Tovorafenib (DAY101)

Pediatric low-grade glioma (pLGG) comprises 30% to 40% of all pediatric CNS tumors and includes WHO grade 1 and 2 glioma, glioneuronal, and neuronal tumors, which the 2021 WHO classification places under pediatric-type diffuse low-grade glioma, circumscribed astrocytic tumors, and glioneuronal and neuronal tumors. The disease is driven predominantly by RAS/MAPK pathway alterations. In a molecularly profiled cohort, 84% of tumors harbored a driver alteration; KIAA1549-BRAF fusion was the most frequent (35%), followed by BRAF p.V600E (17%). In a separate cohort, BRAF V600E was detected in 69 of 405 patients (17%). Company estimates differ in scope: Day One Biopharmaceuticals states both that 50% to 60% of pLGGs are driven by RAF alterations (85% to 90% of them KIAA1549-BRAF fusions) and that approximately 70% of pLGGs in the United States are BRAF-altered. An estimated 15% to 20% of children with neurofibromatosis type 1 (NF1) develop an optic pathway glioma; participants with NF1-driven tumors are excluded from LOGGIC/FIREFLY-2.

No identified publication reports the incidence or prevalence of RAF-altered pLGG requiring first-line systemic therapy, and the component figures below come from different populations, age ranges, and periods; they have not been combined into a published estimate. In the United States, CBTRUS reports an incidence of pilocytic astrocytoma of 0.98 per 100,000 at ages 0 to 19 years and projects 730 new cases in 2025; the LOGGIC/FIREFLY-2 design publication cites 1,200 to 1,500 new pLGG cases per year; and Day One Biopharmaceuticals cites an annual pLGG incidence of 1.3 to 2.1 per 100,000, estimates that approximately 1,100 patients younger than 25 years are newly diagnosed with BRAF-altered pLGG each year, and reports a registry-based prevalence of 26,000 such patients as of January 1, 2017. The proportion of children who need therapy beyond surgery or observation was 165 of 639 (25.8%) starting nonsurgical treatment at diagnosis in the UK CNS9702 cohort (113 chemotherapy, 52 radiotherapy); in the German HIT-LGG-1996 cohort, 184 of 1,031 children proceeded to nonsurgical treatment at diagnosis and 35.2% ultimately received it; and in SIOP-LGG 2004, 1,057 of 3,417 registered, previously untreated patients (30.9%) received chemotherapy.

Overall survival is high, but disease control after first-line chemotherapy is limited. In 4,040 children in SEER, 20-year overall survival was 87% and the 20-year cumulative incidence of death due to glioma was 12%; in an Ontario population-based cohort, 20-year overall survival was 90.1%. Among children with an indication for systemic treatment, the LOGGIC/FIREFLY-2 investigators cite a 10-year overall survival of 94% for pLGG but a 10-year PFS of 44% with standard chemotherapy. In COG A9952 (274 randomized participants), 5-year EFS was 39% with carboplatin and vincristine and 52% with TPCV; in SIOP-LGG 2004 (497 randomized participants), 5-year PFS was 46% with vincristine and carboplatin; and 40% to 50% of patients require subsequent chemotherapy lines. Molecular subgroup modifies prognosis: BRAF V600E tumors had a 10-year PFS of 27% after chemotherapy and radiation therapy versus 60.2% for wild-type tumors and a 5-year PFS of 30.4% after first-line chemotherapy; BRAF p.V600E with CDKN2A deletion had a 10-year PFS of 0% and 10-year overall survival of 41%, whereas tumors with gene fusions or germline NF1 had a 10-year PFS of 67% and overall survival of 98%. Radiation therapy was associated with increased cancer-specific death in SEER (HR 3.9), and upfront radiotherapy was associated with increased late death among Ontario patients with unresectable tumors surviving more than 5 years (HR 3.3).

Late morbidity continues to accumulate beyond 5 years after diagnosis. Among 240 five-year survivors in a St. Jude cohort, the 15-year cumulative incidence was 18% for blindness, 22% for hearing loss, 29% for growth hormone deficiency, 33% for thyroid hormone deficiency, 26% for ACTH deficiency, and 53% for overweight or obesity; monocular legal blindness reached 57% at 15 years among patients with progressive hypothalamic/chiasmatic gliomas, and 61 patients (34%) had an IQ below 85, compared with 16% in the normative sample. After treatment for optic pathway glioma, 18.8% of 117 patients had severe visual impairment or blindness in both eyes at a median of 8.3 years. First-line chemotherapy carries its own toxicity: carboplatin hypersensitivity occurred in 41.9% of patients in one series, with recurrence in 24 of 34 (70.5%) rechallenged patients; visual acuity worsened after chemotherapy in 41% of children with NF1-associated and 39% with sporadic optic pathway glioma; and European recommendations advise central venous catheters, especially for infants and toddlers.

Direct evidence on economic and family burden specific to pLGG is limited. In a US claims and electronic health record study of 154 patients aged 18 years or younger followed for 36 months, 18% to 28% visited an emergency room and 9% to 27% had an inpatient stay in each 6-month interval, mean inpatient stay increased from 5.1 to 8.1 days, and 74% and 56% had prescriptions for anti-infectives and antiemetics. No study of family costs specific to pLGG was identified. Among 86 patients who survived at least 2 years after pediatric neuro-oncology surgery at a US cancer center, 29 (34%) experienced financial toxicity; approximately one third of 254 caregivers of US children with cancer reported that a parent quit or changed work, which was associated with a 13.4-point higher financial burden score (0 to 100 scale) at 1 to 5 years after diagnosis; and 28 Canadian families reported median first-year indirect costs of $9,668 and a median of 55 days of lost income.