FDA Approval Summary: Tovorafenib for Relapsed or Refractory BRAF-altered Pediatric Low-Grade Glioma

Abstract

On April 23, 2024, FDA granted accelerated approval to tovorafenib, a type II RAF kinase inhibitor, for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (pLGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. Efficacy was evaluated in FIREFLY-1 (NCT04775485), a single-arm, open-label, multicenter trial that enrolled patients 6 months to 25 years of age with relapsed or refractory pLGG with an activating BRAF alteration who had received prior systemic therapy. The major efficacy outcome measure was radiologic overall response rate (ORR), defined as the proportion of patients with complete response, partial response, or minor response as determined by blinded independent central review using Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria. A key secondary endpoint was duration of response (DoR). In an efficacy population of 76 patients, the ORR was 51% (95% confidence interval (CI): 40, 63), and the median DoR was 13.8 months (95% CI: 11.3, not estimable). The required post-marketing clinical trial (FIREFLY-2) was well underway at the time of accelerated approval. This represents the first FDA approval of a systemic therapy for the treatment of patients with pLGG with BRAF fusions or rearrangements.

Introduction

Pediatric low-grade gliomas (pLGGs) are the most common primary brain tumor in children with an annual incidence of approximately 1,000 to 1,600 in the United States (1, 2). These tumors are characterized by activation of the MAP kinase pathway with most harboring a single identifiable driver alteration. BRAF alterations occur in up to 70% of pLGG (3, 4), and are generally observed in patients with sporadic pLGG, in contrast to patients with neurofibromatosis type 1 (NF1) who are predisposed to development of pLGG due to a germline NF1 mutation. The KIAA1549:BRAF fusion is the most common BRAF alteration (approximately 35%), followed by BRAF V600E mutations (approximately 15%) (5). Pediatric LGGs are slow-growing with a 10-year overall survival rate exceeding 90%. Despite their designation as “benign”, pLGGs display clinically heterogeneous behavior and may occur anywhere in the central nervous system, with the greatest overall prevalence in the cerebellum. Pilocytic astrocytomas, the most common histologic variant of pLGG, are enriched for the KIAA1549:BRAF fusion and are frequently found in the optic pathway or hypothalamus where they are often diagnosed based on imaging alone, rather than biopsy, due to their characteristic radiologic features and the potential for surgical morbidity due to tumor location. Patients with pLGG who undergo a subtotal resection or have a deep-seated tumor unamenable to surgery more commonly experience multiple progression events associated with significant morbidity (e.g., vision loss, motor impairment, endocrine dysfunction) and potentially mortality (6).

Pediatric LGGs are traditionally managed with surgery, chemotherapy, and in some cases, radiation therapy. Commonly used regimens include carboplatin and vincristine (C + V) and single agent vinblastine which result in a radiologic overall response rate (ORR) of approximately 35 to 52%, including minor responses (7, 8). Although earlier studies evaluating chemotherapy for the treatment of relapsed or refractory pLGG enrolled a molecularly unselected patient population, the relatively recent use of genomic profiling has supported the development of targeted therapies for pLGG. Dabrafenib in combination with trametinib (D + T) was approved by FDA in 2023 for the first-line treatment of pediatric patients 1 year of age and older with LGG with a BRAF V600E mutation who require systemic therapy. This approval was primarily based on improved progression-free survival (PFS) compared to carboplatin in combination with vincristine in a randomized trial (9).

Type I RAF inhibitors such as dabrafenib are not indicated for the treatment of tumors harboring a BRAF fusion due to paradoxical activation which may increase the risk of tumor growth (10). Prior to the approval of tovorafenib, there were no approved targeted therapies for patients with pLGG harboring BRAF fusions.

Regulatory History

In August 2020, tovorafenib received Breakthrough Therapy Designation for the treatment of pediatric patients with LGG harboring an activating RAF alteration that has progressed after one or more prior therapies based on clinical data from the study PNOC014. Tovorafenib received Orphan Drug Designation for the treatment of malignant glioma in September 2020 and Rare Pediatric Disease Designation in July 2021 for the treatment of low-grade gliomas harboring an activating RAF alteration disproportionately affecting children. The New Drug Application for tovorafenib (trade name OJEMDA) for the treatment of BRAF-altered pLGG was submitted under rolling review, with completion on August 31, 2023.

