| 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.
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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.
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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.
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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.
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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. |
