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)