Nonclinical Pharmacology and Toxicology

Tovorafenib is a type II kinase inhibitor that targets RAF kinases (BRAF, CRAF) (11). Tovorafenib exhibited inhibitory activity against BRAF V600E mutant kinase, wild type (WT) BRAF kinase, and WT CRAF kinase in enzymatic assays and antiproliferative activity against BRAF V600E and V600D mutations in cellular assays (12). Tovorafenib had antitumor activity in mice bearing intracranial neuroprogenitor BRAF V600E or KIAA1549:BRAF expressing tumors (13). In a neurofibromatosis type I (NF1) model without BRAF alteration, tovorafenib did not have antitumor activity, and while not statistically significant, an increase in tumor volume in ~17% of mice was observed with treatment (12).

In repeat-dose toxicity studies of up to 3 months’ duration, tovorafenib given orally to rats and monkeys led to anemia and bone marrow suppression, as well as gastrointestinal, epidermal, hematologic, hepatotoxicity, and pro-inflammatory events leading to findings in the thyroid and parathyroid and changes in levels of hormones, calcium, and phosphorus. In rats, tovorafenib caused reversible testicular tubule degeneration/atrophy and reduced epididymal sperm and non-reversible ovarian follicular cysts, decreased corpora lutea, and hyperplasia after a 2-week recovery period. Pregnant rats receiving tovorafenib during organogenesis exhibited resorption and total litter loss. Fertility and early embryonic development assessment of tovorafenib-treated female rats paired with untreated males demonstrated significantly less pregnancies, corpora lutea, implantations, and live embryos. Adverse reproductive findings occurred at exposures below the human exposure at the recommended clinical dose. Tovorafenib may also impair fertility in males and females based on animal findings. Tovorafenib was not genotoxic in vitro or in vivo (12).

Clinical Pharmacology

The recommended dosage of tovorafenib is 380 mg/m² orally once weekly (not to exceed 600 mg), with or without food (12). Although the intended dose in FIREFLY-1 was 420 mg/m², dosing variability relating to dose bands across body surface area subgroups was observed allowing an assessment of other doses within this study (12). There were no clinically significant differences in exposure-response relationships for ORR observed over the actual dose range of 290 to 476 mg/m² (0.76-1.25 times the approved recommended dosage) evaluated in Arm 1 (12). As greater tovorafenib exposure is associated with increased risk of Grade ≥2 adverse events including skin rash, elevated liver enzymes, and elevated creatine phosphokinase, a modest reduction from 420 to 380 mg/m² was recommended to optimize the dose and improve the benefit-to-risk ratio in pediatric patients (12). Based on pharmacokinetic/pharmacodynamic modeling, this dose reduction was also anticipated to partially mitigate the reductions in growth velocity observed in children in FIREFLY-1 (12).

Clinical Trial Design

FDA’s approval of tovorafenib was based on data from FIREFLY-1, a single-arm, open-label, clinical trial conducted globally in patients 6 months to 25 years of age with relapsed or refractory LGG with an activating RAF alteration (including BRAF/CRAF fusions and BRAF V600 mutations), or other locally advanced or metastatic solid tumor with an activating RAF fusion (14). Patients were required to have documented evidence of radiologic progression and at least one measurable lesion. Patients with pLGG harboring additional activating molecular alterations (e.g., IDH1/2 mutations, FGFR mutations) or with a known or suspected diagnosis of NF1 were excluded. Patients received tovorafenib as a single agent once weekly at the recommended Phase 2 dose (RP2D) of 420 mg/m² (not exceeding 600 mg) in 28-day cycles for at least 26 cycles or until disease progression or unacceptable toxicity.

