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.