced solid tumors

“Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics.” (opens the source at this quote in a new tab)

Enrollment period and data cutoff

“Between September 13, 2011 and September 5, 2016, 149 patients were enrolled and received at least 1 dose of tovorafenib (safety population).” (opens the source at this quote in a new tab)
“The data cutoff date for the current analysis was April 11, 2017, at which time, a small number of patients remained on treatment.” (opens the source at this quote in a new tab)

Registry record: sponsor, actual study dates, and number of study locations

Field	Registry record
Sponsor	“Millennium Pharmaceuticals, Inc.”
Responsible party	“Takeda (Millennium Pharmaceuticals, Inc.)”
Study status	“Completed”
Study start (actual)	“2011-09-15”
Primary completion (actual)	“2017-04-11”
Study completion (actual)	“2018-10-16”
Study locations	“This study has 16 locations”
Last update posted	“2020-08-10”

Dose escalation and melanoma dose expansion

“We conducted a first-in-human, phase 1, multicenter, open-label study of tovorafenib in patients with relapsed or refractory advanced solid tumors. The study included a dose escalation phase and a dose expansion phase, with the latter including molecularly defined cohorts of patients with locally advanced, metastatic, and/or unresectable melanoma.” (opens the source at this quote in a new tab)
“The study was initially designed to investigate a Q2D schedule. Subsequently, a protocol amendment introduced planned QW dose escalation cohorts.” (opens the source at this quote in a new tab)

Adult participants

“Eligible patients were aged ≥ 18 years, with relapsed or refractory advanced solid tumors (excluding lymphoma but including melanoma), who had progressed on/after, or were not candidates for standard therapies or for whom no approved therapy was available” (opens the source at this quote in a new tab)

Fasting oral administration and dose levels

“Tovorafenib was administered orally (tablet formulation), with patients fasting (except for water) for at least 2 h before and at least 2 h after taking their dose.” (opens the source at this quote in a new tab)
“Planned QW doses to be administered on days 1, 8, 15, and 22 of a 28-day cycle were a starting dose of 400 mg, followed by dose level increases of 200 mg (i.e., doses of 600 mg, 800 mg, and 1000 mg) in each subsequent cohort until the MTD/RP2D was reached.” (opens the source at this quote in a new tab)

Safety, dose-limiting toxicity, response, and pharmacokinetic assessments

“Following baseline evaluation, response was assessed by investigators every two cycles by computed tomography or magnetic resonance imaging according to Response Evaluation Criteria in Solid Tumors (version 1.1)” (opens the source at this quote in a new tab)

No formal power calculation

“No formal power calculations were carried out. In the dose escalation phase, enrollment of approximately 54 patients was envisaged, with the actual number dependent on the number of dose escalation steps and the number of patients per cohort.” (opens the source at this quote in a new tab)

Participants by schedule

“Tovorafenib was administered Q2D to 30 patients in the dose escalation phase and 80 patients in the dose expansion phase (including 20 patients in a PK expansion cohort) and QW to 20 patients in the dose escalation phase and 19 patients in the dose expansion phase.” (opens the source at this quote in a new tab)

Safety, DLT-evaluable, response-evaluable, and PK-evaluable populations

“The safety population was defined as all patients who received any amount of tovorafenib.” (opens the source at this quote in a new tab)
“The response-evaluable population included all patients with measurable disease who received any amount of tovorafenib and who had at least 1 postbaseline response assessment.” (opens the source at this quote in a new tab)

Treatment exposure and discontinuation

“Patients received a median of 2 cycles of treatment in both the dose escalation and dose expansion phases. The primary reasons for treatment discontinuation were disease progression and adverse events (Supplementary Tables S2 and S3).” (opens the source at this quote in a new tab)

Primary diagnoses

“The most common primary diagnoses in the dose escalation phase were colon cancer and melanoma. In line with the eligibility requirements, most patients in the dose expansion phase had a primary diagnosis of melanoma.” (opens the source at this quote in a new tab)

Adult melanoma and solid tumors: responses by cohort

“Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease.” (opens the source at this quote in a new tab)

Pharmacokinetics of once-weekly dosing

“The mean plasma terminal half-life ( t 1/2 ) of tovorafenib was approximately 70 h (range 31–119 h) as defined in 20 evaluable patients receiving 600 mg QW.” (opens the source at this quote in a new tab)
“While no apparent accumulation was observed with the QW dose regimens, Q2D administration resulted in approximately 2.5-fold accumulation in AUC 48 at steady state.” (opens the source at this quote in a new tab)

Recommended phase 2 dose and dose-limiting toxicities

“In the QW dose escalation phase, cohorts of patients received tovorafenib doses of 400 mg, 600 mg, and 800 mg, in 28-day cycles. DLTs occurred in cycle 1 in 2 patients in the 800 mg cohort; 1 patient had grade 3 hyperbilirubinemia and 1 had grade 3 rash. The MTD selected for the QW expansion cohort was therefore 600 mg to be administered over 28-day cycles.” (opens the source at this quote in a new tab)

Grade 3 or higher adverse events, discontinuations, and deaths

“In the dose expansion phase, 68% of patients experienced a grade 3 or higher TEAE, including 73% of patients in the Q2D cohorts and 47% in the QW cohort.” (opens the source at this quote in a new tab)
“In the QW cohort of the dose expansion phase, 4 of 19 patients (21%) had TEAEs resulting in permanent discontinuation, including atrial flutter, dyspnea, erythema multiforme, and fatigue (1 patient each).” (opens the source at this quote in a new tab)
“There were 13 on-study deaths. The fatal SAEs associated with these deaths predominantly related to the underlying disease or complications thereof and are listed in Supplementary Table S8. Only one death, associated with respiratory failure in a patient in the 280 mg Q2D dose escalation cohort, was deemed by the study investigators to be treatment related.” (opens the source at this quote in a new tab)

Summary: limited relevance of C28001 to pLGG

C28001 enrolled 149 adults (median age 62.5 to 66.0 years across phases) with relapsed or refractory advanced solid tumors, mostly melanoma and colon cancer; it included no participants with pLGG and no children. Dosing was flat (600 mg once weekly recommended) and fasting was required, whereas pediatric trials used body surface area-based dosing without food restrictions. No formal power calculations were performed, response was investigator assessed by RECIST 1.1 without independent review, and median treatment exposure was 2 cycles, so the study provides no information on long-term toxicities relevant to children such as growth velocity. Its relevance to this report is limited to the safety profile in adults, the once-weekly schedule, and pharmacokinetics (mean terminal half-life of approximately 70 hours at 600 mg once weekly).