Patients were enrolled into one of three non-randomized cohorts (“Arms 1, 2, and 3”). The efficacy population consisted of 76 patients (Table 1; ref. 12) from Arm 1 with relapsed or refractory pLGG with an activating BRAF alteration, including KIAA1549:BRAF fusions and BRAF V600E mutations, who had measurable disease at baseline (12). Molecular testing used to detect an activating BRAF alteration for study eligibility included fluorescence in-situ hybridization, immunohistochemistry, and next generation sequencing. The primary safety population included 137 patients with relapsed or refractory RAF-altered pLGG from Arm 1 (BRAF-altered pLGG) and Arm 2 (RAF-altered pLGG extension cohort) (Table 2 [ref. 15]).

Table 1.

Demographics and clinical characteristics of the efficacy population in FIREFLY-1 (Arm 1)

	Efficacy Population N=76
Age at baseline (years)
Median (range)	8.5 (2, 21)
<2 years	0
2 to <6 years	14 (18)
6 to <12 years	40 (53)
12 to <16 years	16 (21)
≥16 years	6 (8)
Sex, n (%)
Male	40 (53)
Female	36 (47)
Race, n (%)
White	40 (53)
Asian	5 (7)
Black or African American	2 (2.6)
Multiple	3 (3.9)
Other	6 (8)
Not reported	20 (26)
Ethnicity, n (%)
Hispanic or Latino	3 (3.9)
Not Hispanic or Latino	50 (66)
Not reported or unknown	23 (30)
Country, n (%)
USA	25 (33)
ex-USA	51 (67)
Primary tumor location, n (%)
Optical pathway	39 (51)
Deep midline structures	9 (12)
Cerebral hemisphere	5 (7)
Brain stem	6 (8)
Cerebellum	5 (7)
Other	12 (16)
Histology, n (%)
Astrocytic	71 (93)
Mixed Glial-neuronal	4 (5)
Other	1 (1.3)
Pre-operative staging, n (%)
Localized disease	60 (79)
Disseminated/metastatic disease	8 (11)
Leptomeningeal spread	8 (11)
Post-operative staging, n (%)
Sub-total resection	35 (46)
Biopsy only, not attempted	40 (53)
Gross total resection	1 (1.3)
BRAF alteration, n (%)
KIAA1549:BRAF fusion	56 (74)
BRAF V600E mutation	12 (16)
Other	8 (11)
Prior MAPK inhibitors1, n (%)
Prior MEK inhibitor	42 (55)
Prior BRAF inhibitor	7 (9)
Prior MEK and BRAF inhibitors	4 (5)
Prior lines of therapy
Median (range)	3 (1, 9)

Source: FDA multidisciplinary review (ref. 12)

Table 2.

Efficacy results by BICR per RAPNO-LGG criteria in FIREFLY-1 (Arm 1)

	N=76
Overall response rate, % (95% CI)a	51 (40, 63)
Complete response, n (%)	0
Partial response, n (%)	28 (37)
Minor response, n (%)	11 (14)
Duration of response (DoR)	N=39
Median (95% CI)b, months	13.8 (11.3, NE)
% with observed DoR ≥6 months	85
% with observed DoR ≥12 months	23
Time to response
Median in months, (range)	5.3 (1.6, 11.2)

Source: OJEMDA (tovorafenib; package insert; ref. 15)

The primary endpoint of FIREFLY-1 was ORR according to blinded independent central review (BICR) as per the Response Assessment in Neuro-Oncology (RANO) high grade glioma (HGG) criteria; a secondary endpoint was ORR according to BICR as per Response Assessment in Pediatric Neuro-Oncology LGG (RAPNO-LGG) criteria (16). 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. 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 (16). Additional efficacy outcome measures were DoR, time to response, and ORR by BICR according to RANO-LGG criteria.

Efficacy Results

Baseline characteristics for the efficacy population (n=76) of FIREFLY-1 are shown in Table 1 (ref. 12) and efficacy results are provided in Table 2 (ref. 15). Exploratory subgroup analyses of ORR demonstrated similar response rates based on BRAF alteration (KIAA1549:BRAF fusion vs. BRAF V600E mutation), exposure to a prior MEK and/or BRAF inhibitor, and number of prior lines of therapy received.

Safety Results

The primary safety population of FIREFLY-1 included 137 patients from Arms 1 and 2 who had relapsed or refractory RAF-altered pLGG and received tovorafenib 420 mg/m² orally once weekly. A pooled safety population of 172 patients also included other adult and pediatric patients with advanced solid tumors who received the RP2D. Among these 172 patients, 49% were exposed to tovorafenib for 1 year or longer.

The most common (≥ 30%) treatment-emergent adverse reactions observed in the pLGG population of 137 patients were rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection (Table 3 [ref. 15]). Laboratory abnormalities worsening from baseline are presented in Supplementary Table S1 (ref. 15).

Table 3.

Treatment-emergent adverse reactions (≥20%) in patients with pLGG who received tovorafenib in FIREFLY-1 (Arms 1 and 2)

	Tovorafenib N=137
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
Skin and Subcutaneous Tissue Disorders
Rasha	77	12
Hair color changes	76	0
Dry skin	36	0
Dermatitis acneiform	31	1
Pruritus	26	1
General Disorders
Fatigue	55	4
Pyrexia	39	4
Edemab	26	0
Infections and Infestations
Viral infectionc	55	7
Upper respiratory tract infection	31	1.5
Paronychia	26	1.5
Gastrointestinal Disorders
Vomitingd	50	4
Constipation	33	0
Nausea	33	0
Abdominal pain	28	0
Diarrheae	22	1.5
Stomatitisf	20	0
Nervous system disorders
Headache	45	1
Vascular Disorders
Hemorrhageg	42	5*

Source: OJEMDA (tovorafenib; package insert; ref. 15)

^aIncludes terms erythema multiforme, eczema, rash erythematous, rash macular, rash follicular, rash pruritic, rash maculopapular, rash, rash papular, rash pustular, skin exfoliation, drug eruption, dermatitis, dermatitis bullous.

^bIncludes terms lip edema, periorbital edema, edema peripheral, localized edema, face edema, vulval edema.

^cIncludes terms viral infection, rhinovirus infection, enterovirus infection, viral upper respiratory tract infection, enterocolitis viral, oral herpes, gastroenteritis viral, influenza, influenza like illness, respiratory syncytial virus infection, enterovirus infection, coronavirus infection, COVID-19, SARS-COV-2 test positive, herpes simplex, parainfluenza virus infection, adenoviral upper respiratory infection, viraemia, adenovirus infection, conjunctivitis viral, eye infection viral, metapneumovirus infection, parvovirus infection, respiratory syncytial virus bronchiolitis, respiratory tract infection viral, viral pharyngitis, viral rhinitis, viral tonsillitis.

^dIncludes terms retching, hematemesis.

^eIncludes terms colitis, enterocolitis.

^fIncludes terms mouth ulceration, mucosal inflammation, aphthous ulcer, cheilitis.

^gIncludes terms tumor hemorrhage, gastrointestinal hemorrhage, subdural hemorrhage, epistaxis, intracranial tumor hemorrhage, upper gastrointestinal hemorrhage, lower gastrointestinal hemorrhage, vaginal hemorrhage, gingival bleeding, post procedural hemorrhage, hemoptysis, anal hemorrhage.

^*Includes one Grade 5 event.

Serious adverse reactions occurred in 45% of patients. A fatal adverse reaction of tumor hemorrhage occurred in 1 patient (1%). Adverse reactions requiring permanent discontinuation occurred in 7% of patients and included tumor hemorrhage and reduction in growth velocity. Dosage interruption due to an adverse reaction occurred in 57% of patients, most commonly due to rash, pyrexia, vomiting and hemorrhage. Dose reductions due to toxicity occurred in 24% of patients, most commonly due to rash and fatigue.

The product label for tovorafenib includes Warnings and Precautions for hemorrhage, skin toxicity including photosensitivity, hepatotoxicity, effect on growth, embryo-fetal toxicity and NF1-associated tumors.

Hemorrhage was a clinically important safety signal observed in patients treated with tovorafenib, occurring in 37% of patients in the pooled safety population (Grade ≥ 3 events in 4%). The most frequent hemorrhagic events were epistaxis (26%), intracranial hemorrhage (9%, including a Grade 5 event) and gingival bleeding (5%). Given the frequency and potentially severe nature of bleeding events observed in study patients, prescribers are advised to monitor for signs and symptoms of hemorrhage and to evaluate as clinically indicated.

Reduction in growth velocity was observed in FIREFLY-1. Twenty patients 3 to 10 years old (representing 15% of the study population younger than 18) were reported to have reduction in growth velocity; two patients discontinued tovorafenib due to these events. Growth velocity recovered after interruption of tovorafenib, and advanced bone age or premature closure of the epiphyses were not observed. To further address the safety signal of reduced growth velocity, FDA issued a postmarketing requirement (PMR) to conduct comprehensive safety analyses to further characterize long-term adverse effects of tovorafenib on growth and development. Also, due to findings in animal studies indicating gonadal toxicity with use of tovorafenib and the generally long life expectancy of patients with pLGG, this signal will be further characterized in a clinical study.

The potential for increased tumor growth in patients with NF1-associated tumors was included in labeling based on nonclinical data. In a genetically engineered mouse model of NF-1 associated plexiform neurofibroma lacking a BRAF alteration, increased tumor volume occurred in ~17% of animals (12). Although cases of patients with pLGG bearing both a BRAF alteration and loss of NF1 are rare, possible tumor growth in the context of NF-1 associated disease was considered relevant for clinician awareness (17).

Regulatory Insights

This is the first FDA drug approval for the treatment of patients with pLGG harboring a BRAF fusion or rearrangement. The accelerated approval of tovorafenib was based on clinically meaningful and durable responses in FIREFLY-1, as assessed by BICR.

Key regulatory considerations included the clinical relevance of the “minor response” category of pLGG response criteria and feasibility of randomized controlled trials (RCTs) in small patient populations with rare tumors given the Sponsor’s proposal to rely on data from an ongoing RCT to confirm the clinical benefit of tovorafenib.

Minor Responses and Supportive Efficacy Data

To evaluate the effectiveness of an oncology drug, FDA has traditionally relied upon calculation of ORR based on complete and partial responses as per validated response criteria for a given solid tumor type. The Response Evaluation Criteria in Solid Tumors (RECIST) have been most frequently used for this purpose. For tumors of the central nervous system, the Response Assessment in Neuro-Oncology (RANO) criteria published in 2010 have been used primarily for the assessment of high-grade gliomas. Response criteria designed specifically for low-grade glioma, RANO-LGG and RAPNO criteria, introduced a “minor response category,” defined as a 25 to <50% reduction in target lesion based on T2/FLAIR measurement. However, the clinical meaningfulness of minor responses (MRs) has not been clearly characterized.

For the tovorafenib application, FDA requested submission of individual case narratives to better understand the clinical impact of MRs. These narratives detailed relevant information about the patient’s diagnosis, treatment history, investigator-reported assessment of the patient’s condition at baseline including functional deficits (e.g., visual deficits, hemiparesis, etc.), assessment of tumor response, and the patient’s response to tovorafenib, including descriptions of changes in symptoms, function, or medical condition as reported by the investigator, parent, or guardian.

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. Improvements in visual acuity were also documented. 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. Accordingly, FDA determined that the inclusion of MRs in the response rate calculation was appropriate for this application.

Randomized Trials in pLGG

As a condition of accelerated approval, a confirmatory study to verify the clinical benefit of tovorafenib is required. FIREFLY-2 is an ongoing, international RCT that is being conducted in the front-line setting to compare tovorafenib to physician’s choice of chemotherapy in patients with pLGG with an activating RAF alteration who require systemic therapy. 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. Results from FIREFLY-2 will also inform the long-term safety of tovorafenib and its impact on growth and development in pediatric patients. At the time of the accelerated approval, FIREFLY-2, which initiated in 2023, was well underway and actively enrolling patients with completion of accrual anticipated by 2026.

A confirmatory RCT of tovorafenib was considered feasible based on the successful conduct of a small RCT (n=110) comparing D + T to C + V in patients with LGG, the results of which supported the traditional approval of the D + T regimen for the treatment of LGG harboring a BRAF V600E mutation and demonstrated that completion of a RCT in patients with rare tumors is possible (18). Further, the steady enrollment of FIREFLY-2 is not anticipated to be impacted by the initial worldwide approval of tovorafenib by the FDA given that the trial is being conducted broadly across North America, the European Union, Asia Pacific, and the Middle East.

Conclusions

Based on the clinically meaningful ORR and DoR observed in FIREFLY-1, the strong plausibility for effectiveness in pLGG given its RAF-targeting mechanism, and the manageable safety profile of tovorafenib in the target population, FDA’s benefit:risk assessment for tovorafenib is favorable (Table 4 [ref. 12]), supporting accelerated approval for the treatment of patients 6 months of age and older with relapsed or refractory pLGG harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. This is the first FDA approval of a targeted agent for the treatment of patients with pLGG harboring a KIAA1549:BRAF fusion, the leading oncogenic driver in these tumors. 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.

Table 4.

FDA benefit-risk summary.

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of condition	Pediatric LGG comprise 30% of all childhood brain tumors with an annual incidence of 1,000 to 1,600 in the US. These tumors are characterized by genomic alterations that activate the MAP kinase pathway. Most pLGG harbor a single identifiable driver alteration with BRAF alterations occurring in up to 70%. The KIAA1549:BRAF fusion is the most commonly identified, present in approximately 35% of tumors. The majority of pLGG are indolent, resulting in a 10-year OS rate exceeding 90%; however, the clinical behavior of tumors can vary, and patients may experience multiple progression events. Affected patients are at risk for significant morbidity including neurocognitive impairment, vision/hearing loss, endocrinopathies and other complications which may result from tumor location or traditionally administered treatments.	Pediatric LGG is a serious and potentially life-threatening disease. Patients with relapsed or refractory pLGG are at risk for significant morbidity and complications (e.g., functional, neurologic, endocrine) from either worsening of disease or from treatments administered.
Current treatment options	Pediatric LGG has historically been treated with surgery, chemotherapy and sometimes radiation therapy (RT). There is no consensus on the standard treatment approach for progressive pLGG. Chemotherapy is typically used to delay or obviate the need for RT; the regimen of carboplatin and vincristine, and single agent vinblastine are most commonly used and result in an ORR of approximately 35-52%, including minor responses. The targeted therapies dabrafenib, a BRAF inhibitor, and trametinib, are approved in combination for the treatment of pediatric patients 1 year of age and older with LGG harboring a BRAF V600E mutation who require systemic therapy. The approval of this regimen was based on the results of a randomized trial evaluating dabrafenib and trametinib compared to carboplatin and vincristine, which demonstrated improvement in ORR and PFS (18). In a separate study of D + T, in a cohort including 34 patients with relapsed or refractory pLGG, an ORR of 25% (95% CI: 12, 42) as assessed by RANO-LGG (CR + PR) was observed with a DoR of at least 12 months. There are no approved targeted therapies for the treatment of pLGG with BRAF fusions, representing a patient population with high unmet medical need. Approved Type I BRAF inhibitors including dabrafenib do not inhibit signaling from the KIAA1549:BRAF fusion.	Pediatric LGG is typically treated with surgical resection, and sometimes radiation therapy. Prior to the approval of tovorafenib, there were no FDA-approved targeted therapies for patients with pLGG harboring BRAF rearrangements, including the KIAA1549:BRAF fusion, the most frequently identified oncogenic driver. Safe and effective treatments for this morbid and potentially fatal condition are needed.
Benefit	The primary efficacy data supporting approval of tovorafenib were derived from 76 patients enrolled in Arm 1 of FIREFLY-1, an open-label, multicenter trial conducted globally in patients 6 months to 25 years of age with relapsed or refractory LGG with an activating RAF alteration (including BRAF/CRAF fusions and BRAF V600E mutations), or locally advanced or metastatic solid tumor with an activating RAF fusion. Results from the efficacy population demonstrated an ORR of 51% (95% CI: 40, 63), including minor, partial, and complete responses with a median DoR of 13.8 months (95% CI: 11.3, NE) according to BICR as per RAPNO-LGG. The response rate was generally similar in patients regardless of BRAF alteration, prior use of BRAF and/or MEK inhibitor, and number of prior lines of systemic therapy. Review of individual case narratives containing descriptive investigator-reported data of the patient experience indicated preliminary signals of improvement in disease-associated signs or symptoms in some patients who demonstrated minor responses. All patients in the efficacy set with BRAF V600 mutations (n=12) harbored BRAF V600E mutations; however, the indication for tovorafenib includes patients with BRAF V600 mutations, encompassing the rarer mutation types V600K and V600D. Preclinical data was submitted to support the activity of tovorafenib against BRAF V600D mutations in addition to BRAF V600E mutations.	Substantial evidence of effectiveness supporting accelerated approval was demonstrated for tovorafenib in the indicated patient population based on results of Arm 1 (n=76) of FIREFLY-1. The observed ORR was large in magnitude and the responses were sufficiently durable. Responses were observed in patients with KIAA1549:BRAF fusions, BRAF V600E mutations, and patients with BRAF rearrangements and duplications that were identified by FISH and presumed to be a KIAA1549:BRAF fusion. The response rate was generally consistent regardless of BRAF alteration type, prior use of MAPK inhibitors and number of prior lines of therapy. FDA determined that it was most appropriate to rely upon response as assessed by the RAPNO-LGG criteria as the primary efficacy outcome measure due to the nonenhancing nature of pLGG. Minor responses were included in the calculation of the response rate based upon the review of data provided in the application supporting their clinical meaningfulness. Preclinical data, tovorafenib’s established mechanism of action and review of the scientific literature describing relevant BRAF V600 mutations in pLGG supported inclusion of rare BRAF V600 mutation subtypes in the indication statement. A confirmatory study to verify the clinical benefit of tovorafenib is required. FIREFLY-2, an ongoing, international, randomized controlled trial is being conducted in the frontline to compare tovorafenib to physician’s choice of chemotherapy in patients with RAF-altered pLGG who require systemic treatment.
Risk and risk management	The primary safety population consisted of 137 patients enrolled to Arms 1 and 2 of FIREFLY-1 with relapsed or refractory RAF-altered pLGG. A pooled safety population (n=172) included all patients from FIREFLY-1 (n=140) and other adult and pediatric patients who received tovorafenib at the RP2D of 420 mg/m2 (maximum 600 mg) once weekly. The Warnings and Precautions for the USPI for tovorafenib include hemorrhage, skin toxicity/photosensitivity, hepatotoxicity, effect on growth, embryo-fetal toxicity, and potential for increased growth of NF1-associated tumors. Intracranial hemorrhage was a clinically relevant adverse reaction that occurred at a rate of 11% in the target population and included a Grade 5 treatment-emergent adverse reaction. The most common adverse reactions in Arm 1 of FIREFLY-1 (≥ 30%) were rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased phosphate, decreased hemoglobin, increased creatine phosphokinase, increased alanine aminotransferase, decreased albumin, decreased lymphocytes, decreased leukocytes, increased aspartate aminotransferase, decreased potassium, and decreased sodium.	The treatment-emergent adverse reactions observed with tovorafenib treatment in FIREFLY-1 and the pooled safety population were similar to those observed with other in-class products. The safety profile of tovorafenib is acceptable in the context of a serious disease that may be life-threatening. Potential toxicities are adequately addressed in the Warnings and Precautions section and the dose modification recommendations in product labeling. PMRs have been issued to obtain additional data to characterize tovorafenib’s long-term safety, impact on growth and development, potential for gonadal toxicity, and drug-drug interactions. A PMC was also agreed upon to provide adequate analytical and clinical validation results from clinical trial data to support future labeling of a companion diagnostic test to identify patients with pLGG harboring a BRAF fusion or rearrangement, or BRAF V600 mutation who may benefit from tovorafenib.

Source: FDA multidisciplinary review (ref. 12)